High-solubility high-content amoxicillin powder and a preparation method thereof

Abstract

The present application relates to the technical field of veterinary pharmaceutical preparations, and more particularly to a high-solubility high-content amoxicillin powder and a preparation method thereof.The raw materials of the amoxicillin powder include, in mass fractions, amoxicillin 30-80 parts, powdered activated carbon 10-65 parts, a pH regulator 1-5 parts, a surfactant 1-5 parts, and an ionic liquid solubilizer 1-5 parts; the ionic liquid solubilizer is preferably 1-butyl-3-methylimidazolium tetrafluoroborate.The preparation process adopts stepwise dissolution, ultrasonic degassing, and spray drying after mixing to obtain the finished product.Through the synergistic effect of activated carbon adsorption drug loading, pH adjustment, interfacial tension control, and ionic strength synergism, the solubility of amoxicillin in water is increased from 1.27 mg / mL to 9.42 mg / mL, about 7 times, and the amoxicillin can be rapidly dissolved within 5 minutes at 40-50 DEG C, which is significantly better than similar products on the market, is suitable for efficient drug administration in large-scale livestock and poultry breeding, and has a good application prospect.

Description

Technical Field

[0001] This invention relates to the field of veterinary drug formulation technology, and more specifically to a highly soluble, high-content amoxicillin powder and its preparation method. Background Technology

[0002] Amoxicillin belongs to the beta-binding molecule. Beta-lactam antibiotics are broad-spectrum antibiotics with a wide antibacterial spectrum and strong bactericidal activity, widely used in livestock and poultry farming for the prevention and treatment of gastrointestinal, respiratory, and systemic bacterial infections. Currently, high-concentration amoxicillin soluble powder is the mainstream formulation in veterinary clinical use. This formulation is convenient for administration via drinking water, has rapid absorption, and high bioavailability, making it suitable for large-scale livestock farming. However, amoxicillin itself has an inherent drawback of poor water solubility; the raw material's solubility in water is only about 1.27 mg / mL (this solubility was tested at 0-5℃, while the solubility of amoxicillin at room temperature (25℃) is about 4 mg / mL. It is known to those skilled in the art that higher temperatures result in higher solubility), making it difficult to meet the clinical requirements for rapid dissolution and high-concentration administration. Low solubility not only leads to slow drug dissolution and uneven concentrations in drinking water, but also causes drug waste and reduced efficacy, limiting its application in severe infections and large-scale herd administration scenarios.

[0003] To improve the solubility of amoxicillin, current production technologies often employ methods such as adjusting pH, adding solubilizers, and using water-soluble carriers. For example, alkalizing the solvent to increase pH can enhance dissolution, or adding water-soluble excipients such as lactose or glucose can improve dispersibility. The solubility of mainstream amoxicillin soluble powder products on the market is approximately 3-6 mg / mL. Although this is an improvement over the raw material, the solubility increase is limited, making it difficult to achieve efficient and rapid dissolution. Simply adjusting pH can only increase solubility by about 80%, which cannot meet the requirements of high-concentration, rapid dissolution in clinical drug use. Conventional solubilizers and excipients have problems such as weak solubilizing effect, insufficient stability, and easy introduction of impurities, and cannot achieve a balance between drug content, solubility, and stability.

[0004] Current technologies still have significant shortcomings: first, insufficient solubilization, making it difficult to achieve several-fold increases; second, slow dissolution rate, failing to meet the needs of rapid clinical drug preparation; third, poor stability, easily leading to excessive levels of related substances; and fourth, a lack of preparation schemes that integrate high drug loading, high solubility, rapid solubility, and stability. Therefore, developing a highly soluble, high-content, rapidly dissolving, and stable amoxicillin soluble powder formulation and process, through synergistic solubilization with compound excipients and a mild preparation process, can significantly improve water solubility and dissolution rate while ensuring drug purity and clinical efficacy. This is of great practical significance for improving veterinary antibiotic formulations and enhancing the level of drug use in animal husbandry. Summary of the Invention

[0005] The first aspect of the present invention provides a highly soluble and high-content amoxicillin powder, the raw materials for which are prepared by mass parts include: 30-80 parts amoxicillin, 10-65 parts powdered activated carbon, 1-5 parts pH adjuster, 1-5 parts surfactant, and 1-5 parts ionic liquid solubilizer.

