Cefprozil crystal form and preparation method thereof

Abstract

The invention discloses a cefprozil crystal form and a preparation method, and belongs to the technical field of chemical bulk drugs, an X-ray powder diffraction pattern (XRPD) of the crystal form X comprises the following characteristic peaks: 8.8, 12.2, 13.3, 18.2, 18.8, 20.8, 21.2, 22.4 and 23.0, and the solubility of the new crystal form X of cefprozil is slightly soluble. N-heptane is used for secondary crystallization and crystal growing, a crystal form X cefprozil is obtained, and the solubility of the crystal form X cefprozil is slightly soluble; the crystal form has the advantages of perfect crystal form structure, high purity, good crystal form and good crystal form structure stability, and can meet the requirement of 80% in-vitro dissolution rate in pharmacopeia without being prepared into tablets through micronization treatment.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical bulk drugs, and more particularly relates to a crystalline form of cefprozil and a preparation method thereof. BACKGROUND

[0002] Cefprozil is a second-generation cephalosporin broad-spectrum antibacterial drug, and has strong antibacterial activity against G+, G- bacteria and anaerobic bacteria, especially G+ bacteria. Cefprozil has good safety and very low adverse reactions. It was approved for marketing by FDA in December 1991, and is clinically used for mild and moderate infections caused by sensitive bacteria, including upper and lower respiratory tract infections, and skin and skin soft tissue infections. The biggest advantage of cefprozil in the pediatric drug market is its safety. The unique structure-activity relationship of the product determines its own advantages, and its preparation has good prospects.

[0003] For the crystalline form of the compound, the methods reported so far mainly include the following: There are relatively few patents for the crystalline form of the compound in the prior art. Patent CN108530467A discloses a purification method of cefprozil. The patent mainly adds cefprozil DMF complex into purified water, adds hydrochloric acid to adjust to clarity, then adds ferric chloride solution, filters, drops ammonia water, adjusts the pH to 4.5-5.5, and then adds tin dichloride methanol solution, crystallizes, filters, and dries to obtain cefprozil. However, the cefprozil yield of this method is low, and no related crystal form is disclosed.

[0004] Patent CN108299468A reports that cefprozil is dissolved in deionized water, ethanol and dichloromethane, heated to reflux to dissolve and prepared into a supersaturated solution, cooled, decolorized, filtered, crystallized, filtered and dried to obtain cefprozil. Due to the poor thermal stability of cefprozil, the heating reflux time in the workshop production is often long, which can easily convert cefprozil into isomers, thereby significantly reducing the normal yield and quality, so the patent has little application value in actual industrial production.

[0005] The crystalline form of cefprozil bulk drug currently has the disadvantages of poor water solubility, which limits its application in other dosage forms. Therefore, actively developing new crystalline forms of cefprozil is of great significance for breaking the patent protection, increasing the application of its dosage forms, and improving the product competitiveness of the company. According to the description in the pharmacopoeia, the solubility of cefprozil is slightly soluble, and the solubility is 100-1000 mL; and cefprozil is generally used as a tablet, As a slightly soluble cefprozil, it cannot meet the release of effective components after the disintegration of the drug and the bioavailability, therefore, the more common method at present is to crush the drug particles by micronization technology, which can greatly improve the dissolution rate and make the drug be absorbed by the human body faster and take effect faster.

[0006] However, although the micronization technique belongs to physical change, there are potential adverse effects on the drug, such as: (1) The micronization greatly increases the specific surface area of the drug, resulting in very high surface energy of the particles, which makes the particles in a thermodynamic unstable state, having a strong tendency to spontaneously aggregate to reduce the surface energy, which will cause the particles to re-agglomerate; (2) The crystal structure may be destroyed, forming an unordered and amorphous layer on the surface of the particles, resulting in polymorphic transformation, eventually leading to the generation of mixed crystals, changing the solubility and stability of the drug; (3) The fine particles after micronization are easy to generate and carry static electricity, causing the particles to be adsorbed to each other or to the equipment wall, resulting in poor flowability, inconvenient weighing, large material transfer loss and other problems.

