Zinc gluconate raw material medicine with specific crystal form and preparation method of zinc gluconate raw material medicine
By controlling the composition of the crystallization solvent and using a two-stage vacuum drying process, the problems of low drying efficiency and difficulty in controlling the crystal form of zinc gluconate were solved, and high-purity, low-hygroscopic zinc gluconate with a specific crystal form was prepared, improving production efficiency and product stability, and making it suitable for the pharmaceutical industry.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-04
- Publication Date
- 2026-04-14
AI Technical Summary
Existing zinc gluconate suffers from problems such as low drying efficiency, difficulty in controlling crystal form, poor product stability, and high process energy consumption, resulting in inconsistent product quality and poor storage stability.
The process involves controlling the composition of the crystallization solvent and the concentration of ethanol, combined with a two-stage vacuum drying process. This includes drying at 40-70℃ to a moisture content of 20-40% under a vacuum of not less than 0.08 MPa, and then further drying at 2-12 rpm and 40-70℃ to a moisture content of 6-12%.
A specific crystalline form of zinc gluconate with high purity, low hygroscopicity, and stable physicochemical properties was prepared, ensuring the quality uniformity of the active pharmaceutical ingredient and the shelf life of the finished product, improving drying efficiency and equipment utilization, and reducing energy consumption.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical manufacturing technology, specifically to a zinc gluconate raw material with a specific crystal form and its preparation method. Background Technology
[0002] Zinc gluconate (chemical formula: C) 12 H 22 O 14 Zinc gluconate (Zn) is the zinc salt of gluconate. As an important organic zinc supplement, it has wide applications in medicine, food additives, cosmetics, and nutritional fortifiers. In the pharmaceutical industry, zinc gluconate is mainly used as a raw material for zinc supplements. Clinically, it is used to prevent and treat zinc deficiency-related diseases, such as anorexia, growth retardation, malnutrition, recurrent oral ulcers, and acne in children. It can also be used to enhance immunity.
[0003] The Pharmacopoeia of the People's Republic of China clearly stipulates the quality standards for zinc gluconate raw materials, requiring them to be white crystalline or granular powders, and setting strict indicators for purity, solubility, and heavy metal limits. For solid oral dosage forms, the physicochemical properties of the raw material, especially its crystal form, are key factors affecting the formulation process performance, product quality stability, and clinical efficacy. Different crystal forms can lead to significant differences in the raw material's solubility, dissolution rate, hygroscopicity, stability, and bioavailability. Therefore, obtaining and stably producing raw materials with suitable crystal forms is crucial for ensuring batch-to-batch consistency, efficacy, and safety of the drug.
[0004] Currently, the industrial production of zinc gluconate typically involves unit operations such as synthesis, crystallization, separation, and drying. In the drying stage, traditional methods such as box-type forced-air drying are commonly used. These methods often suffer from low drying efficiency, long cycles, and high energy consumption. More importantly, improper temperature and humidity control during the drying process can easily lead to changes in the product's crystal form, uneven particle size distribution, or localized overheating and degradation, resulting in an impure crystal form, increased hygroscopicity, or decreased physical stability in the final product. This can adversely affect subsequent formulation production and even the long-term storage of the drug.
[0005] Therefore, we propose a specific crystal form of zinc gluconate active pharmaceutical ingredient and its preparation method to alleviate or solve the above problems.
[0006] The information disclosed above in this background section is only for enhancing the understanding of the background section of this invention, and therefore may include prior art that is not known to those skilled in the art. Summary of the Invention
[0007] To address the aforementioned technical problems, this invention provides a zinc gluconate raw material with a specific crystal form and its preparation method, thereby solving the problems of low drying efficiency, difficulty in controlling crystal form, poor product stability, and high process energy consumption in the prior art.
[0008] To achieve the above objectives, the present invention provides a specific crystal form of zinc gluconate raw material, the powder X-ray diffraction pattern of which, when expressed at a 2θ angle, has characteristic peaks at the following positions: 5.3±0.2°, 8.3±0.2°, 9.7±0.2°, 10.3±0.2°, 11.3±0.2°, 13.4±0.2°, 16.8±0.2°, 18.4±0.2°, 19.3±0.2°, 20.8±0.2°, 22.6±0.2°, 23.4±0.2°, 24.3±0.2°, 24.8±0.2°, and 30.7±0.2°.
[0009] Its powder X-ray diffraction pattern also has characteristic peaks at 2θ of 5.7±0.2°, 21.6±0.2°, 25.6±0.2°, 28.2±0.2°, 29.2±0.2° and 32.0±0.2°.