[0006] As an implementable example, the ionic liquid solubilizer includes one of 1-butyl-3-methylimidazolium tetrafluoroborate, 1-ethyl-3-methylimidazolium acetate, or tetrabutylammonium bis(trifluorosulfonyl)imide salt.

[0007] Furthermore, the ionic liquid solubilizer is 1-butyl-3-methylimidazolium tetrafluoroborate.

[0008] In this invention, the dosage of amoxicillin is limited to 30-80 parts to ensure a high effective drug content, meeting the mainstream specifications for 80% amoxicillin soluble powder in veterinary medicine. This avoids insufficient effective ingredients or the inability to form a stable solubilizing system, achieving high drug loading and making clinical administration more convenient. The dosage of powdered activated carbon is limited to 10-65 parts. Its porous structure enables sufficient adsorption and drug loading, avoiding poor solubilization or excessive dilution of the active pharmaceutical ingredient due to insufficient dosage. It can load amoxicillin in molecular form into the pores, destroying the original needle-like crystals, significantly improving solubility and stability, while also assisting in the adsorption of intestinal pathogens to improve efficacy. The dosage of pH adjuster is limited to 1-5 parts. The system is moderately adjusted to a weakly alkaline environment to enhance amoxicillin solubility, avoiding degradation caused by insufficient or excessive adjustment. This improves the dissolution environment, synergistically solubilizes, and inhibits impurity formation. The surfactant dosage is limited to 1-5 parts, which effectively reduces the gas-water interfacial tension in the activated carbon pores and assists in ultrasonic air removal to improve adsorption efficiency, significantly increasing the dissolution rate and solubility, achieving rapid dissolution and high solubility. The ionic liquid solubilizer dosage is limited to 1-5 parts, which can reasonably adjust the ionic strength, accelerate dissolution, and avoid the effects of insufficient or excessive dosage on solubility and system stability. It can work synergistically with pH adjusters to achieve rapid dissolution in 5 minutes at 40-50℃, further improving drug solubility.

[0009] The 1-butyl-3-methylimidazolium tetrafluoroborate used in this invention as an ionic liquid solubilizer can significantly improve the water solubility of amoxicillin. It effectively regulates the ionic strength of the system, weakens the association between amoxicillin molecules, and promotes the dissociation and transfer of drug molecules to the aqueous phase. Simultaneously, it can synergistically regulate the pH and ionic environment of the solution with pH adjusters, improve drug wettability and dispersibility, inhibit amoxicillin crystallization and maintain its highly dispersed state. Combined with the adsorption and drug-carrying effect of activated carbon, it further enhances drug solubility and dissolution rate, achieving rapid dissolution. Experimental verification shows that the solubilizing effect of 1-butyl-3-methylimidazolium tetrafluoroborate is significantly better than that of 1-ethyl-3-methylimidazolium acetate and tetrabutylammonium bis(trifluorosulfonyl)imide salt, increasing the solubility of amoxicillin by approximately 7 times compared to the raw material, meeting the clinical needs of high-solubility, high-content veterinary drug preparations.

[0010] As an feasible example, the powdered activated carbon has a mesh size of 100-200 mesh, a pore size of 2-100 nm, and a specific surface area of ​​500-600 m². 2 / g.

[0011] This invention specifies the mesh size, pore size, and specific surface area of ​​powdered activated carbon: 100-200 mesh, 2-100 nm pore size, and 500-600 nm specific surface area. 2 / g allows activated carbon to possess suitable particle size distribution, sufficient pore structure, and large specific surface area. This ensures uniform dispersion in the system and prevents agglomeration, while also providing ample adsorption sites for amoxicillin. This allows for efficient loading of drug molecules into the pores, significantly disrupting the original needle-like crystal morphology of amoxicillin, thereby greatly improving its water solubility and dissolution rate. At the same time, the suitable pore size and specific surface area ensure sufficient drug loading and prevent desorption. Combined with the synergistic effect of surfactants and ionic liquids, this further improves the solubility and stability of the formulation, ensuring product uniformity and ease of use.

