Preparation method of ceftriaxone sodium single-crystal structure
By optimizing the recrystallization process, high-purity and high-stability ceftriaxone sodium single crystals were prepared, which solved the problem of unstable drug quality and achieved improvements in drug quality and production efficiency.
Patent Information
- Application Number
- CN202510651056.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-20
- Publication Date
- 2025-09-23
AI Technical Summary
Existing technologies make it difficult to prepare high-purity, high-quality ceftriaxone sodium single crystals, resulting in unstable drug quality and affecting bioavailability and therapeutic effects.
Ceftriaxone sodium single crystals were prepared using recrystallization technology by controlling temperature, stirring speed, and solvent composition. This involved rotary evaporation of high-purity original ceftriaxone sodium and seed crystals in a methanol solution, gradually heating and slowly cooling the solution, and filtering to obtain the finished crystals.
High-purity and high-stability single crystals of ceftriaxone sodium were obtained, which improved the quality of the drug, improved its solubility and bioavailability, extended its shelf life, reduced adverse reactions, and increased production efficiency.
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Figure CN120682252A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of drug research and development, and particularly relates to a method for preparing a single crystal structure of ceftriaxone sodium. Background Art
[0002] Recrystallization technology is a method of purifying solid substances through a dissolution and recrystallization process, and is widely used in the fields of medicine, chemical industry, materials, etc. For ceftriaxone sodium, recrystallization technology is a process in which the crude product is dissolved in an appropriate solvent and recrystallized by controlling conditions such as temperature, stirring speed, and solvent composition, thereby obtaining high-purity, high-quality ceftriaxone sodium crystals. Different crystal forms of ceftriaxone sodium have a significant impact on the quality, stability, and efficacy of the drug. Undesirable crystal forms may lead to reduced solubility and poor dissolution, which in turn affects the bioavailability and therapeutic effect of the drug. In pharmaceutical production, differences in crystal forms may lead to unstable quality between batches, affecting the uniformity and reliability of the drug. They may also exhibit different stability during storage and transportation, affecting the shelf life and safety of the drug.
[0003] Optimizing the crystallization process and preparing efficient, stable new seed crystals can help improve product purity, particle size, and fluidity, ensuring drug quality meets clinical needs. This can improve drug solubility, dissolution, and bioavailability, thereby enhancing efficacy. Furthermore, stable crystal forms can help extend drug shelf life and reduce adverse reactions. They can also address issues such as small particle size, uneven distribution, and agglomeration encountered in industrial production, thereby improving the efficiency and economic benefits of the pharmaceutical industry.
[0004] In summary, the development of new crystal forms is an important way to improve the quality of ceftriaxone sodium. Summary of the Invention
[0005] The object of the present invention is to provide a method for preparing a single crystal structure of ceftriaxone sodium that can improve the crystal form.
[0006] To achieve the above object, the present invention provides a method for preparing a single crystal structure of ceftriaxone sodium, comprising: a. Prepare the original drug and ceftriaxone sodium seed crystals of ceftriaxone sodium, the purity of the original drug of ceftriaxone sodium is greater than 85%, the purity of the seed crystals of ceftriaxone sodium is greater than 99.5%, take Xg of the original drug of ceftriaxone sodium, take 0.5% * Xg of ceftriaxone sodium seed crystals, take 80 * Xml of methanol, the concentration of methanol is 15-25%, and the above three are placed in the bottle and mixed, where X is a constant; b. Place the bottle into a rotary evaporator and stir to mix. Gradually heat the mixed solution in the bottle to 60-70°C while stirring for 10-20min. c. The mixed solution was refluxed in a rotary evaporator until the original ceftriaxone sodium drug and the ceftriaxone sodium seed crystals were completely dissolved, and then the mixed solution was stirred for 30-60 min while slowly lowering the temperature of the mixed solution during the stirring process; d. After the mixed solution is cooled and stirred, filter the mixed solution immediately and place the filter paper used for filtration in a dry place to allow it to evaporate naturally to obtain the finished crystals.
[0007] As an improvement of the above scheme, in step a, 1 g of the original research drug of ceftriaxone sodium, 5 mg of ceftriaxone sodium seed crystals, and 80 ml of methanol are taken and mixed.
