Method for regulating crystal form of drug by oxidizing nanocellulose and application thereof

Abstract

The present application belongs to the field of chemical engineering and medicine manufacturing, and particularly relates to a method for regulating drug crystal form by oxidizing nanocellulose and application. By inducing the generation of sulfathiazole crystals in TCNF solutions with different concentrations, the nucleation and growth process of the sulfathiazole crystals is controlled, so that different morphologies and structures of the sulfathiazole crystal forms are obtained, and the transformation of the sulfathiazole crystals from flaky, prismatic to regular hexagonal crystal forms is realized. The sulfathiazole crystal form prepared by the method has better crystal morphology and consistency, the method is simple and effective, is suitable for crystal form optimization and large-scale production of polymorphic drugs, and has important industrial application value.

Description

Technical Field

[0001] This invention belongs to the field of chemical engineering and pharmaceutical manufacturing, and specifically relates to a method and application of regulating drug crystal form by oxidizing nanocellulose. Background Technology

[0002] The crystal form of a drug is one of the most important characteristics of its solid form. It not only determines the drug's physicochemical properties but also significantly affects its preparation process, stability, solubility, and bioavailability. Crystal form control has always been a highly focused research area in drug development. By controlling the crystal form, drug stability and solubility can be optimized, thereby improving efficacy. However, crystal form control faces many challenges in practice, especially in obtaining polymorphs with stable structures and superior properties, which often requires complex processes and conditions.

[0003] Traditionally, drug crystallization has been achieved primarily through crystallization under varying conditions, such as changes in solvent type, concentration, temperature, and crystallization rate. These methods are based on inducing different crystal structures through the rearrangement of solute molecules. However, this approach often relies on changes in the external environment, lacks precise control, and exhibits randomness in crystal formation. Furthermore, the formation of different crystal forms often depends on the experimenter's experience, and because different crystal forms compete with each other in solution, it is difficult to ensure the stability and reproducibility of specific crystal forms. Therefore, in the field of crystal form control, relying on simple changes in physical conditions is no longer sufficient to meet the current demands of drug development for efficient, reproducible, and predictable crystal form control.

[0004] In recent years, with the rapid development of nanotechnology and molecular materials science, polymer-induced drug crystal form control has gradually become an emerging research direction. Polymers can selectively bind to drug molecules through intermolecular interactions, regulating the nucleation and growth of drug crystals. This molecular-level crystal form control method offers higher precision and controllability compared to traditional methods involving changes in physical conditions. For example, common polymers such as polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) are widely used in drug crystal form control, effectively influencing crystal formation through hydrogen bonds and van der Waals forces with drug molecules. Especially in the development of polymorphic drugs, polymer-induced methods provide a new approach for discovering new crystal forms and improving drug performance.

[0005] An important background to this invention is the recent research on the polymorphism of drugs such as sulfathiazole. Sulfathiazole is a commonly used antibacterial drug, and its polymorphic properties have attracted much attention. This study found that the polymorphism of these drugs can be effectively controlled through polymer-induced methods. Summary of the Invention

[0006] This invention provides a method for regulating drug crystal forms through polymers. This method induces and controls drug crystal forms, thereby improving the physicochemical properties of drugs, such as solubility, stability, and bioavailability. The core of this invention lies in controlling the formation and stability of drug crystal forms by selecting suitable polymer materials (such as oxidized cellulose nanoparticles) and combining them with crystallization processes. This method is applicable to the development of polymorphic drugs; by controlling the concentration of the polymer material, the formation of polymorphs with superior properties can be effectively induced.

[0007] The technical solution of the present invention is to provide an application of oxidized cellulose nanoparticles (TCNF) in regulating drug crystal forms.

[0008] This invention provides a method for regulating drug crystal form using oxidized cellulose nanofiber (TCNF), comprising the steps of: mixing the drug and oxidized cellulose nanofiber in a solution and crystallizing; the drug being in a supersaturated state in the solution; and controlling the nucleation and growth of the drug crystal form by adjusting the concentration of the oxidized cellulose nanofiber.