[0010] A method for preparing a specific crystal form of zinc gluconate active pharmaceutical ingredient includes the following steps:
[0011] (1) Dissolve crude zinc gluconate in purified water and heat to obtain zinc gluconate solution;
[0012] (2) Cool and filter the solution obtained in step (1) to obtain a clear zinc gluconate solution;
[0013] (3) Add ethanol to the clarified solution to make the concentration of ethanol in the solution reach 10-20% (w / w), and let it stand at 10-30℃ for 8-24 hours to crystallize.
[0014] (4) After crystallization, solid-liquid separation is performed. The obtained solid is washed with purified water to obtain zinc gluconate filter cake.
[0015] (5) Granulate the wet filter cake into wet particles with a particle size of 4-10 mesh;
[0016] (6) The wet particles are dried in the first stage at 40-70°C and a vacuum degree of not less than 0.08 MPa until the moisture content of the particles is 20-40%;
[0017] (7) Place the particles after the first stage of drying in a rotary dryer and carry out the second stage of drying under the conditions of 2-12 rpm, 40-70℃ and vacuum degree not less than 0.08 MPa until the moisture content of the particles is 6-12%.
[0018] In step (6), the preferred drying temperature for wet particles is 45°C-55°C, and the preferred drying temperature for particles is 28%-32%.
[0019] The drying temperature in step (7) is more preferably 55℃-65℃.
[0020] Compared with the prior art, the beneficial effects of the present invention are:
[0021] This invention enables the stable and repeatable preparation of zinc gluconate crystals with specific powder X-ray diffraction patterns by controlling the composition of the crystallization solvent, the crystallization temperature, and a unique two-stage vacuum drying process. This crystal product exhibits high purity, a melting point of 172-175℃, extremely low hygroscopicity, and stable physicochemical properties. It is resistant to crystallization, agglomeration, or degradation during long-term storage, ensuring the uniformity of quality as a raw material and the shelf life of the finished product.
[0022] Compared to traditional single-stage air drying, this invention shortens the total drying time and improves equipment utilization and production efficiency. Vacuum conditions and a gentle temperature setting reduce energy consumption and effectively prevent quality deterioration caused by localized overheating of the material. Furthermore, the preparation method is simple to operate, with clearly defined and easily controllable key process parameters. The laboratory-scale to scale-up production practices demonstrated in the examples show that this invention exhibits excellent process reproducibility and yield stability, enabling the transformation from laboratory to industrial production and facilitating large-scale industrial production.
[0023] The above overview is for illustrative purposes only and is not intended to be limiting in any way. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features of the invention will become readily apparent from the accompanying drawings and the following detailed description. Attached Figure Description
[0024] Figure 1 This is the X-ray diffraction spectrum of zinc gluconate powder according to the present invention.
[0025] Figure 2 This is the powder X-ray diffraction spectrum of the present invention. Detailed Implementation
[0026] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. It should be noted that the drawings are schematic and not illustrated to scale. For clarity and convenience, the relative sizes and proportions of the parts shown in the drawings have been exaggerated or reduced in size. Any size is only illustrative and not limiting.
[0027] Preparation Example 1: A method for preparing crude zinc gluconate, comprising the following steps:
[0028] 120 kg of purified water was added to a 500 L enamel-lined reactor, and 30 kg of gluconate-δ-lactone was added with stirring. The reaction was carried out at 40℃~60℃ for 1~2 hours. Then 7.5 kg of zinc oxide was added, and the reaction was continued at 60℃~80℃ for 3~5 hours. The reaction solution was cooled to below 35℃ and filtered through a titanium rod to obtain a zinc gluconate solution. 24 kg of ethanol (95%) was added and stirred evenly. The solution was allowed to crystallize at 20℃~30℃ for 12~24 hours. After centrifugation, the solution was dried in a forced-air dryer at 40℃~60℃ to obtain 36.3 kg of white solid crude zinc gluconate (yield 94.5%) with a purity greater than 98%.
[0029] Example 1: Preparation of a specific crystal form of zinc gluconate active pharmaceutical ingredient, with preferred parameter combinations.
[0030] Add 10 g of crude zinc gluconate obtained in Preparation Example 1 and 30 g of purified water to a 100 ml round-bottom flask, stir, and heat to 70 ± 2 °C until dissolved and clear. Stop heating, cool the solution in the flask to 35 °C or below using cold water, filter to obtain a zinc gluconate solution, and then add 7.5 g of 95% (w / w) ethanol, at which point the ethanol concentration in the solution is 15% (w / w). Stir well and allow to crystallize at 28 °C for 8 hours.