[0008] As an improvement of the above scheme, in step b, the original ceftriaxone sodium drug, ceftriaxone sodium seed crystals and methanol are at room temperature of 15-25°C when they are first mixed, and the heating rate of the mixed solution is 2-5°C / min.
[0009] As an improvement of the above solution, in step b, the initial stirring speed of the mixed solution is 100-130 rpm, the stirring speed is increased by 10-15 rpm / h, and the final stirring speed is 150-170 rpm.
[0010] As an improvement of the above solution, in step c, the cooling rate of the mixed solution is 0.5-2°C / h.
[0011] The present invention has the following beneficial effects: This experiment explored the recrystallization technology of ceftriaxone sodium. By optimizing key parameters such as solvent selection, temperature control, and crystallization rate, a small amount of high-purity single-crystalline ceftriaxone sodium was obtained. This process successfully established an efficient and stable method for preparing ceftriaxone sodium, providing guidance for subsequent improvements. BRIEF DESCRIPTION OF THE DRAWINGS
[0012] Figure 1 is an SEM photograph of a single crystal of ceftriaxone sodium under an embodiment; Figure 2 This is an inverted microscope photograph of a single crystal of ceftriaxone sodium according to an embodiment; Figure 3 This is a SEM photo of the original research drug of ceftriaxone sodium under an embodiment; Figure 4 This is an inverted microscope photograph of the original research drug of ceftriaxone sodium under an embodiment; Figure 5 This is a TG comparative analysis chart of ceftriaxone sodium single crystal and ceftriaxone sodium original drug under an embodiment; Figure 6 This is a DSC comparative analysis diagram of a single crystal of ceftriaxone sodium and an original research drug of ceftriaxone sodium under an embodiment; Figure 7 This is an IR comparative analysis chart of a single crystal of ceftriaxone sodium and an original research drug of ceftriaxone sodium under an embodiment; Figure 8 This is a Raman comparative analysis chart of a single crystal of ceftriaxone sodium and an original research drug of ceftriaxone sodium according to an embodiment. DETAILED DESCRIPTION
[0013] The invention discloses a method for preparing a ceftriaxone sodium single crystal structure.
[0014] 1. Experimental materials and instruments Experimental materials: original research drug of ceftriaxone sodium; ceftriaxone sodium seed crystals, obtained by recrystallization, grinding and screening of crude ceftriaxone sodium, with a purity greater than 99.5%; anhydrous ethanol (analytical grade) and methanol (analytical grade).
[0015] 2. Experimental Instruments See Table 1 below.
[0016] name model electronic balance ME204E Field emission scanning electron microscopy JSM-7900F Simultaneous thermal analyzer STA 449 F3 Jupiter Fourier transform infrared absorption spectrometer TENSOR27 X-ray diffractometer Xpert Pro Raman spectrometer ATR3110 Rotary evaporator EYELA Inverted phase contrast microscope DMIL-LED 3. An embodiment of the preparation method a. Take 1g of the original ceftriaxone sodium drug, take 5mg of ceftriaxone sodium seed crystals, take 80ml of methanol (the concentration of methanol is 25%), and mix the above three in the bottle.
[0017] b. The mixed solution was gradually heated to 60°C, with an initial temperature of 15°C and a heating rate of 10°C / h. The mixed solution was stirred while heating, with an initial stirring rate of 125 rpm, an increasing stirring rate of 15 rpm / h, a final stirring rate of 150 rpm, and a stirring time of 20 min.
[0018] c. Reflux the mixed solution in a rotary evaporator until the original ceftriaxone sodium drug and the ceftriaxone sodium seed crystals are completely dissolved. After both samples are completely dissolved, continue stirring for 30 minutes. During the stirring process, slowly reduce the temperature of the mixed solution at a cooling rate of 0.5°C / h.
[0019] d. After the reaction is completed, the mixed solution is filtered while hot, and the filter paper used for filtration is placed in a dry place and allowed to evaporate naturally to obtain the finished crystal, i.e., single crystal structure of ceftriaxone sodium.
[0020] 4. SEM and inverted phase contrast microscopy measurements A JSM-7900F field emission scanning electron microscope (SEM) operating at 15 kV was used. The sample was placed on a metal sheet adhered with double-sided tape and intermittently sprayed with gold under argon protection before observation. The crystal morphology was also observed using an inverted phase contrast microscope.
