A sorafenib co-amorphous drug and a preparation method and application thereof

Abstract

The application discloses a kind of sorafenib co-amorphous drug and its preparation method and application.Co-amorphous drug is made of active ingredient sorafenib and ligand according to 1:1 mole ratio;Ligand is selected from any one of L-phenylalanine, L-proline, L-arginine and indometacin;Sorafenib and ligand form single homogeneous amorphous structure by intermolecular interaction.By X-ray powder diffraction, differential scanning calorimetry and infrared spectroscopy, the results show that sorafenib and ligand form single homogeneous amorphous structure by intermolecular hydrogen bond interaction.Compared with sorafenib crystalline raw material and physical mixture, the application improves the equilibrium solubility and dissolution rate of sorafenib in physiological medium, and shows excellent physical stability, can effectively inhibit the recrystallization of drug during storage, provides a new preparation strategy for improving the oral bioavailability of sorafenib.

Description

Technical Field

[0001] This invention relates to sorafenib, and more particularly to a sorafenib co-amorphous drug with improved drug solubility and dissolution rate, its preparation method and application; belonging to the field of pharmaceutical technology. Background Technology

[0002] Sorafenib is an oral, multi-target tyrosine kinase inhibitor widely used clinically to treat malignant tumors such as hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer. However, sorafenib is classified as a Class II drug in the Biopharmaceutics Classification System (BCS), characterized by high permeability but extremely poor water solubility. Its extremely low saturated solubility and dissolution rate severely limit its oral bioavailability, thus hindering further improvement in its clinical therapeutic efficacy. To address the issues of poor water solubility and low bioavailability of sorafenib, existing technologies mainly focus on the following two approaches:

[0003] Chinese invention patent CN106699652A discloses a sorafenib α-aminobutyrate and its preparation method, representing existing salt-forming modification technology. This technology generates a crystalline salt by reacting sorafenib with α-aminobutyric acid in an acid-base reaction, aiming to achieve better water solubility and safety compared to commercially available sorafenib p-toluenesulfonate. However, this salt-forming modification technology requires a strict pKa difference between the drug and the ligand to form a stable ionic bond. These stringent physicochemical conditions greatly limit the range of safe ligands that can be selected. Moreover, like many salts (such as methanesulfonates and p-toluenesulfonates), this technology carries potential toxicity or genotoxicity risks. Most importantly, when the salt compound enters the complex pH environment of the gastrointestinal tract, it is prone to disproportionation reactions in vivo, causing the drug to recrystallize as a free base, thus significantly diminishing its solubility advantage and destabilizing it in vivo.

[0004] Chinese invention patent application CN118948847A discloses a solid dispersion containing sorafenib and its preparation method, representing existing polymer solid dispersion technology. The composition comprises sorafenib or a salt thereof, a binder (povidone K30), and a carrier (crosslinked povidone). A fluidized bed granulation and coating process is employed, utilizing the physical spatial barrier and adhesive effects of the polymer carrier to disperse the drug within a polymer network, aiming to improve the dissolution rate and dissolution stability of sorafenib. However, traditional polymer solid dispersions mainly rely on the macroscopic physical encapsulation of the carrier to inhibit crystallization, resulting in weak specific interactions between molecules. This leads to two problems with the technology: First, in order to maintain the amorphous state, a large amount of high molecular weight polymer carriers must be added, resulting in low drug loading, large final formulation volume and dosage, which seriously reduces patient compliance. Second, high molecular weight polymers (such as povidones) usually have strong hygroscopicity. In long-term storage, especially in humid and hot environments, the intrusion of moisture can act as a plasticizer, greatly increasing the migration ability of drug molecules, causing the amorphous drug to undergo rapid phase separation and recrystallization, which poses a great challenge to its physical stability. Summary of the Invention

[0005] To address the problems of poor water solubility, slow dissolution rate, low oral bioavailability, and insufficient physical stability of the amorphous system in existing sorafenib raw materials, this invention provides a sorafenib co-amorphous drug and its preparation method that significantly improves drug solubility and dissolution rate while ensuring excellent physical stability of the system through intermolecular interactions, effectively avoiding the recrystallization risk in the process of amorphous drug formulation. Furthermore, the preparation process is simple, environmentally friendly, and suitable for industrial production.

[0006] Another objective of this invention is to provide the application of the aforementioned sorafenib co-amorphous drug in the preparation of oral pharmaceutical formulations that improve the oral bioavailability of sorafenib, in order to solve the problems of insufficient absorption of existing oral sorafenib formulations and the tendency for recrystallization during storage, which affects the stability of the formulation.