[0007] Therefore, a cefprozil crystal form and a preparation method are sought, which has a relatively optimal solubility, can be directly prepared into tablets without the need for micronization treatment, and has excellent crystal form stability and bioavailability. SUMMARY

[0008] To solve the above problems and overcome the shortcomings of the prior art, the present application provides a cefprozil crystal form and a preparation method, which has a relatively optimal solubility, excellent crystal form stability and bioavailability, and can effectively solve the problem of potential adverse effects caused by the micronization of cefprozil as a slightly soluble drug recorded in the current pharmacopoeia.

[0009] The specific technical solution of the present application to solve the above technical problems is: a new crystal form X of cefprozil, characterized in that the X-ray powder diffraction pattern (XRPD) of the crystal form X includes the following characteristic peaks: 8.8, 12.2, 13.3, 18.2, 18.8, 20.8, 21.2, 22.4 and 23.0.

[0010] Further, the solubility of the new crystal form X of cefprozil is slightly soluble.

[0011] A preparation method of a new crystal form X of cefprozil, which prepares the new crystal form X of cefprozil, characterized by comprising the following steps: (1) Solvent clarification: Mix cefprozil and a polar solvent, and then add acid liquid dropwise until it is clear; (2) First crystallization: Reduce the temperature of the system of step (1) to -15~-25℃, add a certain amount of organic solvent I, adjust the pH to 6.4~6.7 using an organic base, and crystallize for 20-40 min to precipitate cefprozil solid; (3) Second crystallization: Add a certain amount of organic solvent II to step (2), and after crystal growth, filtration and drying, crystal form X cefprozil can be obtained.

[0012] Furthermore, the polar solvent is methanol, isopropanol, or acetonitrile; the mass ratio of cefprozil to the polar solvent is 1:5~15.

[0013] Furthermore, the organic solvent I is dichloromethane; and the organic solvent II is n-heptane.

[0014] Furthermore, the mass ratio of cefprozil to organic solvent I is 1:3~5; the mass ratio of cefprozil to organic solvent II is 1:5~8.

[0015] Furthermore, the organic base includes triethylamine, dicyclohexylamine, and N,N-diisopropylethylamine.

[0016] The beneficial effects of this invention are: This invention innovatively utilizes dichloromethane for primary crystallization to generate crystal nuclei, followed by secondary crystallization and growth using n-heptane to obtain a crystal form X of cefprozil. This crystal form X includes the following characteristic peaks: 8.8, 12.2, 13.3, 18.2, 18.8, 20.8, 21.2, 22.4, and 23.0.

[0017] Among them, the solubility of crystal form X cefprozil is slightly soluble; it has a perfect crystal structure, high purity, good crystal form, and good crystal structure stability. Tablets prepared without micronization can meet the 80% in vitro dissolution requirement in the pharmacopoeia. Attached Figure Description

[0018] Appendix Figure 1 This is the X-ray powder diffraction pattern of cefprozil crystals prepared in Example 1 of the present invention; Appendix Figure 2 This is the X-ray powder diffraction pattern of cefprozil crystals prepared in Example 2 of the present invention; Appendix Figure 3 This is the X-ray powder diffraction pattern of cefprozil crystals prepared in Example 3 of the present invention; Appendix Figure 4 This is an X-ray powder diffraction pattern of commercially available cefprozil crystals; Appendix Figure 5 This is an image of a crystal optical microscope prepared according to Example 1 of the present invention; Appendix Figure 6 This is an image of a crystal optical microscope prepared according to Example 2 of the present invention; Appendix Figure 7 This is an image of a crystal optical microscope prepared according to Example 3 of the present invention; Appendix Figure 8is a crystal optical microscope imaging figure prepared by the present application comparative example 1; attached Figure 9 is a crystal optical microscope imaging figure prepared by the present application comparative example 2; attached Figure 10 is a crystal optical microscope imaging figure prepared by the present application comparative example 3; attached Figure 11 is a crystal optical microscope imaging figure prepared by the present application comparative example 4; attached Figure 12 is a crystal optical microscope imaging figure prepared by the present application comparative example 5; DETAILED DESCRIPTION In the description of the present application, specific details are merely to enable a full understanding of the embodiments of the present application, but as a person skilled in the art should know that the implementation of the present application is not limited to these details. In addition, well-known structures and functions are not described or shown in detail to avoid obscuring the essential points of the embodiments of the present application. For those skilled in the art, the specific meaning of the above terms in the present application can be understood in specific circumstances.