[0021] SEM images and inverted microscope results of ceftriaxone sodium single crystal and ceftriaxone sodium original drug are as follows Figure 1-4 As shown. The crystals of ceftriaxone sodium single crystals are large and uniform (50-100μm), which is larger than the crystal size of the original ceftriaxone sodium drug (10-50μm). The single crystals have a regular cubic or prismatic structure with clear edges and no obvious cracks or holes. This indicates that the internal structure of the crystals is dense, the physical stability is high, and it is not easy to absorb moisture or degrade. The crystals of the original drug are irregular in shape, with blunt edges and long columnar shapes. The crystal surface of the single crystal is smooth and the crystal face is complete. The crystal surface of the original drug is rough, with visible micropores or cracks, and micropores or cracks may be visible on the attached excipient particles. Under an inverted phase contrast microscope, the single crystals are transparent and light yellow, with uniform size, complete crystal shape, and thin square flakes.
[0022] 5. Thermogravimetric analysis (TG) 4 mg of single crystal of ceftriaxone sodium and 4 mg of original research drug of ceftriaxone sodium were respectively taken for comparative experiments. The instrument temperature was increased from room temperature to 300°C at a heating rate of 20.0°C / min and the nitrogen flow rate was 18.0 ml / min.
[0023] The TG spectra of ceftriaxone sodium single crystal and ceftriaxone sodium original drug are as follows Figure 5 As shown, the results show that the single crystals and the original drug exhibit roughly the same weight loss temperature trend. The initial weight loss (<100°C) results in a mass loss of approximately 1-2%, attributed to adsorbed trace amounts of water or residual solvent, indicating high single crystal purity and minimal residual solvent. The weight loss from 0-200°C is approximately 6.8%, with a water of crystallization content of 5.6% (<theoretical content of 9.52%). The main decomposition temperature of the single crystals (220°C) is significantly higher than that of the original drug (200°C), indicating a more stable single crystal structure and stronger intermolecular forces (such as hydrogen and ionic bonds) than traditional polymorphs. In summary, the thermal stability of the recrystallized product is improved, with a slightly higher decomposition temperature, likely due to enhanced crystal structure integrity.
[0024] 6. Differential Scanning Spectroscopy (DSC) 4 mg of single crystal of ceftriaxone sodium and 4 mg of original research drug of ceftriaxone sodium were respectively taken for comparative experiments. The instrument temperature was increased from room temperature to 300°C at a heating rate of 20.0°C / min and the nitrogen flow rate was 18.0 ml / min.
[0025] like Figure 6The following are the DSC spectra of ceftriaxone sodium single crystal and the original drug of ceftriaxone sodium. The results show that the change trends of the single crystal and the original drug are basically the same. There are three endothermic peaks in the DSC curve of the original drug, with corresponding peak top temperatures (Tp) of 65°C, 137°C, 202°C and an exothermic peak of 273°C. Among them, the endothermic peak corresponding to 65°C is the weight loss stage of evaporation of adsorbed water, the endothermic peak corresponding to 137°C is the weight loss stage of evaporation of crystallized water, the endothermic peak corresponding to 202°C is the volatilization weight loss stage, and the exothermic peak corresponding to 273°C is the thermal decomposition weight loss stage. The endothermic peak corresponding to 101°C in the single crystal is the endothermic peak of the adsorbed water and bound water stages merged into a broad peak, so its intensity is stronger than that of the original drug. The small endothermic peak corresponding to 249°C is the volatilization weight loss stage. Since the heat absorption in this section is small, the corresponding weight loss is also very small, so it is not obvious on the TG.
[0026] 7. Infrared absorption spectroscopy analysis Ceftriaxone sodium single crystal and original research drug were analyzed by infrared spectroscopy on a TENSOR27 Fourier transform infrared absorption spectrometer using the KBr pellet method.