[0007] To achieve the above objectives, the present invention is specifically implemented through the following technical solutions:

[0008] A sorafenib co-amorphous drug comprising the active ingredient sorafenib and a ligand; wherein the ligand is selected from any one of L-phenylalanine, L-proline, L-arginine and indomethacin; wherein sorafenib and the ligand form a single homogeneous amorphous structure through intermolecular interactions; and wherein the molar ratio of sorafenib to the ligand is 1:1.

[0009] To further achieve the purpose of this invention, preferably, the X-ray powder diffraction (PXRD) pattern of the amorphous drug does not contain sharp crystalline diffraction peaks of sorafenib and its ligand raw materials, but instead presents broad and diffuse amorphous diffraction peaks.

[0010] Preferably, the co-amorphous drug has a single glass transition temperature (Tg) in differential scanning calorimetry (DSC) analysis.

[0011] More preferably, when the ligand is L-phenylalanine, the Tg of the co-amorphous drug is 90.88°C; when the ligand is L-proline, the Tg of the co-amorphous drug is 87.65°C; when the ligand is L-arginine, the Tg of the co-amorphous drug is 91.20°C; and when the ligand is indomethacin, the Tg of the co-amorphous drug is 64.38°C.

[0012] The preparation method of the sorafenib co-amorphous drug is as follows: sorafenib and the ligand are mixed in a molar ratio of 1:1, placed in the ball mill jar of a planetary ball mill, and subjected to high-energy mechanical ball milling at room temperature, and the product is collected.

[0013] Preferably, the ball mill rotates at a speed of 350-450 rpm and the milling time is 150-210 minutes.

[0014] Preferably, the mass of sorafenib prepared in a single high-energy mechanical ball milling process is 200-500 mg.

[0015] The application of the aforementioned amorphous sorafenib in the preparation of oral pharmaceutical formulations that improve the oral bioavailability of sorafenib.

[0016] Preferably, the oral pharmaceutical preparation is an oral solid dosage form; the oral solid dosage form is selected from tablets, capsules, granules and powders.

[0017] Preferably, the oral solid dosage form comprises the sorafenib co-amorphous drug and pharmaceutically acceptable excipients, the excipients including one or more of fillers, disintegrants, glidants and lubricants; the oral solid dosage form is prepared by directly compressing, encapsulating or granulating the sorafenib co-amorphous drug with the excipients.

[0018] Compared with the prior art, the present invention has the following advantages and effects:

[0019] 1) The four ligands of this invention—L-phenylalanine, L-proline, L-arginine, and indomethacin—serve as co-formations for constructing amorphous drugs. Each ligand contains a carboxyl group (-COOH) as a strong hydrogen bond donor and acceptor group, serving as the core site for non-covalent intermolecular bonding. All four ligands can spontaneously form a strong and specific intermolecular heterogeneous hydrogen bond network with key sites in the sorafenib molecule, such as the significantly polar urea group (-NH-) and amide bond (-C=O). From a physicochemical perspective, this non-covalent crosslinking based on specific structural units completely disrupts the original crystal lattice network of sorafenib and synergistically increases the steric hindrance of the molecular conformation in the mixed system at the thermodynamic and kinetic levels, thereby effectively restricting the spatial migration and structural relaxation of high-energy amorphous drug molecules.

[0020] 2) This invention maintains the high-energy state and disordered characteristics of the amorphous phase, eliminating the lattice dissociation energy during the dissolution process and giving sorafenib a significantly enhanced rapid dissolution capability; the specific intermolecular interactions within the system of this invention reduce the free energy of the mixed system and increase the molecular migration barrier, synergistically suppressing the relaxation and transformation of the high-energy state at the thermodynamic and kinetic levels, suppressing the tendency of recrystallization, and exhibiting superior physical stability.

[0021] 3) The amorphous drug sorafenib of this invention uses endogenous amino acids or high-safety small molecules as ligands. It utilizes non-covalent intermolecular interaction forces to make the drug and ligands tightly bound. It can form a stable multi-component system without meeting the harsh acid-base salt formation conditions, breaking through the limitation of pKa difference value and fundamentally avoiding the potential toxicity and in vivo disproportionation risks of salt formation modification.

[0022] 4) The system of this invention does not rely on a large polymer carrier, but forms a single homogeneous structure at the molecular level through a strong hydrogen bond network between the drug and ligand, without the need to add an additional polymer carrier, effectively solving the problem of low drug loading in traditional polymer solid dispersions.