[0019] Specific embodiments of the present application: In order to better understand the present application with specific examples, it is worth emphasizing that the effect of this embodiment and various embodiments within the scope of the present application, including the respective reagents and the content of the reagent ratio, have no substantial difference, can realize the effect described in the present application and solve the above problems, other combinations are not repeated here; Example 1: (1) 10 g of cefprozil, 50 ml of methanol were mixed, and 6 mol / L hydrochloric acid solution was added dropwise until the system was completely clear; (2) The temperature of the system was reduced to -15~-25℃, 30 ml of dichloromethane was added, and the pH was adjusted to 6.4~6.7 using triethylamine, and the temperature was reduced to -35~-45℃ for crystallization, and the crystallization time was 30 min; (3) 50 m of n-heptane was added dropwise to step (2), and the dropwise addition was controlled to end in 1.0 h, and the crystal was maintained at -35~-45℃ for about 4 h, and then filtered, and the filter cake was washed with n-heptane, and dried at 30℃ to obtain 9.58 g of cefprozil crystal form X, the product yield was 95.8%, and the purity was 99.71%.

[0020] The new crystal form X of cefprozil obtained was subjected to X-ray powder diffraction, and the results are shown in Figure 1 As can be seen from the figure, the crystal form X includes the following characteristic peaks: 8.8, 12.2, 13.3, 18.2, 18.8, 20.8, 21.2, 22.4 and 23.0.

[0021] Example 2: (1) mixed 15 g of cefprozil with 180 ml of isopropyl alcohol, and then added 6 mol / L hydrochloric acid solution dropwise until the system was completely clear; (2) reduced the temperature of the system to -15 to -25 °C, added 75 ml of dichloromethane, adjusted the pH to 6.4 to 6.7 using dicyclohexylamine, and then crystallized at -35 to -45 °C for 40 min; (3) added 105 ml of n-heptane dropwise to step (2), controlled the dropwise addition to end in 2 h, maintained the temperature at -35 to -45 °C for about 6 h, and then filtered, washed the filter cake with n-heptane, and dried to obtain 14.11 g of cefprozil crystal form X, with a product yield of 94.1% and a purity of 99.85%.

[0022] The obtained cefprozil crystal form X was subjected to X-ray powder diffraction, and the results are shown in Figure 1 From the figure, it can be seen that the crystal form X includes the following characteristic peaks: 8.8, 12.2, 13.3, 18.2, 18.8, 20.8, 21.2, 22.4, and 23.0.

[0023] Example 3: (1) mixed 15 g of cefprozil with 225 ml of acetonitrile, and then added 6 mol / L hydrochloric acid solution dropwise until the system was completely clear; (2) reduced the temperature of the system to -15 to -25 °C, added 60 ml of dichloromethane, adjusted the pH to 6.4 to 6.7 using N,N-diisopropylethylamine, and then crystallized at -35 to -45 °C for 35 min; (3) added 120 ml of n-heptane dropwise to step (2), controlled the dropwise addition to end in 1.5 h, maintained the temperature at -35 to -45 °C for about 5 h, and then filtered, washed the filter cake with n-heptane, and dried to obtain 14.02 g of cefprozil crystal form X, with a product yield of 93.5% and a purity of 99.80%. The obtained cefprozil crystal form X was subjected to X-ray powder diffraction, and the results are shown in Figure 1 From the figure, it can be seen that the crystal form X includes the following characteristic peaks: 8.8, 12.2, 13.3, 18.2, 18.8, 20.8, 21.2, 22.4, and 23.0.

[0024] In order to more intuitively show the process advantages of the present application, the preparation method of the present application using cefprozil crystal form X and the same process using equivalent replacement are compared, Comparative Example 1: The preparation method is the same as that of Example 1, except that in the preparation process of the present comparative example, dichloromethane is replaced with n-heptane; Comparative Example 2: The preparation method is the same as that of Example 1, except that in the preparation process of the present comparative example, n-heptane is replaced with dichloromethane; Comparative Example 3: The preparation method is the same as that of Example 1, except that the organic solvent is a mixture of organic solvent I and organic solvent II in the preparation process of the present comparative example, and the total amount of the additive is the same as that of the present application; Specifically: the temperature of the system is reduced to -15~ -25℃, 30ml of dichloromethane and 50ml of n-heptane are added, triethylamine is used to adjust the pH to 6.4~6.7, the temperature is reduced to -35~ -45℃ for crystallization, and the temperature is maintained at -35~ -45℃ for about 4h, then the filter cake is washed and dried at 30℃.