[0009] Furthermore, the oxidized cellulose nanomaterial solution is mixed with the drug and crystallized.

[0010] The concentration of the oxidized cellulose nanomaterial is 0.1wt%-1wt%, preferably 0.5wt%-1wt%, more preferably 0.8wt%-1wt%; the supersaturation S of the drug is 1-8, preferably 3-5. The mass ratio of the drug to the oxidized cellulose nanomaterial is 1:0.5-10, preferably 1:4-8, more preferably 1:7-8.

[0011] The drugs include sulfathiazole, drugs having a sulfathiazole core or a sulfathiazole-like core, and drugs having a p-aminobenzenesulfonamide core or a p-aminobenzenesulfonamide-like core. Drugs having a sulfathiazole core or a sulfathiazole-like core may involve introducing other functional groups onto the sulfathiazole, altering the relative positions of the amino and sulfonamide groups, introducing other functional groups onto the benzene ring or thiazole ring, or replacing one or more elements on the sulfathiazole core, etc., without affecting the crystal form regulation effect similar to sulfathiazole when combined with polymer materials. Drugs having a p-aminobenzenesulfonamide core or a p-aminobenzenesulfonamide-like core may involve introducing other functional groups onto the p-aminobenzenesulfonamide core, altering the relative positions of the amino and sulfonamide groups, introducing other functional groups onto the benzene ring, amino, or sulfonamide group, or replacing one or more elements on the p-aminobenzenesulfonamide core, without affecting the crystal form regulation effect similar to sulfathiazole when combined with polymer materials. Specific examples include sulfamethoxazole, sulfadiazine, and sulfamethoxypyrimidine.

[0012] The concentration of the oxidized cellulose nanoparticle TCNF solution is 0.1wt%-1wt%, preferably 0.5wt%-1wt%, and more preferably 0.8wt%-1wt%. By adjusting the concentration of oxidized cellulose nanoparticle TCNF, sulfathiazole crystals gradually transform from plate-like and prismatic shapes into regular hexagonal shapes. The crystal morphology is closely related to the concentration of oxidized cellulose nanoparticles.

[0013] In the process of regulating drug crystal form through oxidized cellulose nanoparticles, the drug and oxidized cellulose nanoparticles are mixed in solution and stirred to achieve uniform mixing.

[0014] In the process of regulating the crystal form of drugs through the oxidation of nanocellulose, the crystallization method is ice bath cooling crystallization, specifically, cooling to room temperature in an ice bath for crystallization.

[0015] The preparation method of oxidized nanocellulose TCNF solution includes: dispersing the raw material of oxidized nanocellulose in water, adding 2,2,6,6-tetramethylpiperidine-1-oxy, sodium bromide and sodium hypochlorite to react, then adding ethanol to terminate the reaction, washing with water until neutral, and obtaining oxidized nanocellulose TCNF solution.

[0016] The raw materials for the oxidized nanocellulose include any one or any combination of pulp, cotton, wood, and straw, etc., with the cotton, wood, and straw undergoing pretreatment first. The mass ratio of the raw materials for the oxidized nanocellulose to water is 1:100-300, preferably 1:150.

[0017] The mass ratio of 2,2,6,6-tetramethylpiperidin-1-oxy, sodium bromide, and pulp is 0.01-0.02:0.05-0.3:1, preferably 0.016:0.1:1.

[0018] The volume-to-mass ratio of sodium hypochlorite to pulp is 6-7 mL:1 g, preferably 6.7 mL:1 g, and the sodium hypochlorite content is 13%.

[0019] In the preparation of oxidized nanocellulose TCNF solution, 2,2,6,6-tetramethylpiperidin-1-oxy and sodium bromide are added first, followed by the slow addition of sodium hypochlorite.

[0020] In the preparation of the oxidized cellulose nanoparticle (TCNF) solution, the reaction temperature is room temperature, preferably 25°C, and the reaction time is 4 hours.