[0023] 5) This invention uses mechanical ball milling to prepare amorphous systems, which has the characteristics of green and environmentally friendly process, simple operation and good reproducibility, and is conducive to achieving rapid conversion and stable control of solid form.

[0024] 6) This invention significantly improves the poor solubility of sorafenib and achieves long-term physical stability of the amorphous phase, solving the problem that existing salt-forming modification and polymer solid dispersion technologies cannot simultaneously achieve high safety, high drug loading and excellent physical stability. Attached Figure Description

[0025] Figure 1 PXRD patterns of crystalline sorafenib, amorphous sorafenib, and four types of amorphous sorafenib prepared in Examples 1-12.

[0026] Figure 2 DSC chromatograms of amorphous sorafenib and the four amorphous sorafenib drugs prepared in Examples 1-4.

[0027] Figure 3 FTIR images of crystalline sorafenib, physical mixtures (PMs), and four amorphous sorafenib preparations prepared in Examples 1-4.

[0028] Figure 4 In vitro dissolution curves of crystalline sorafenib, amorphous sorafenib, and the four amorphous sorafenib drugs prepared in Examples 1-4 in phosphate buffer at pH 6.8.

[0029] Figure 5 A comparison of the equilibrium solubility of crystalline sorafenib, amorphous sorafenib, physical mixtures, and four types of amorphous sorafenib prepared in Examples 1-4.

[0030] Figure 6 PXRD diagrams of the physical stability of amorphous sorafenib (Comparative Example 2) and four amorphous sorafenib drugs prepared in Examples 1-4 under two drying conditions: 4℃ / 0% RH and 40℃ / 0% RH.

[0031] Figure 7 PXRD diagrams of the physical stability of amorphous sorafenib (Comparative Example 2) and four types of amorphous sorafenib prepared in Examples 1-4 under two humid heat conditions: 25°C / 60% RH and 40°C / 75% RH. Detailed Implementation

[0032] To better understand the present invention, the present invention will be further described below with reference to the embodiments. However, it should be noted that the scope of protection claimed by the present invention is not limited to the scope described in the following embodiments.

[0033] In recent years, co-amorphous drug technology has attracted widespread attention as an emerging solid-state modification strategy. Unlike traditional polymer solid dispersions, co-amorphous systems are single-phase homogeneous amorphous binary systems formed by the active pharmaceutical ingredient (API) and low molecular weight ligands through intermolecular interactions (such as hydrogen bonding and π-π stacking). This system can not only effectively maintain the amorphous high-energy state, significantly improving the apparent solubility and dissolution rate of poorly soluble drugs, but also effectively inhibit recrystallization of drugs during storage by utilizing strong intermolecular interactions, exhibiting excellent physical stability.

[0034] The active ingredient used in this invention is sorafenib, chemically named 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureo]phenoxy}-N2-methylpyridine-2-carboxamide. Its molecular formula is C2. 21 H 16 ClF3N4O3, with a molecular weight of 464.82 and CAS number 284461-73-0. It should be noted that the sorafenib used in the embodiments of this invention is in free base form, and its chemical structure is as follows:

[0035] Unlike the conventional approach of selecting ligands based on pharmacological activity or biological applications, this invention starts from the underlying logic of molecular structure and solid-state chemistry. It discovers that small molecules with specific physicochemical characteristics, as co-formers of amorphous systems, whether endogenous amino acids (L-phenylalanine, L-proline, L-arginine) or highly safe small molecule drugs (indomethacin), share a key technical feature in their molecular structure: they all contain abundant hydrogen bond donor and acceptor groups, especially carboxyl (-COOH) structural units that can serve as core bonding points. Based on this structural feature, these small molecules can act as highly efficient non-covalent ligands, utilizing their highly polar carboxyl groups and other active groups to spontaneously form a strong and specific intermolecular heterogeneous hydrogen bond network with key hydrogen bond sites such as the urea group (-NH-) and amide bond (-C=O) in the sorafenib molecule. These four ligands perform similar physicochemical functions in the system of this invention. They thoroughly disrupt the inherent lattice network of sorafenib through strong, specific non-covalent interactions and significantly increase the steric hindrance of molecular conformation in the mixed system. This synergistically restricts the spatial migration and structural relaxation of high-energy amorphous drug molecules at the thermodynamic and kinetic levels, ultimately achieving long-term physical stability of the amorphous phase of sorafenib. Therefore, the small molecules used as ligands in this invention not only avoid the potential toxicity and stringent pH conditions associated with traditional salt-forming modifications but also provide a material basis for constructing an efficient and stable sorafenib delivery system through a unified solid-state intermolecular interaction mechanism.