[0012] As an implementable example, the pH adjuster includes one or more of sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, or sodium tartrate.

[0013] More preferably, the pH adjuster is sodium carbonate.

[0014] In this invention, sodium carbonate is selected as a pH adjuster, which can adjust the pH of the system to a slightly alkaline state, improve the amoxicillin dissolution environment, and synergistically solubilize; at the same time, it stabilizes the drug structure, reduces degradation impurities, and improves the stability and dissolution rate of the formulation.

[0015] As an example of implementation, the surfactant includes one or more of anionic surfactants, cationic surfactants, nonionic surfactants, or amphoteric surfactants.

[0016] Furthermore, the anionic surfactant includes one or more of sodium dodecyl sulfate, sodium dodecylbenzene sulfonate, sodium lauryl ether sulfate, sodium dioctyl sulfosuccinate, sodium fatty acid methyl ester sulfonate, or sodium dodecyl sulfonate.

[0017] This invention preferentially uses sodium dodecyl sulfate as an anionic surfactant. On the one hand, it can significantly reduce the gas-water interfacial tension in the pores of activated carbon, and with the help of ultrasonic treatment, it can efficiently remove the air inside the activated carbon, allowing amoxicillin drug molecules to enter the activated carbon channels more fully and be adsorbed and loaded, thus improving the uniformity and stability of drug loading. On the other hand, it can improve the wettability and dispersibility of drug powder, reduce the aggregation of amoxicillin molecules, accelerate the dissolution rate of the drug in water, and work synergistically with activated carbon, ionic liquid and pH adjuster to achieve a significant solubilization effect. At the same time, it can improve the uniformity of the formulation after reconstitution, meeting the clinical needs of mixed drinking water administration.

[0018] A second aspect of this invention provides a method for preparing amoxicillin powder with high solubility and high content, comprising the following steps: S1. Mix water and surfactant, heat, then add powdered activated carbon, and sonicate to remove bubbles to obtain activated carbon solution; S2. Mix amoxicillin, pH adjuster and ionic liquid solubilizer, add water, and heat until homogeneous to obtain amoxicillin solution; S3. Mix the activated carbon solution and amoxicillin solution, dry them using a spray dryer, and collect the powder to obtain amoxicillin powder with high solubility and high content.

[0019] As an example of implementation, in step S1, the mass ratio of water to surfactant is (10-20):1.

[0020] Furthermore, in step S1, the heating temperature is 25-35℃.

[0021] As an example of implementation, in step S2, the mass ratio of amoxicillin to water is 1:(100-200).

[0022] Furthermore, in step S2, the heating temperature is 40-50℃.

[0023] As an example of implementation, the drying temperature is 50-60℃.

[0024] Beneficial effects (I) This invention significantly improves the solubility of amoxicillin in water, achieving a dual technological breakthrough in high dissolution and high content. The solubility of raw amoxicillin in water is only 1.27 mg / mL (tested at 0~5℃). After preparation using the formulation and process of this invention, the solubility can reach 9.42 mg / mL (tested at 0~5℃), which is about 7 times higher than that of raw materials. This is far higher than that of mainstream 80% amoxicillin soluble powder products on the market, which can meet the needs of high-concentration mixed drinking water administration in large-scale livestock and poultry farming, effectively improve drug bioavailability and clinical efficacy, and solve the problems of uneven administration and decreased efficacy caused by insufficient solubility of traditional products.

[0025] (II) This invention significantly improves drug dispersion and formulation stability through a combination of specific activated carbon adsorption for drug loading and a gentle spray drying process. It utilizes 100-mesh activated carbon with a pore size of 2-100 nm and a specific surface area of ​​500-600 m². 2 Using powdered activated carbon as a carrier, amoxicillin can be highly dispersed in the porous structure, destroying its original needle-like crystal morphology, reducing the aggregation and recrystallization between drug molecules, making the product more stable during storage, less prone to degradation, discoloration or clumping, extending the product's shelf life, and improving the consistency of formulation quality.