[0021] In the preparation of oxidized cellulose nanoparticle (TCNF) solution, the solution is washed with water until neutral, then sonicated and concentrated.

[0022] This invention has found that when preparing oxidized cellulose nanoparticle (TCNF) suspensions, introducing carboxyl groups via TEMPO oxidation can enable cellulose materials to obtain good water solubility and a stable three-dimensional network structure, thereby providing an effective steric hindrance effect during drug crystallization.

[0023] The morphology and crystal form of sulfathiazole crystals differed significantly under different TCNF concentrations. At low TCNF concentrations (e.g., 0.1 wt%), sulfathiazole mainly formed hexagonal platy and prismatic crystals. With increasing TCNF concentration, the crystals gradually transformed into hexagonal crystals, and at a TCNF concentration of 1.0 wt%, sulfathiazole primarily formed uniform, regular hexagonal crystals, indicating that the steric hindrance effect of TCNF significantly regulated the crystal morphology.

[0024] X-ray powder diffraction (PXRD) results showed that the crystal forms induced by different concentrations of TCNF exhibited different diffraction peaks. Particularly at higher TCNF concentrations, the sulfathiazole crystal form primarily exhibited the characteristic peaks of crystal form III. Furthermore, Fourier transform infrared spectroscopy (FTIR) analysis indicated that in high-concentration TCNF solutions, the carboxyl and hydroxyl groups in the sulfathiazole crystals formed strong interactions with the cellulose material, which further stabilized the crystal structure of sulfathiazole.

[0025] The main advantages of this invention include:

[0026] 1. Wide range of applications

[0027] The method of this invention is applicable to the control of crystal form in a variety of drugs, and is particularly effective for drugs with polymorphism. Besides sulfathiazole, this invention can also be applied to other sulfonamide drugs with similar core structures or functional groups, achieving effective regulation of their crystal form through a similar method. Furthermore, the method of this invention can be extended to other drugs, especially those with similar chemical behaviors in terms of crystal form control, providing a highly versatile technical solution for the field of drug crystal form regulation.

[0028] 2. The process is simple and easy to implement.

[0029] The method of this invention is based on conventional drug preparation processes and is easy to implement in existing production lines. The polymer materials are inexpensive, the experimental operation is simple, and it has high prospects for industrial application.

[0030] 3. Environmentally friendly and biocompatible

[0031] TEMPO oxidized cellulose is an environmentally friendly material derived from natural cellulose, exhibiting excellent biocompatibility and degradability. This makes the material used in this invention not only environmentally friendly but also suitable for the pharmaceutical industry, meeting the requirements of green chemistry and biocompatible drug production.

[0032] 4. Reduce the uncertainty of crystal formation

[0033] This invention reduces uncertainties in the crystal formation process by using oxidized nanocellulose, enhancing the repeatability and consistency of crystal formation. By controlling the polymer concentration and the supersaturation of the drug solution, it ensures that the same crystal form results are obtained in each experiment or production run, thereby improving the consistency and quality control level of drug production.

[0034] In summary, this invention provides a method for controlling drug crystal form through polymer induction, which can effectively improve the solubility, stability and bioavailability of drugs, and is particularly suitable for the crystal form optimization and regulation of polymorphic drugs. Attached Figure Description

[0035] Figure 1 This is a schematic diagram of the sulfathiazole molecule and the structure of oxidized nanocellulose.

[0036] Figure 2 The images show the FTIR spectra of pulp and oxidized cellulose nanoparticles. Characteristic absorption peaks for both pulp and oxidized cellulose appear at 1050 cm⁻¹, 1630 cm⁻¹, 2920 cm⁻¹, and 3442 cm⁻¹, respectively, and are associated with OH stretching vibration and asymmetric CH stretching vibration. An absorption peak at 1728 cm⁻¹ was observed in the oxidized cellulose spectrum, representing the stretching vibration of the carboxyl group, indicating that the carboxyl group was successfully introduced into the oxidized cellulose nanoparticles. The carboxyl functional group influences the crystal nucleation and growth of sulfathiazole.