[0036] Therefore, the sorafenib co-amorphous drug provided by the present invention is composed of the active ingredient sorafenib and a ligand in a molar ratio of 1:1; the ligand is selected from any one of L-phenylalanine, L-proline, L-arginine and indomethacin; sorafenib and the ligand form a single homogeneous amorphous structure through intermolecular interactions.

[0037] Analysis of molecular structure characteristics and the formation rules of non-covalent interactions in solid-state systems reveals that sorafenib molecules possess significant steric hindrance. Its main hydrogen bond donor and acceptor sites, such as urea and amide groups, which participate in intermolecular interactions, exhibit specific spatial distribution characteristics. Under a 1:1 molar ratio, key binding groups (such as carboxyl groups) in the sorafenib molecule and ligand molecules are more conducive to achieving sufficient spatial matching and intermolecular interactions, thereby promoting the formation of heterogeneous hydrogen bond networks. This molar ratio helps reduce the amount of free components that do not fully participate in interactions, decreases the tendency for local component enrichment, phase separation, and recrystallization, and thus facilitates the formation of a homogeneous and stable single amorphous system.

[0038] This invention, through PXRD analysis, confirmed that the four co-amorphous drugs of this invention—sorafenib-L-phenylalanine, sorafenib-L-proline, sorafenib-L-arginine, and sorafenib-indomethacin—all formed a single amorphous phase. In the PXRD patterns, the sharp crystal diffraction peaks of sorafenib and the ligand active pharmaceutical ingredients completely disappeared, replaced by broad and diffuse amorphous diffraction peaks, indicating that the drugs and ligands achieved homogeneous mixing at the molecular level, and the crystal structure was completely destroyed.

[0039] This invention, through DSC analysis, confirmed that all four sorafenib co-amorphous drugs of this invention possess a single Tg, further demonstrating the formation of a single homogeneous system. For example, the Tg of the sorafenib-L-phenylalanine co-amorphous system is 90.88℃; the Tg of the sorafenib-L-proline co-amorphous system is 87.65℃; the Tg of the sorafenib-L-arginine co-amorphous system is 91.20℃; and the Tg of the sorafenib-indomethacin co-amorphous system is 64.38℃. These Tg values ​​are all significantly higher than room temperature, indicating that the system has high physical stability under room temperature storage.

[0040] This invention, through FTIR analysis, confirmed a significant intermolecular hydrogen bonding interaction between sorafenib and its ligand. Compared to the crystalline sorafenib raw material, the characteristic peaks of the -NH functional group of sorafenib (3301-3377 cm⁻¹) were observed in the infrared spectra of various co-amorphous systems. -1 (region) and characteristic peaks of the -C=O functional group (1649-1708 cm⁻¹) -1 Significant shifts, broadenings, or disappearances were observed in all regions. These spectroscopic changes indicate that a strong hydrogen bond network has formed between the hydrogen bond donor / acceptor groups of sorafenib and the corresponding groups of the ligands, which is the main driving force for maintaining the stability of the co-amorphous system.

[0041] This invention tested the in vitro dissolution performance of sorafenib co-amorphous drugs. In phosphate buffer at pH 6.8, all four co-amorphous systems exhibited a significant "spring-parachute" phenomenon. Compared to the extremely slow dissolution of crystalline sorafenib, the co-amorphous systems of this invention achieved higher drug concentrations in the initial stage (0-4 minutes). The highest concentrations in the sorafenib-indomethacin and sorafenib-L-phenylalanine co-amorphous systems reached 110-120 μg / mL, significantly improving the drug dissolution rate.

[0042] This invention tested the equilibrium solubility of the aforementioned sorafenib co-amorphous drugs. The test results showed that, compared to sorafenib crystals (approximately 14.0 μg / mL) and their physical mixtures, the co-amorphous system of this invention significantly improved the equilibrium solubility. The sorafenib-indomethacin co-amorphous system exhibited the highest equilibrium solubility, reaching approximately 57.6 μg / mL; the sorafenib-phenylalanine co-amorphous system achieved an equilibrium solubility of approximately 33.10 μg / mL.

[0043] This invention also tested the physical stability of the sorafenib co-amorphous drug. The test results showed that the co-amorphous system of this invention exhibited good physical stability under low-temperature and high-temperature drying conditions (4°C or 40°C, 0% RH). Except for slight crystallization in a few systems under long-term high-temperature storage, it remained completely amorphous after six months of storage. Particularly noteworthy is that under more challenging humid and hot conditions, the sorafenib-L-phenylalanine and sorafenib-indomethacin co-amorphous systems of this invention demonstrated excellent resistance to hygroscopic recrystallization. After six months of storage under high-humidity test conditions (25°C / 60% RH) and three months of storage under high-temperature and high-humidity test conditions (40°C / 75% RH), both systems still showed broad and diffuse amorphous characteristics in their X-ray powder diffraction patterns, with no detected crystal diffraction peaks. Their stability was significantly better than that of the co-amorphous system composed of amorphous sorafenib active pharmaceutical ingredient and other ligands.