[0031] After crystallization, the crystallization solution was vacuum filtered, and the filter cake was rinsed once with 10 grams of purified water. The resulting filter cake was then granulated through a 4-mesh sieve. The granulated wet zinc gluconate was dried in a vacuum drying oven at 45°C and a vacuum degree ≥0.08 MPa until the moisture content reached 34.6%. It was then transferred to a rotary dryer and dried at 55°C, a vacuum degree ≥0.08 MPa, and a rotation speed of 6 rpm until the moisture content reached 7.4%. This yielded a zinc gluconate sample with a specific crystal form, weighing 7.6 grams, with a yield of 76% and a purity greater than 99.5%.
[0032] The product's melting point was found to be 172-175℃.
[0033] Example 2: Preparation of a specific crystal form of zinc gluconate active pharmaceutical ingredient under moderate ethanol concentration and moderate drying temperature conditions.
[0034] Add 100 g of crude zinc gluconate obtained in Preparation Example 1 and 300 g of purified water to a 500 ml round-bottom flask, stir, and heat to 70 ± 2 °C until dissolved and clear. Stop heating, cool the solution in the flask to 35 °C or below using cold water, filter to obtain a zinc gluconate solution, and then add 75 g of 95% (w / w) ethanol. At this point, the ethanol concentration in the solution is 15% (w / w). Stir well and allow to crystallize at 25 °C for 12 hours.
[0035] After crystallization, the crystallization solution was vacuum filtered, and the filter cake was rinsed once with 30 g of purified water. The resulting filter cake was then granulated through a 4-mesh sieve. The granulated wet zinc gluconate was dried in a vacuum drying oven at 50°C and a vacuum degree ≥0.08 MPa until the moisture content reached 28.2%. It was then transferred to a rotary dryer and dried at 60°C, a vacuum degree ≥0.08 MPa, and a rotation speed of 6 rpm until the moisture content reached 8.2%, yielding a sample of zinc gluconate crystal form X, weighing 85.4 g, with a yield of 85.4% and a purity greater than 99.5%.
[0036] The product's melting point was found to be 172-175℃.
[0037] Example 3: Preparation of a specific crystal form of zinc gluconate active pharmaceutical ingredient under low ethanol concentration and high drying temperature conditions.
[0038] Add 100 g of crude zinc gluconate obtained in Preparation Example 1 and 300 g of purified water to a 500 ml round-bottom flask, stir, and heat to 70 ± 2 °C until dissolved and clear. Stop heating, cool the solution in the flask to below 35 °C with cold water, filter to obtain zinc gluconate solution, then add 50 g of 95% (w / w) ethanol, at which point the ethanol concentration in the solution is 10.6% (w / w), stir well, and let it stand at 20 °C for 24 hours to crystallize.
[0039] After crystallization, the crystallization solution was vacuum filtered, and the filter cake was rinsed once with 30 grams of purified water. The resulting filter cake was then granulated through a 4-mesh sieve. The granulated wet zinc gluconate was dried in a vacuum drying oven at 55°C and a vacuum degree ≥0.08 MPa until the moisture content was 30.5%. It was then transferred to a rotary dryer and dried at 65°C, a vacuum degree ≥0.08 MPa, and a rotation speed of 5-6 rpm until the moisture content was 8.8%, yielding a sample of zinc gluconate crystal form X, weighing 78.5 grams, with a yield of 78.5% and a purity greater than 99.5%.
[0040] The product's melting point is measured to be 172℃~175℃.
[0041] Example 4: Preparation of a specific crystal form of zinc gluconate active pharmaceutical ingredient under high ethanol concentration and moderate drying temperature conditions.
[0042] Add 100 g of crude zinc gluconate obtained in Preparation Example 1 and 300 g of purified water to a 500 ml round-bottom flask, stir, and heat to 70 ± 2 °C until dissolved and clear. Stop heating, cool the solution in the flask to below 35 °C with cold water, filter to obtain zinc gluconate solution, then add 100 g of 95% (w / w) ethanol, at which point the ethanol concentration in the solution is 19% (w / w), stir evenly, and let it stand at 20 °C for 12 hours to crystallize.