[0027] IR comparison of ceftriaxone sodium single crystal and original drug Figure 7 As shown, the results show that the absorption peak positions and peak shapes of key functional groups such as the β-lactam ring (C=O vibration, 1700-1800cm-1), carboxylate (COO⁻ symmetric vibration, 1400-1600cm-1), amino group (NH stretching vibration, 3300-3500cm-1), thioether bond (CS vibration, 600-800cm-1), and COC (ether bond multi-peak vibration, 1000-1300cm-1) are basically overlapping, with no additional peaks or peaks missing, indicating that no new impurities were introduced into the single crystal or no functional group breakage occurred. In summary, the prepared single crystal structure is basically consistent with the chemical skeleton structure of the original drug and is the target product.
[0028] 8. Raman spectroscopy analysis Raman scattering data of ceftriaxone sodium single crystal and original ceftriaxone sodium were collected using a Raman spectrometer. Laser wavelength: 780 nm, laser power: 100.0 mW, slit: 50 μm, measurement range: 50–3500 cm -1 , integration time: 5s, sampling interval: 500ms.
[0029] The Raman comparative analysis results of ceftriaxone sodium single crystal and ceftriaxone sodium original drug are as follows Figure 8 As shown, the results show that the single crystal of ceftriaxone sodium has a wavelength of 650 cm -1 、1380cm -1 and 1580cm -1The peaks of single crystals are usually sharper and stronger (due to the highly ordered crystal structure), while the peaks of original drugs are weaker, especially in the range of 300-600 cm -1 In the range, the scattering peak intensity and number of the original drug are significantly lower and more than those of the single crystal, and some split peaks appear, indicating that the original drug contains polymorphs, excipient interference or amorphous components, while the ceftriaxone sodium single crystal has a higher degree of crystallinity.
[0030] 9. Quality Evaluation of Ceftriaxone Sodium Single Crystals 9.1 Moisture content determination results Moisture content is one of the key quality indicators specified in the Pharmacopoeia. Karl Fischer titration determined the moisture content of ceftriaxone sodium single crystals to be 4.12%, meeting the Pharmacopoeia standard of less than 11%. Compared to the original ceftriaxone sodium obtained using the refined crystallization process (4.75% moisture content), this crystal form exhibits a reduced moisture content.
[0031] 9.2 Solution stability determination The change in absorbance of the ceftriaxone sodium single crystal solution with storage time is shown in Table 2 below.
[0032] Placement time (t / h) Absorbance (A) 0 0.4501 3 0.4547 6 0.4604
[0033] 10. Discussion This experiment explored a new recrystallization technology to try to solve the problem of the difficulty in obtaining ceftriaxone sodium single crystals. Through exploration and investigation of different culture conditions, ceftriaxone sodium single crystals of good quality and appropriate size were prepared under laboratory conditions. The physical and chemical properties such as crystal appearance, crystal particle size, thermal stability and purity effect were characterized and evaluated, aiming to discover the characterization differences between ceftriaxone sodium single crystals and traditional crystal forms.
[0034] When it comes to the recrystallization process of ceftriaxone sodium, selecting the appropriate solvent system is crucial. This study identified a water-methanol mixture as the optimal recrystallization solvent system. Water, as the primary solvent, fully dissolves ceftriaxone sodium, while methanol, as the antisolvent, promotes the crystallization process.
[0035] Temperature control is a crucial factor influencing recrystallization. This study used a gradient cooling technique to determine the optimal dissolution and crystallization temperatures. The mixed solution was completely dissolved by refluxing on a rotary evaporator at 60°C for 30 minutes. After dissolution, stirring was performed at a cooling rate of 0.5°C / h for 30 minutes. The results showed that this temperature favored the formation of large, high-quality crystals of ceftriaxone sodium and also facilitated the separation of impurities. The stirring rate also significantly affected the recrystallization process. Appropriate stirring promotes heat and mass transfer, facilitating uniform crystallization, while excessive stirring can lead to crystal fragmentation. Adding a small amount of high-quality ceftriaxone sodium seed crystals during the initial crystallization phase can significantly improve the crystallization rate and quality. Adding 0.5%*Xg of ceftriaxone sodium seed crystals shortened the crystallization time by 30% and achieved a more uniform crystal size distribution.
[0036] After optimizing the recrystallization process parameters for ceftriaxone sodium under laboratory conditions, the IR and Raman spectra of ceftriaxone sodium single crystals revealed structural peaks that were essentially consistent with those of the original drug, although slight shifts were observed in certain regions. Peak positions reflect the frequency of molecular vibrations and are closely related to molecular structure. Slight shifts may indicate intra- or intermolecular changes, presumably caused by alterations in the crystal form of ceftriaxone sodium.