[0044] This invention employs mechanical ball milling to prepare amorphous systems, which features a green and environmentally friendly process, simple operation, and good reproducibility, facilitating rapid conversion and stable control of solid-state forms. The preferred process parameters for mechanical ball milling are: a milling speed of 350-450 rpm and a milling time of 150-210 minutes. More preferably, the milling speed is 400 rpm and the milling time is 180 minutes.

[0045] Example 1

[0046] Preparation of the sorafenib-L-phenylalanine co-amorphous drug. The active ingredient sorafenib and the ligand L-phenylalanine were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature. The milling speed was set to 400 rpm, and the milling time was 180 minutes. After milling, the powder sample was collected to obtain the sorafenib-phenylalanine co-amorphous drug. The obtained sample was passed through a 100-mesh sieve (150 µm) and stored in a desiccator at room temperature for later use.

[0047] Example 2

[0048] Preparation of the sorafenib-L-proline co-amorphous drug. The active ingredient sorafenib and the ligand L-proline were weighed and mixed at a molar ratio of 1:1, and the mixture was prepared according to the ball milling conditions described in Example 1 (400 rpm, 180 minutes). The powder sample was collected to obtain the sorafenib-proline co-amorphous drug.

[0049] Example 3

[0050] Preparation of the sorafenib-L-arginine co-amorphous drug. The active ingredient sorafenib and the ligand L-arginine were weighed and mixed at a molar ratio of 1:1, and the mixture was prepared according to the ball milling conditions described in Example 1 (400 rpm, 180 minutes). The powder sample was collected to obtain the sorafenib-arginine co-amorphous drug.

[0051] Example 4

[0052] Preparation of the sorafenib-indomethacin co-amorphous drug. The active ingredient sorafenib and the ligand indomethacin were weighed and mixed at a molar ratio of 1:1. The mixture was then ball-milled under the conditions described in Example 1 (400 rpm, 180 minutes). The powder sample was collected to obtain the sorafenib-indomethacin co-amorphous drug.

[0053] Example 5

[0054] Preparation of the sorafenib-L-phenylalanine co-amorphous drug. The active ingredient sorafenib and the ligand L-phenylalanine were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature at 350 rpm for 150 minutes. After milling, the powder sample was collected to obtain the sorafenib-phenylalanine co-amorphous drug.

[0055] Example 6

[0056] Preparation of the sorafenib-L-proline co-amorphous drug. The active ingredient sorafenib and the ligand L-proline were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature at 350 rpm for 150 minutes. After milling, the powder sample was collected to obtain the sorafenib-proline co-amorphous drug.

[0057] Example 7

[0058] Preparation of the sorafenib-L-arginine co-amorphous drug: The active ingredient sorafenib and the ligand L-arginine were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature at 350 rpm for 150 minutes. After milling, the powder sample was collected to obtain the sorafenib-arginine co-amorphous drug.

[0059] Example 8

[0060] Preparation of the sorafenib-indomethacin co-amorphous drug: The active ingredient sorafenib and the ligand indomethacin were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the grinding jar of a planetary ball mill and ground at room temperature at 350 rpm for 150 minutes. After grinding, the powder sample was collected to obtain the sorafenib-indomethacin co-amorphous drug.

[0061] Example 9

[0062] Preparation of the sorafenib-L-phenylalanine co-amorphous drug. The active ingredient sorafenib and the ligand L-phenylalanine were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature at 450 rpm for 210 minutes. After milling, the powder sample was collected to obtain the sorafenib-phenylalanine co-amorphous drug.

[0063] Example 10

[0064] Preparation of the sorafenib-L-proline co-amorphous drug. The active ingredient sorafenib and the ligand L-proline were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the grinding jar of a planetary ball mill and ground at room temperature at 450 rpm for 210 minutes. After grinding, the powder sample was collected to obtain the sorafenib-proline co-amorphous drug.

[0065] Example 11

[0066] Preparation of the sorafenib-L-arginine co-amorphous drug. The active ingredient sorafenib and the ligand L-arginine were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the grinding jar of a planetary ball mill and ground at room temperature at 450 rpm for 210 minutes. After grinding, the powder sample was collected to obtain the sorafenib-arginine co-amorphous drug.