[0043] After crystallization, the crystallization solution was vacuum filtered, and the filter cake was rinsed once with 30 grams of purified water. The resulting filter cake was then granulated through a 4-mesh sieve. The granulated wet zinc gluconate was dried in a vacuum drying oven at 50°C and a vacuum degree ≥0.08 MPa until the moisture content reached 26.8%. It was then transferred to a rotary dryer and dried at 60°C, a vacuum degree ≥0.08 MPa, and a rotation speed of 5-6 rpm until the moisture content reached 7.8%, yielding a sample of zinc gluconate crystal form X, weighing 87.8 grams, with a yield of 87.8% and a purity greater than 99.5%.
[0044] The melting point was found to be 172℃~175℃.
[0045] Example 5: Preparation of a specific crystal form of zinc gluconate active pharmaceutical ingredient, validating a wide parameter range.
[0046] 100 kg of purified water was added to a 500 L enamel-lined reaction vessel, followed by 30 kg of crude zinc gluconate obtained in Preparation Example 1. Stirring was started at 60 rpm, and circulating hot water was used to raise the temperature. When the temperature inside the vessel reached 70±5℃, stirring and dissolving was continued for 0.5 hours. Heating was then stopped, and the solution in the reaction vessel was cooled to below 35℃ by purging with cold water. The solution was filtered through a titanium rod, and the resulting zinc gluconate solution was transferred to a 1000 L enamel-lined crystallizing vessel.
[0047] Add 2.1 kg of 95% (w / w) ethanol to the crystallization tank. At this point, the ethanol concentration in the solution is 15.1% (w / w). Stir well and let it stand for crystallization for 12 hours at a temperature of 20±2℃.
[0048] After crystallization, the slurry was transferred to a centrifuge at 1400 rpm and centrifuged until no liquid flowed out. It was then rinsed once with 10 kg of purified water to obtain a zinc gluconate filter cake. The filter cake was granulated through a 6-mesh sieve using a gyratory granulator. The granulated wet zinc gluconate was then dried in a vacuum drying oven at 50±2℃ and a vacuum of ≥0.08 MPa for 12 hours. The moisture content was measured to be 28.6% using a rapid moisture analyzer. The vacuum-dried zinc gluconate was then transferred to a double cone dryer at 6 rpm, 60±2℃, and a vacuum of ≥0.08 MPa for 6 hours. The moisture content was measured to be 7.6%, and the material was collected.
[0049] The dried material was pulverized to obtain zinc gluconate crystal form X as the finished product, weighing 27.84 kg, with a yield of 90.28% and a purity greater than 99.5%.
[0050] The melting point was found to be 172℃~175℃.
[0051] Experimental Example 1: Characterization of Crystal Structure
[0052] The product obtained in Example 5 was analyzed using powder X-ray diffraction (PXRD) according to Method 2, General Chapter 0451, Part IV, Chinese Pharmacopoeia 2025 Edition. The 2θ values (±0.2°) of its main characteristic diffraction peaks were consistent with the data listed in the table below, confirming that it is the specific crystal form described in this invention. The powder X-ray diffraction spectrum is shown below. Figure 2 As shown.
[0053] Table 1: XRD characteristic peaks of zinc gluconate of a specific crystal form
[0054] Peak No. 2Θ (°) Peak No. 2Θ (°) 1 5.3±0.2 12 21.6±0.2 2 5.7±0.2 13 22.6±0.2 3 8.3±0.2 14 23.4±0.2 4 9.7±0.2 15 24.3±0.2 5 10.3±0.2 16 25.6±0.2 6 11.3±0.2 17 24.8±0.2 7 13.4±0.2 18 28.2±0.2 8 16.8±0.2 19 29.2±0.2 9 18.4±0.2 20 30.7±0.2 10 19.3±0.2 21 32.0±0.2 11 20.8±0.2 / /
[0055] Experiment Example 2: Hygroscopicity Test
[0056] Following the method described in Example 5, three batches of zinc gluconate raw material with a specific crystal form were continuously produced and prepared. Samples were taken and labeled as Sample 1, Sample 2, and Sample 3, respectively. Hygroscopicity was tested according to the method of General Chapter 9103, Part IV, Chinese Pharmacopoeia 2025 Edition. The results are shown in the table below:
[0057] Table 2: Hygroscopicity of a specific crystal form of zinc gluconate
[0058] Sample Lot No. Weight of Vessel (g) Sample + Weight of Vessel (g) Sample + Weight of Vessel After 24 Hours (g) Weight Gain (g) Hygroscopicity Sample 1 29.93625 31.28467 31.28791 0.00324 0.24% Sample 2 29.12923 30.20374 30.20642 0.00268 0.25% Sample 3 28.09228 29.15264 29.15497 0.00233 0.22%
[0059] Test results showed that after being left open for 24 hours, the percentage of moisture absorption and weight gain of the three batches of zinc gluconate samples was all around 0.25%, indicating that the moisture absorption of the obtained products was very low.