[0025] Comparative Example 4: The preparation method is the same as that of Example 1, except that dichloromethane is replaced by ethyl acetate in the preparation process of the present comparative example; Comparative Example 5: The preparation method is the same as that of Example 1, except that n-heptane is replaced by n-hexane in the preparation process of the present comparative example; According to the detection standard of the national pharmacopoeia for the dissolution of tablet drugs, Pharmacopoeia dissolution test standard: take the same standard cefprozil crystal raw material tablet, according to the dissolution and release determination method (general rule 0931 first method), with water 900ml as the dissolution medium, the speed is 75 revolutions per minute, according to the operation. After 30 minutes, take the solution, filter, take the filtrate as the test solution; another cefprozil reference substance is added to water, dissolved and diluted to 0.28mg per 1ml, as the reference solution. Take the above two solutions, according to the method under the content determination, calculate the dissolution amount of each tablet. The limit is 80% of the marked amount, which should meet the requirements.

[0026]

[0027] Note: the above photos are taken in the crystallization system containing the relevant organic solvent, and after dilution with the same concentration (dilution of the relevant organic solvent), the optical microscope is used for shooting; The raw material is a solid powder, which appears black light shadow (powder is difficult to completely spread into a very thin layer) under the optical microscope, so the picture is not attached.

[0028] (1) In Examples 1-4, the present application adds dichloromethane with lower polarity and large difference in solubility parameter to the methanol mother liquor, so that the solubility of cefprozil is sharply decreased and instantaneously reaches extremely high supersaturation, thereby explosively forming a large number of crystal nuclei. The system with the crystal nuclei is poured into n-heptane with extremely low polarity and extremely strong non-polarity. The compatibility of n-heptane with the methanol / dichloromethane mixed solvent is poor, again causing a cliff-like decrease in solubility, but this decrease occurs on the basis of the crystal nuclei, thereby providing a strong and sustained driving force to promote the slow and orderly growth of the crystal nuclei, so as to obtain a slightly soluble cefprozil crystal with perfect crystal structure, and a tablet prepared without micronization treatment has excellent in-vitro dissolution rate, which is described in detail in Figures 5-7 ; The present application creatively uses dichloromethane for primary crystallization to generate crystal nuclei, and then uses n-heptane for secondary crystallization to grow the crystal nuclei, so as to obtain a crystal form X of cefprozil, which includes the following characteristic peaks: 8.8, 12.2, 13.3, 18.2, 18.8, 20.8, 21.2, 22.4 and 23.0, which is described in detail in the attached Figures 1-3 ; (2) Compared with Examples 1-4, Comparative Examples 1-3 differ in that the same solvent is used for primary crystallization and secondary crystallization, i.e. dichloromethane or n-heptane or a mixture of dichloromethane and n-heptane; As can be seen from the table data, the solubility of the cefprozil crystal of Comparative Examples 2-3 is slightly soluble, and the difference with the solubility of the cefprozil crystal published in the Chinese Pharmacopoeia is not large. The in-vitro dissolution rate experiment shows that the in-vitro dissolution rate of Comparative Examples 1-3 is only 67-74%, which is consistent with the theoretical data of the in-vitro dissolution rate of the slightly soluble cefprozil crystal. In order to meet the requirements of the in-vitro dissolution rate of the tablet, micronization treatment is currently used; This may be due to the fact that: In Comparative Example 1, oil precipitation occurs. In the n-heptane system with very poor solubility, the molecules are more inclined to form disordered liquid oil droplets rather than ordered crystal nuclei, and amorphous solids, gel-like substances or poor-quality crystals wrapped with serious impurities are obtained, which have no research value, which is described in detail in Figure 8 ; In Comparative Examples 2-3, since the same solvent is used for primary crystallization and secondary crystallization, new crystal nuclei cannot be prevented from being continuously generated during the growth process, and the final product is a crystal mixture with extremely wide particle size distribution, which contains both the crystal nuclei with "large number and small size" that are initially generated and the finer crystals that are newly generated during the growth process, i.e. a serious mixed crystal problem occurs, which finally leads to unstable product quality and poor solubility, and cannot meet the needs of the preparation, which is described in detail in Figures 9-10 ; (3) Compared with Examples 1-4, Comparative Example 4 differs in that: In the present application, dichloromethane with lower polarity and large difference in solubility parameter is added in the methanol mother liquor, so that the solubility of cefprozil is sharply decreased and instantaneously reaches extremely high supersaturation, thereby a large number of crystal nuclei are explosively formed; However, when ethyl acetate is used for nucleation, although ethyl acetate has similar polarity to dichloromethane, there is a large difference in physical properties between the two, and in the whole system of ethyl acetate and n-heptane, cefprozil molecules are easy to form stable crystal lattice structure with ethyl acetate, and the ethyl acetate molecules are wrapped in to form ethyl acetate solvate, which is described in detail in Figure 11 ; From the photos, the above crystal structure presents irregular structure, with flaky and flocculent, and also similar to the cefprozil crystal structure of the present application; After further research, the ethyl acetate solvate loses stability during the drying process, resulting in the collapse of the crystal structure, caking, or conversion to amorphous, which has no research value; (4) Compared with Examples 1-4, Comparative Example 5: Both n-heptane and n-hexane belong to very strong non-polar solvents, and in the early stage, cefprozil crystals are uniformly generated, with a small amount of flaky, and the crystal form structure is similar to the cefprozil crystal structure of the present application, but the quantity is less and relatively dispersed, which is described in detail in Figure 12 ; However, during the drying and molding process in the later stage, the comparative example 5 will produce broken crystal caking phenomenon, which may be related to the boiling point of the residual n-hexane (69°C). When the water pump is used for filtration, the system pressure may be reduced to about 15-20 kPa, at this time the boiling point of n-hexane will be reduced to room temperature, which means that even at room temperature, n-hexane is very easy to boil and vaporize; This leads to that if the solvent is wrapped inside the crystal, its rapid evaporation may cause the crystal to crack or even break, producing fine powder; and the evaporated solvent recondenses at the outer position of the crystal bed layer as the boiling point increases, causing the crystal to caking and forming hard block, which ultimately leads to unstable product quality, poor solubility, and cannot meet the needs of the preparation.