[0067] Example 12

[0068] Preparation of the sorafenib-indomethacin co-amorphous drug: The active ingredient sorafenib and the ligand indomethacin were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the grinding jar of a planetary ball mill and ground at room temperature at 450 rpm for 210 minutes. After grinding, the powder sample was collected to obtain the sorafenib-indomethacin co-amorphous drug.

[0069] Comparative Example 1

[0070] Sorafenib crystal raw material: Commercially available sorafenib raw material is used directly, which is in a stable crystal form.

[0071] Comparative Example 2

[0072] Sorafenib amorphous material: Weigh pure sorafenib raw material without adding any ligands, place it in a ball mill jar, and grind it under the same conditions as described in Example 1 (400 rpm, 180 minutes) to prepare pure sorafenib amorphous material.

[0073] Comparative Example 3

[0074] Physical mixtures: Sorafenib was weighed separately from L-phenylalanine, L-proline, L-arginine, and indomethacin, and placed in a mortar at a molar ratio of 1:1. The mixtures were then gently ground for several minutes to achieve a simple physical mixture, resulting in sorafenib-phenylalanine physical mixture, sorafenib-proline physical mixture, sorafenib-arginine physical mixture, and sorafenib-indomethacin physical mixture.

[0075] Comparative Example 4

[0076] Based on the salt-forming modification technology of existing technology CN106699652A, sorafenib α-aminobutyrate crystals were prepared according to the method of Example 1 in Chinese invention patent application CN106699652A. Sorafenib, α-aminobutyric acid, ethanol, and water were mixed and heated to 80°C for reaction and crystallization. The mixture was then cooled to 10°C to allow full crystal precipitation. The crystal slurry was filtered and dried to obtain the sorafenib α-aminobutyrate product.

[0077] Comparative Example 5

[0078] Based on the existing polymer solid dispersion technology (CN118948847A), a polymer solid dispersion containing sorafenib is prepared by dissolving 100 mg of sorafenib and 200 mg of the binder povidone K30 in a methanol-dichloromethane mixture (volume ratio 1:3, solid material to mixed solvent weight ratio 1:10) to form a drug-containing solution. Subsequently, at an inlet air temperature of 60-70°C, the solution is sprayed into a powder bed of 200 mg crosslinked povidone powder using a fluidized bed granulator. Finally, the solvent is removed in the fluidized bed, and the mixture is dried with circulating air to obtain the sorafenib solid dispersion.

[0079] The performance characterization and test results are as follows:

[0080] PXRD analysis: The samples were characterized using X-ray powder diffraction. For example... Figure 1 As shown, the sorafenib crystalline raw material in Comparative Example 1 exhibits sharp characteristic crystallization diffraction peaks. The four sorafenib co-amorphous drugs prepared in Examples 1-4, as well as the pure sorafenib amorphous product (also known as amorphous sorafenib) in Comparative Example 2, did not show the sharp diffraction peaks of the raw material in their spectra; instead, they exhibited typical broad, diffuse "bun peaks" (amorphous halos). This indicates that through mechanical ball milling, sorafenib and its ligands have been completely converted into an amorphous state, forming a single homogeneous co-amorphous system.

[0081] DSC analysis: The thermal properties of the samples were tested using a differential scanning calorimeter. For example... Figure 2 As shown, the four co-amorphous drugs prepared in Examples 1-4 all exhibited only a single Tg on the DSC curves, and no melting endothermic peaks were observed for each component. This indicates that sorafenib and its ligands formed a single-phase co-amorphous system with good intermolecular miscibility. Figure 2 As shown, the specific measured Tg values ​​are as follows:

[0082] Example 1 (sorafenib-L-phenylalanine): glass transition occurred at 90.88°C;

[0083] Example 2 (sorafenib-L-proline): glass transition occurred at 87.65°C;

[0084] Example 3 (sorafenib-L-arginine): glass transition occurred at 91.20°C;

[0085] Example 4 (sorafenib-indomethacin): glass transition occurred at 64.38°C;

[0086] Comparative Example 2 (amorphous sorafenib): underwent a glass transition at 71.01℃.