[0060] Experiment Example 3: Purity and Related Substances Inspection
[0061] The purity and possible organic impurities (gluconic acid, glucuronic acid, gluconic acid-δ-lactone) of the product obtained in Example 5 were determined by high performance liquid chromatography (HPLC).
[0062] Chromatographic conditions and system suitability:
[0063] Column: AQ-C18 (4.6mm×250mm, 5μm)
[0064] Mobile phase: 10 mmol / L dipotassium hydrogen phosphate solution (containing 10 mmol / L tetrabutylammonium hydrogen sulfate, pH adjusted to 7.2 with 1 mol / L KOH solution) - methanol (95:5, v / v)
[0065] Flow rate: 0.7 mL / min; Detection wavelength: 210 nm; Column temperature: 30℃; Injection volume: 20 μL;
[0066] The solution preparation method specifically includes the following steps:
[0067] Test solution: Weigh 0.25 g of zinc gluconate raw material accurately, place it in a 50 ml volumetric flask, dissolve and dilute to the mark with ultrapure water, and shake well.
[0068] Control solution: Measure 1.0 ml of the test solution and place it in a 100 ml volumetric flask. Dissolve and dilute to the mark with ultrapure water and shake well.
[0069] Impurity reference solution: Weigh appropriate amounts of gluconic acid reference standard, glucuronic acid reference standard, and glucono-β-lactone reference standard, and dilute with water to a solution containing approximately 5 μg each of gluconic acid, glucuronic acid, and glucono-β-lactone per 1 ml.
[0070] The above solutions were precisely pipetted into the liquid chromatograph, and the chromatograms were recorded. Analysis showed that no gluconic acid, glucuronic acid, glucosinolate, or other unknown organic impurities were detected in the sample of Example 5.
[0071] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.
[0072] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A specific crystal form of zinc gluconate active pharmaceutical ingredient, characterized in that, Its powder X-ray diffraction pattern, expressed in 2θ angles, has characteristic peaks at the following positions: 5.3±0.2°, 8.3±0.2°, 9.7±0.2°, 10.3±0.2°, 11.3±0.2°, 13.4±0.2°, 16.8±0.2°, 18.4±0.2°, 19.3±0.2°, 20.8±0.2°, 22.6±0.2°, 23.4±0.2°, 24.3±0.2°, 24.8±0.2°, and 30.7±0.2°.
2. The zinc gluconate specific crystal form active pharmaceutical ingredient according to claim 1, characterized in that, Its powder X-ray diffraction pattern also has characteristic peaks at 2θ of 5.7±0.2°, 21.6±0.2°, 25.6±0.2°, 28.2±0.2°, 29.2±0.2° and 32.0±0.2°.
3. The zinc gluconate specific crystal form active pharmaceutical ingredient according to claim 1 or 2, characterized in that, Its melting point is 172℃-175℃.
4. A method for preparing a specific crystal form of zinc gluconate active pharmaceutical ingredient according to any one of claims 1-3, characterized in that, Includes the following steps: (1) Dissolve crude zinc gluconate in purified water and heat to obtain zinc gluconate solution; (2) Cool and filter the solution obtained in step (1) to obtain a clear zinc gluconate solution; (3) Add ethanol to the clarified solution to make the concentration of ethanol in the solution reach 10-20% (w / w), and let it stand at 10-30℃ for 8-24 hours to crystallize. (4) After crystallization, solid-liquid separation is performed. The obtained solid is washed with purified water to obtain zinc gluconate filter cake. (5) Granulate the wet filter cake into wet particles with a particle size of 4-10 mesh; (6) The wet particles are dried in the first stage at 40-70°C and a vacuum degree of not less than 0.08 MPa until the moisture content of the particles is 20-40%; (7) Place the particles after the first stage of drying in a dryer and carry out the second stage of drying under the conditions of 2-12 rpm, 40-70℃ and vacuum degree not less than 0.08 MPa until the moisture content of the particles is 6-12%.
5. The method for preparing a specific crystal form of zinc gluconate active pharmaceutical ingredient according to claim 4, characterized in that, In step (1), the heating temperature for dissolving is 65-75℃, and the dissolving time is 0.5-2 hours.
6. The method for preparing a specific crystal form of zinc gluconate active pharmaceutical ingredient according to claim 4, characterized in that, In step (7), the dryer is a rotatable and vacuum-capable dryer.