[0037] Figure 3 The diagram shows the three crystal forms of sulfathiazole crystallized under water cooling conditions.

[0038] Figure 4 The image shows the XRD pattern of sulfathiazole in water, which is a mixture of three crystal forms: II, III, and IV. Form II is square, form III is prismatic, and form IV is a flattened hexagonal.

[0039] Figure 5The experimental results show the effect of oxidized nanocellulose on the crystal form control of sulfathiazole at different concentrations. a) XRD patterns of sulfathiazole crystals formed in water, 0.1 wt% TCNF solution, 0.3 wt% TCNF solution, 0.5 wt% TCNF solution, and 1.0 wt% TCNF solution; b) Sulfathiazole crystals formed in 0.1 wt% TCNF solution; c) Sulfathiazole crystals formed in 0.3 wt% TCNF solution; d) Sulfathiazole crystals formed in 0.5 wt% TCNF solution; e) Sulfathiazole crystals formed in 1.0 wt% TCNF solution. Detailed Implementation

[0040] Example 1: Preparation of TEMPO-oxidized cellulose nanoparticles

[0041] 6 g of pulp was dispersed in 900 mL of water to form a suspension. 0.096 g of 2,2,6,6-tetramethylpiperidin-1-oxy (TEMPO) and 0.6 g of sodium bromide (NaBr) were added to this suspension, followed by slow addition of 40 mL of sodium hypochlorite solution (NaClO, 13%). The reaction was carried out at 25 °C with stirring for 4 hours. After the reaction, the reaction was terminated with ethanol, and the precipitate was washed with water until neutral to obtain a TEMPO-oxidized cellulose nanofiber (TCNF) suspension. The TCNF suspension was treated with ultrasound and concentrated to obtain a homogeneous 1 wt% TCNF solution.

[0042] A 1 wt% TCNF solution was diluted with water to obtain 0.1 wt%, 0.3 wt%, and 0.5 wt% TCNF solutions, respectively.

[0043] Example 2: Preparation and control of sulfathiazole crystal form (0.1 wt%, low concentration TCNF solution)

[0044] (1) TCNF-induced crystal formation

[0045] Add 20 mg of sulfathiazole (S = 4.85) to 16 mL of 0.1 wt% TCNF solution, stir evenly, and then place in an ice bath to cool to room temperature, allowing it to crystallize naturally.

[0046] (2) Crystal separation and drying

[0047] After crystallization for 12 hours, the crystals were separated using filter paper and washed with distilled water. The crystals were then vacuum-dried at 40°C for 24 hours to obtain sulfathiazole crystal samples. The results showed that under 0.1 wt% TCNF conditions, sulfathiazole crystals exhibited a plate-like or prismatic shape. Figure 5 As shown, it has crystal forms II, III, and IV.

[0048] Example 3: Preparation and control of sulfathiazole crystal form (0.3 wt%, low concentration TCNF solution)

[0049] (1) TCNF-induced crystal formation

[0050] Add 20 mg of sulfathiazole (S = 4.85) to 16 mL of 0.3 wt% TCNF solution, stir evenly, and then place in an ice bath to cool to room temperature, allowing it to crystallize naturally.

[0051] (2) Crystal separation and drying

[0052] After crystallization for 12 hours, the crystals were separated using filter paper and washed with distilled water. The crystals were then vacuum-dried at 40°C for 24 hours to obtain sulfathiazole crystal samples. The results showed that under 0.3 wt% TCNF conditions, sulfathiazole crystals exhibited a plate-like or prismatic shape. Figure 5 As shown, its composition is of the III crystal form.

[0053] Example 4: Preparation and control of sulfathiazole crystal form (0.5 wt%, medium concentration TCNF solution)

[0054] (1) TCNF-induced crystal formation

[0055] Add 20 mg of sulfathiazole (S = 4.85) to 16 mL of 0.5 wt% TCNF solution, stir evenly, and then place in an ice bath to cool to room temperature, allowing it to crystallize naturally.