[0087] FTIR analysis: Infrared spectroscopy was used to characterize the intermolecular interactions of the sample. Figure 3 Each sample group includes two FTIR spectra for comparison: the physical mixture (PM) corresponding to Comparative Example 3 and the co-amorphous samples obtained in Examples 1 to 4. The FTIR spectra of sorafenib crystal raw material are also listed as a reference. Spectra marked "PM" represent the physical mixture of sorafenib and its corresponding ligand prepared according to the method described in Comparative Example 3, while spectra not marked "PM" represent the corresponding co-amorphous samples prepared in Examples 1 to 4. Comparative Example 3 was set up as a physical mixture control to distinguish the differences in intermolecular interactions between simple physical mixing and the co-amorphous system formed by mechanical ball milling. Figure 3 As can be seen, the infrared spectra of each physical mixture in Comparative Example 3 are basically a simple superposition of the spectra of sorafenib crystalline raw material and the corresponding ligands, and the positions of the absorption peaks of the key characteristic functional groups of sorafenib have not changed significantly. In contrast, the absorption peaks of the relevant characteristic functional groups in the co-amorphous samples obtained in Examples 1 to 4 show obvious shifts, broadening or partial disappearance, indicating that intermolecular hydrogen bonding has formed between sorafenib and the corresponding ligands.

[0088] Example 1 (Sorafenib-Phenylalanine Co-amorphous Drug): The characteristic NH peak of sorafenib (mainly derived from urea and amide bonds) shifted and significantly broadened to 3373, 3334, and 3296 cm⁻¹. -1 The carbonyl (C=O) peak shifted to 1703 and 1645 cm⁻¹. -1 .

[0089] Example 2 (Sorafenib-proline co-amorphous drug): The characteristic NH peak of sorafenib shifted to 3336, 3305, and 3292 cm⁻¹. -1 Furthermore, most of the characteristic peaks disappeared; the carbonyl peak red-shifted to 1635 cm⁻¹. -1 And broaden.

[0090] Example 3 (Sorafenib-arginine co-amorphous drug): The NH characteristic peak broadened significantly until it disappeared, and the carbonyl peak shifted to 1670 and 1593 cm⁻¹. -1 .

[0091] Example 4 (Sorafenib-Indomethacin co-amorphous drugs): N - The H characteristic peak broadens significantly until it disappears, and the carbonyl peak red-shifts to 1683 cm⁻¹. -1 .

[0092] Figure 3 The results confirmed that sorafenib’s hydrogen bond donors (NH in urea and amide bonds) and acceptors (carbonyl groups) formed intermolecular hydrogen bonds with corresponding groups (such as carboxyl and hydroxyl groups) in the ligand molecules.

[0093] FTIR analysis showed that the co-amorphous systems of Examples 1 to 4 exhibited a high degree of consistency in spectroscopic behavior. The key hydrogen bond binding sites of sorafenib (NH and carbonyl groups in urea and amide bonds) all showed significant shifts or broadenings in the same pattern, further confirming that the four ligands acted through the same physicochemical mechanism, namely, using strong hydrogen bond donor and acceptor groups such as carboxyl groups (-COOH) as the core sites for non-covalent intermolecular bonding, spontaneously forming a specific heterogeneous hydrogen bond network with sorafenib.

[0094] like Figure 3 As shown, the infrared spectra of the four physical mixtures in Comparative Example 3 are essentially simple linear superpositions of the spectra of sorafenib crystals and the active pharmaceutical ingredients of each ligand, with no significant changes in the positions of the key characteristic peaks of sorafenib. This indicates that no new intermolecular interactions are generated between the drug and the ligands under simple physical mixing conditions. In contrast, the significant shifts or broadening of the characteristic peaks in Examples 1 to 4 demonstrate that the present invention has successfully constructed a specific heterogeneous hydrogen bond network at the molecular level.

[0095] In vitro dissolution test: Using phosphate buffer (containing 0.5% sodium dodecyl sulfate) at pH 6.8 as the dissolution medium, the in vitro dissolution curve of the sample was determined. Figure 4 As shown, Comparative Example 1 (sorafenib crystal raw material) exhibited an extremely slow dissolution rate. In contrast, the co-amorphous drugs of Examples 1 to 4 exhibited a significant "spring-parachute" phenomenon. Within the first 4 minutes of dissolution, Examples 1 (sorafenib-phenylalanine) and Example 4 (sorafenib-indomethacin) rapidly reached peak concentrations, with peak concentrations of approximately 110-120 µg / mL; Examples 2 and 3 also showed much higher initial dissolution rates than the sorafenib crystal raw material. Throughout the 300-minute test period, Figure 4 The results showed that the drug concentrations of all co-amorphous drugs were consistently significantly higher than those of sorafenib crystal raw material.