[0037] In terms of crystal structure differences, ceftriaxone sodium single crystals exhibited highly regular morphology, smooth surface, and uniform size under SEM and inverted phase contrast microscopy, indicating good physical stability and processability, which can improve drug flowability, compressibility, and tablet hardness, while reducing sticking and punching issues during production. No obvious cracks or holes were observed on the surface of the ceftriaxone sodium single crystals, indicating a dense internal structure that is less susceptible to moisture absorption or degradation during storage. This improved crystal morphology not only enhances the product's appearance quality but also improves the drug's solubility and bioavailability.
[0038] In terms of stability in aqueous solution, ceftriaxone sodium single crystals also performed well. Experimental results showed that at the time points of 0, 3, and 6 hours, the absorbance of the aqueous solution of ceftriaxone sodium single crystals only increased by 0.0103. The remarkable stability exhibited by ceftriaxone sodium single crystals in aqueous solution further proves its superiority as a pharmaceutical preparation. This stability not only helps to extend the shelf life of the drug and reduce quality risks during storage and transportation, but may also bring higher safety and efficacy to clinical medication. In the future, with the continuous development of pharmaceutical preparation technology, the stability advantages of ceftriaxone sodium single crystals are expected to be further explored, providing new ideas and methods for the research and development and application of antibiotic drugs. At the same time, this also reminds us that in the process of drug research and development and production, we should pay more attention to the research and control of drug stability to improve the quality and efficacy of drugs.
[0039] The foregoing descriptions of specific exemplary embodiments of the present invention are for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many variations and modifications are possible in light of the foregoing teachings. The exemplary embodiments have been selected and described for the purpose of explaining the specific principles of the invention and their practical application, thereby enabling those skilled in the art to realize and utilize a variety of exemplary embodiments of the invention and various options and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.
Claims
1. A method for preparing a single crystal structure of ceftriaxone sodium, characterized in that The following steps are involved: a. Prepare the original drug and ceftriaxone sodium seed crystals of ceftriaxone sodium, the purity of the original drug of ceftriaxone sodium is greater than 85%, the purity of the seed crystals of ceftriaxone sodium is greater than 99.5%, take Xg of the original drug of ceftriaxone sodium, take 0.5% * Xg of ceftriaxone sodium seed crystals, take 80 * Xml of methanol, the concentration of methanol is 15-25%, and the above three are placed in a bottle and mixed, where X is a constant; b. Place the bottle into a rotary evaporator and stir to mix. Gradually heat the mixed solution in the bottle to 60-70°C while stirring for 10-20min. c. The mixed solution was refluxed in a rotary evaporator until the original ceftriaxone sodium drug and the ceftriaxone sodium seed crystals were completely dissolved, and then the mixed solution was stirred for 30-60 min while slowly lowering the temperature of the mixed solution during the stirring process; d. After the mixed solution is cooled and stirred, filter the mixed solution immediately and place the filter paper used for filtration in a dry place to allow it to evaporate naturally to obtain the finished crystals.
2. The method for preparing the single crystal structure of ceftriaxone sodium according to claim 1, wherein: In the step a, 1 g of the original research drug of ceftriaxone sodium, 5 mg of ceftriaxone sodium seed crystals, and 80 ml of methanol are taken and mixed.
3. The method for preparing the single crystal structure of ceftriaxone sodium according to claim 2, wherein: In the step b, the original ceftriaxone sodium drug, the ceftriaxone sodium seed crystals and the methanol are at room temperature of 15-25° C. when they are first mixed, and the heating rate of the mixed solution is 2-5° C. / min.
4. The method for preparing the single crystal structure of ceftriaxone sodium according to claim 3, wherein: In the step b, the initial stirring speed of the mixed solution is 100-130 rpm, the stirring speed is increased by 10-15 rpm / h, and the final stirring speed is 150-170 rpm.
5. The method for preparing the single crystal structure of ceftriaxone sodium according to claim 4, wherein: In the step c, the cooling rate of the mixed solution is 0.5-2°C / h.