[0026] (III) This invention enables rapid dissolution of amoxicillin, significantly improving the convenience of clinical use. Through the synergistic effect of sodium carbonate adjusting pH, ionic liquid enhancing ionic strength, and sodium dodecyl sulfate reducing interfacial tension, combined with gentle heating conditions of 40-50℃, the drug can be completely dissolved within 5 minutes, eliminating the need for prolonged stirring or standing. This simplifies on-site drug preparation and improves the efficiency of drug administration in aquaculture, making it particularly suitable for emergency treatment and large-group centralized drug administration scenarios.

[0027] (iv) The formulation of this invention has high purity and low content of related substances, resulting in superior drug safety. Under mild dissolution and low-temperature spray drying conditions, amoxicillin degrades less, and the formation of impurities is effectively inhibited. The content of related substances is only 2.4%, which is far below the 7.5% upper limit stipulated by the veterinary drug quality standard. This reduces the risk of adverse drug reactions, improves the safety of medication for livestock and poultry, and meets the requirements for the green, safe, and efficient development of veterinary formulations.

[0028] (V) This invention combines antibacterial and intestinal protection effects, resulting in a more comprehensive therapeutic effect. The activated charcoal in the formula not only acts as a drug carrier to improve solubility but also adsorbs pathogens and toxins in the animal's intestines, reducing intestinal inflammation and protecting the intestinal mucosa. It synergizes with the antibacterial effect of amoxicillin, improving the cure rate of bacterial infectious diseases and reducing gastrointestinal symptoms such as diarrhea. This integrated approach of "antibacterial + intestinal protection" is more suitable for the comprehensive prevention and control of bacterial diseases in livestock and poultry. Attached Figure Description

[0029] Figure 1The graph shows the determination of the solubility of high-solubility, high-content amoxicillin powder in water in Example 1.

[0030] Figure 2 This is the test chromatogram for amoxicillin reference standard.

[0031] Figure 3 This is a chromatogram showing the determination of the solubility of amoxicillin reference standard in water.

[0032] Figure 4 This is a schematic diagram of the peak elution of high-solubility, high-content amoxicillin powder in Example 1.

[0033] Figure 5 This is a SEM image of amoxicillin reference standard.

[0034] Figure 6 This is a SEM image of the highly soluble, high-content amoxicillin powder (2μm) from Example 1.

[0035] Figure 7 This is a SEM image of the highly soluble and high-content amoxicillin powder (10 μm) from Example 1.

[0036] Figure 8 The graph shows the determination of the solubility of amoxicillin powder in water for Comparative Example 1.

[0037] Figure 9 This is a chromatogram showing the solubility of Anlisu (80% amoxicillin soluble powder) produced by Shandong Huachen Pharmaceutical Co., Ltd. in water.

[0038] Figure 10 This is a chromatogram showing the solubility of 80% amoxicillin soluble powder from Inner Mongolia Federal Animal Health Pharmaceutical Co., Ltd. in water.

[0039] Figure 11 The graph shows the determination of the solubility of amoxicillin powder in water for Comparative Example 2.

[0040] Figure 12 The graph shows the determination of the solubility of amoxicillin powder in water for Comparative Example 3. Detailed Implementation

[0041] Example 1 The first aspect of this example provides a highly soluble, high-content amoxicillin powder, the raw materials for which, by mass parts, include: 80 parts amoxicillin, 15 parts powdered activated carbon, 2 parts pH adjuster sodium carbonate, 2 parts surfactant sodium dodecyl sulfate, and 1 part ionic liquid solubilizer 1-butyl-3-methylimidazolium tetrafluoroborate.

[0042] The powdered activated carbon has a mesh size of 100 mesh, a pore size of 50 nm, and a specific surface area of ​​500-600 m². 2 / g.

[0043] The second aspect of this example provides a method for preparing highly soluble, high-content amoxicillin powder, including the following steps: S1. Mix water and sodium dodecyl sulfate at a mass ratio of 20:1, heat to 30°C, add powdered activated carbon, and sonicate to remove bubbles to obtain an activated carbon solution. S2. Mix amoxicillin, pH adjuster and ionic liquid solubilizer, add water, the mass ratio of amoxicillin to water is 1:150; dissolve uniformly under heating at 50℃ to obtain amoxicillin solution. S3. Mix the activated carbon solution and amoxicillin solution, dry them in a spray dryer at 60°C, and collect the powder to obtain amoxicillin powder with high solubility and high content.