[0029] In summary: The cefprozil of the present application creatively uses dichloromethane for primary crystallization to generate crystal nuclei, and then uses n-heptane for secondary crystallization to grow crystals, to obtain a crystal form X cefprozil, which includes the following characteristic peaks: 8.8, 12.2, 13.3, 18.2, 18.8, 20.8, 21.2, 22.4 and 23.0; The crystal form X cefprozil has slightly soluble solubility; has perfect crystal form structure, high purity, good crystal form, and stable crystal form structure, and the tablet prepared without micronization treatment can meet the requirement of 80% in vitro dissolution rate required in the pharmacopoeia.

Claims

1. A crystalline form X of cefprozil characterized by The X-ray powder diffraction pattern of the crystal form X comprises the following characteristic peaks: 8.8, 12.2, 13.3, 18.2, 18.8, 20.8, 21.2, 22.4 and 23.

0.

2. The crystalline Form X of cefprozil according to claim 1, characterized in that The solubility of the crystal form X of cefprozil is slightly soluble.

3. A crystalline form X of cefprozil, a process for preparing the same, prepared according to claim 1 or 2, characterized in that The method comprises the following steps: (1) dissolving and clarifying: After mixing cefprozil and a polar solvent, acid solution is added dropwise until the solution is clear; (2) first crystallization: The temperature of the system in step (1) is reduced to -15~-25℃, a certain amount of organic solvent I is added, the pH is adjusted to 6.4~6.7 using an organic base, and cefprozil solid is precipitated after crystallization for 20-40 min; (3) second crystallization: A certain amount of organic solvent II is added dropwise to step (2), and after crystallization, filtration and drying, crystal form X cefprozil is obtained.

4. The crystalline Form X of cefprozil of claim 3, characterized in that The polar solvent is methanol or isopropanol or acetonitrile; the mass ratio of cefprozil to the polar solvent is 1:5~15.

5. The crystalline Form X of cefprozil of claim 3, characterized in that The organic solvent I is dichloromethane; the organic solvent II is n-heptane.

6. The crystalline Form X of cefprozil of claim 5, characterized in that The mass ratio of cefprozil to the organic solvent I is 1:3~5; the mass ratio of cefprozil to the organic solvent II is 1:5~8.

7. The crystalline Form X of cefprozil of claim 3, characterized in that The organic base comprises triethylamine, dicyclohexylamine and N,N-diisopropyl ethylamine.

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