[0056] (2) Crystal separation and drying

[0057] After crystallization, the crystals were separated using filter paper and washed repeatedly with distilled water. The crystals were then vacuum-dried at 40°C for 24 hours to obtain sulfathiazole crystal samples. The results showed that under 0.5 wt% TCNF conditions, the morphology of sulfathiazole crystals began to change to a hexagonal shape. Figure 5 As shown, its composition is of the III crystal form.

[0058] Example 5: Preparation and control of sulfathiazole crystal form (1.0 wt%, high concentration TCNF solution)

[0059] (1) TCNF-induced crystal formation

[0060] Add 20 mg of sulfathiazole (S = 4.85) to 16 mL of 1.0 wt% TCNF solution, stir evenly, and then place in an ice bath to cool and allow it to crystallize naturally.

[0061] (2) Crystal separation and drying

[0062] After crystallization, the crystals were separated using filter paper and washed repeatedly with distilled water. The crystals were then vacuum-dried at 40°C for 24 hours to obtain a hexagonal sulfathiazole crystal sample. Figure 5 As shown, its composition is of the III crystal form.

[0063] Results Analysis

[0064] Under 1.0 wt% TCNF conditions, the generated sulfathiazole crystals are mainly regular hexagonal crystals with large crystal size, showing high crystal uniformity and good structural stability.

[0065] Through multiple embodiments, this invention demonstrates that adjusting the TCNF concentration can effectively regulate the crystal formation and morphological changes of sulfathiazole. Under different TCNF concentrations, sulfathiazole crystals gradually transform from plate-like and prismatic shapes to hexagonal crystals, and the structural and morphological changes of the crystals are confirmed by PXRD, FTIR, and microscopic analysis. This provides a new technical approach for optimizing the crystal form of sulfathiazole.

Claims

1. The application of oxidized nanocellulose in regulating drug crystal form, characterized in that, The oxidized nanocellulose is prepared by the following method: the raw material of oxidized nanocellulose is dispersed in water, 2,2,6,6-tetramethylpiperidine-1-oxy, sodium bromide and sodium hypochlorite are added to react, ethanol is added to terminate the reaction, and the mixture is washed with water until neutral to obtain the product; the drug is sulfathiazole.

2. A method for regulating drug crystal form by oxidizing cellulose nanoparticles, characterized in that the steps include... include: The drug and oxidized cellulose nanoparticles are mixed in solution and crystallized. The drug is in a supersaturated state in the solution. By adjusting the concentration of oxidized cellulose nanomaterials, the nucleation and growth of drug crystals can be controlled. The oxidized nanocellulose is prepared by the following method: the raw material of oxidized nanocellulose is dispersed in water, 2,2,6,6-tetramethylpiperidin-1-oxy, sodium bromide and sodium hypochlorite are added to react, ethanol is added to terminate the reaction, and the mixture is washed with water until neutral to obtain the product; The drug in question is sulfathiazole.

3. The method for regulating drug crystal form by oxidizing cellulose nanoparticles according to claim 2, characterized in that, The oxidized cellulose nanomaterial solution is mixed with the drug and crystallized.

4. A method for regulating drug crystal form by oxidizing cellulose nanoparticles according to claim 2 or 3, characterized in that, The concentration of the oxidized cellulose nanomaterial is 0.1wt%-1wt%.

5. A method for regulating drug crystal form by oxidizing cellulose nanoparticles according to claim 2 or 3, characterized in that, The supersaturation S of the drug is 1-8.

6. A method for regulating drug crystal form by oxidizing cellulose nanoparticles according to claim 2 or 3, characterized in that, Crystallization is achieved through cooling in an ice bath.

7. A method for regulating drug crystal form by oxidizing cellulose nanoparticles according to claim 2 or 3, characterized in that, The raw materials for the oxidized nanocellulose include any one or any combination of pulp, cotton, wood, and rice straw.

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