[0044] Comparative Example 1 The specific implementation method in this example is the same as in Example 1, except that: the raw materials do not include activated carbon, and the pH of the system is adjusted to 7.0.

[0045] Comparative Example 2 The specific implementation method in this example is the same as in Example 1, except that the raw materials for preparation do not include sodium dodecyl sulfate.

[0046] Comparative Example 3 The specific implementation method in this example is the same as in Example 1, except that the raw materials for preparation do not include ionic liquid solubilizers.

[0047] Performance testing 1. Solubility test: The test method followed the content determination section of the quality standard for 80% amoxicillin soluble powder for veterinary use. The chromatographic column used LiChrosorb RP-18 as the packing material (LiChrosorb RP-18 is an irregularly shaped silica support with reversed-phase properties). The mobile phase consisted of a phosphate solution (pH 6.2, prepared by dissolving 2.39 g of disodium hydrogen phosphate and 7.26 g of potassium dihydrogen phosphate in 1000 mL of water) and methanol in a 95:5 (volume ratio). The detection wavelength was 227 nm; the column temperature was 35℃; and the flow rate was 0.6 mL / min. The theoretical plate number, calculated based on the amoxicillin peak, was not less than 1700.

[0048] Accurately weigh 0.5 g of amoxicillin powder (equivalent to 0.4 g of effective amoxicillin) from Example 1, place it in a 50 mL volumetric flask, dilute with water to the mark, sonicate in an ultrasonic bath for 10 minutes, filter, accurately measure 5 μL of the filtrate, inject it into the liquid chromatograph, and record the chromatogram. Separately, accurately weigh approximately 20 mg of commercially available amoxicillin reference standard, place it in a 50 mL volumetric flask, add 2.5 mL of pH 6.0 phosphate buffer (dissolve 10.5 g of dipotassium hydrogen phosphate and 59.8 g of potassium dihydrogen phosphate in 1000 mL of water by stirring), and 2 mL of acetonitrile. Sonicate for 2 minutes, dilute with water to the mark, and determine using the same method. Calculate the result by peak area using the external standard method.

[0049] Example 1: Determination of the solubility of high-solubility, high-content amoxicillin powder in water (see graph). Figure 1 As shown, the test chromatogram of amoxicillin reference standard is as follows. Figure 2 As shown in the figure, the solubility spectrum of amoxicillin reference standard in water is as follows. Figure 3 As shown.

[0050] The results showed that the solubility of amoxicillin reference material in water was approximately 1.27 mg / mL (tested at 0~5℃), while the solubility of the sample in Example 1 in water was 9.42 mg / mL (tested at 0~5℃), representing an increase of approximately 7 times.

[0051] 2. Impurity content test The test method refers to the impurity content determination section of the quality standard for 80% amoxicillin soluble powder for veterinary use.

[0052] Take 5 μL of the amoxicillin test solution from Example 1 and inject it into the liquid chromatograph. Record the chromatogram up to twice the retention time of the main peak. Calculate the area using the area normalization method. The sum of the areas of all impurity peaks should not exceed 7.5%. For detailed test results, see [link to test results]. Figure 4 .

[0053] Experimental results show that the impurity peak area of ​​the sample in Example 1 accounts for 2.4% of the total area, which meets the requirements for veterinary drugs.

[0054] 3. Scanning electron microscopy test The prepared 2μm and 10μm amoxicillin powders from Example 1 and the amoxicillin reference standard were scanned using SEM. The test results are detailed in [link to SEM image]. Figure 5-7 .

[0055] The results showed that after treatment with the method in Example 1, most of the amoxicillin needle-like crystals disappeared, and some were adsorbed into the pores of the activated carbon.

[0056] 4. Comparative Analysis The solubility test chromatogram of Comparative Example 1 is as follows: Figure 8As shown, without adding activated carbon, adjusting the solution pH to 7.0 can achieve an amoxicillin solubility of 2.1 mg / mL (tested at 0~5℃). The solubility spectra of Anlisu (80% amoxicillin soluble powder) from Shandong Huachen Pharmaceutical Co., Ltd., and the solubility spectra of 80% amoxicillin soluble powder from Inner Mongolia Federal Animal Health Pharmaceutical Co., Ltd., are shown below. Figure 9-10 As shown. The test results show that the solubility of Anlisu from Shandong Huachen Pharmaceutical Co., Ltd. in water is 3.02 mg / mL (tested at 0~5℃), and the solubility of 80% amoxicillin soluble powder from Inner Mongolia Federal Animal Health Pharmaceutical Co., Ltd. in water is 5.05 mg / mL (tested at 0~5℃).

[0057] The solubility test chromatogram of Comparative Example 2 is as follows: Figure 11 As shown, when the formulation is changed and sodium dodecyl sulfate is not added, the solubility in water of the sample is approximately 4.22 mg / mL (tested at 0~5℃), which is 45% of the solubility of the final formulation in Example 1. This indicates that sodium dodecyl sulfate has a significant effect on reducing the surface tension of activated carbon pores and on solubilizing it.

[0058] The solubility test chromatogram of Comparative Example 3 is as follows: Figure 12 As shown, when the formulation is changed, the solubility of the sample prepared without the addition of ionic liquid in water is approximately 7.92 mg / mL (tested at 0~5℃), which is 84% ​​of the solubility of the final formulation in Example 1. This indicates that ionic liquid can achieve solubilization by changing the ionic strength of the solution.

Claims

1. A highly soluble, high-content amoxicillin powder, characterized in that, The raw materials for preparation, by mass parts, include: 30-80 parts amoxicillin, 10-65 parts powdered activated carbon, 1-5 parts pH adjuster, 1-5 parts surfactant, and 1-5 parts ionic liquid solubilizer. The ionic liquid solubilizer includes one of 1-butyl-3-methylimidazolium tetrafluoroborate, 1-ethyl-3-methylimidazolium acetate, or tetrabutylammonium bis(trifluorosulfonyl)imide salt.

2. The amoxicillin powder with high solubility and high content according to claim 1, characterized in that, The powdered activated carbon has a mesh size of 100-200 mesh, a pore size of 2-100 nm, and a specific surface area of ​​500-600 m². 2 / g.

3. The amoxicillin powder with high solubility and high content according to claim 1, characterized in that, The pH adjuster includes one or more of sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, or sodium tartrate.

4. The amoxicillin powder with high solubility and high content according to claim 1, characterized in that, The surfactants mentioned include one or more of anionic surfactants, cationic surfactants, nonionic surfactants, or amphoteric surfactants.

5. The amoxicillin powder with high solubility and high content according to claim 4, characterized in that, The anionic surfactants include one or more of sodium dodecyl sulfate, sodium dodecylbenzene sulfonate, sodium lauryl ether sulfate, sodium dioctyl sulfosuccinate, sodium fatty acid methyl ester sulfonate, or sodium dodecyl sulfonate.

6. A method for preparing highly soluble, high-content amoxicillin powder according to any one of claims 1-5, characterized in that, Includes the following steps: S1. Mix water and surfactant, heat, then add powdered activated carbon, and sonicate to remove bubbles to obtain activated carbon solution; S2. Mix amoxicillin, pH adjuster and ionic liquid solubilizer, add water, and heat until homogeneous to obtain amoxicillin solution; S3. Mix the activated carbon solution and amoxicillin solution, dry them using a spray dryer, and collect the powder to obtain amoxicillin powder with high solubility and high content.

7. The method for preparing highly soluble, high-content amoxicillin powder according to claim 6, characterized in that, In step S1, the heating temperature is 25-35℃.

8. The method for preparing high-solubility, high-content amoxicillin powder according to claim 6, characterized in that, In step S2, the mass ratio of amoxicillin to water is 1:(100-200).

9. The method for preparing highly soluble, high-content amoxicillin powder according to claim 6, characterized in that, In step S2, the heating temperature is 40-50℃.

10. The method for preparing high-solubility, high-content amoxicillin powder according to claim 6, characterized in that, The drying temperature is 50-60℃.

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