[0096] Equilibrium solubility test: The equilibrium solubility in pH 6.8 phosphate buffer at 37°C was determined after 24 hours. For example... Figure 5 As shown, the co-amorphous drug of the present invention significantly improves the equilibrium solubility of sorafenib, and its solubilizing effect is significantly better than that of the corresponding physical mixture in Comparative Example 3. Specific measurement results are as follows:

[0097] Comparative Example 1 (Sorafenib crystal raw material): Solubility is approximately 13.93 µg / mL;

[0098] Comparative Example 2 (amorphous sorafenib): solubility approximately 22.42 µg / mL;

[0099] Example 1 (sorafenib-phenylalanine co-amorphous drug): solubility was 33.10 µg / mL (approximately 2.3 times higher than the 14.26 µg / mL of the phenylalanine physical mixture in Comparative Example 3).

[0100] Example 2 (Sorafenib-proline co-amorphous drug): Solubility was 23.33 µg / mL; (approximately 1.7 times higher than the 13.92 µg / mL of the proline physical mixture in Comparative Example 3).

[0101] Example 3 (Sorafenib-arginine co-amorphous drug): Solubility was 30.41 µg / mL (approximately 2.8 times higher than the 10.69 µg / mL of the physical mixture of arginine in Comparative Example 3).

[0102] Example 4 (sorafenib-indomethacin co-amorphous drug): solubility was 57.60 µg / mL (approximately 4.0 times higher than the 14.36 µg / mL of the indomethacin physical mixture in Comparative Example 3).

[0103] As can be seen from the above data, the equilibrium solubility of the four physical mixtures in Comparative Example 3 (10.69~14.36 µg / mL) is basically the same as that of sorafenib crystal raw material (13.93 µg / mL), which proves that simple physical mixing cannot bring solubilization benefits. However, the solubility of the co-amorphous systems in Examples 1 to 4 showed a significant leap, which fully demonstrates that the solubilization effect of the present invention does not stem from simple physical solubilization by the ligands, but rather from the complete destruction of the drug lattice and the formation of a high-energy amorphous structure in the system of the present invention.

[0104] Physical stability test: The samples prepared in Examples 1 to 4 and Comparative Example 2 (amorphous sorafenib) were stored for 6 months under low temperature drying (4℃ / 0% RH), high temperature drying (40℃ / 0% RH), high humidity conditions (25℃ / 60% RH), and high temperature and high humidity conditions (40℃ / 75% RH), respectively. Samples were taken periodically for X-ray powder diffraction to examine the physical stability of the samples under different storage conditions.

[0105] Figure 6 The PXRD results of amorphous sorafenib (Comparative Example 2) and the co-amorphous sorafenib drugs obtained in Examples 1 to 4 are shown under drying conditions. Figure 6 The leftmost image shows the spectra stored at 0 days and 6 minutes under 4℃ / 0% RH conditions. Figure 6The right side of the image shows the spectra after 0 days and 6 minutes of storage at 40℃ / 0% RH. The topmost label, "Amorphous Sorafenib," represents the pure amorphous sorafenib obtained in Comparative Example 2, serving as a ligand-free single-component amorphous control. The groups below it represent binary co-amorphous systems formed by sorafenib and different ligands from Examples 1 to 4. Figure 6 As can be seen, amorphous sorafenib (Comparative Example 2) and samples from Examples 1 to 4 all exhibited broad, diffuse diffraction peaks in their initial state, indicating that all samples were in an amorphous state. Under 4℃ / 0% RH conditions, all samples maintained their amorphous characteristics during the 6-month storage period. Under 40℃ / 0% RH conditions, except for the sorafenib-proline co-amorphous system which showed crystallization diffraction peaks after 6 months of storage, the other samples mainly maintained broad, diffuse amorphous peaks. The above results indicate that... Figure 6 The main difference between the topmost sample and the products of Examples 1 to 4 lies in the different system composition. The former is a single-component amorphous sorafenib control, while the latter is a binary co-amorphous system formed after the introduction of different ligands. The purpose of setting up this control is to compare the effect of the introduction of co-formed compounds on the physical stability of the amorphous form of sorafenib under dry storage conditions.

[0106] Figure 7 The PXRD results of amorphous sorafenib (Comparative Example 2) and the co-amorphous sorafenib drugs obtained in Examples 1 to 4 are shown under humid heat conditions. Figure 7 The spectrum on the left side of the middle image is under the condition of 25℃ / 60% RH. Figure 7 The spectrum on the right side of the image is under conditions of 40℃ / 75% RH. The topmost label, "Amorphous Sorafenib," represents the pure amorphous sorafenib obtained in Comparative Example 2, serving as a ligand-free single-component amorphous control. The groups below it represent binary co-amorphous systems formed by sorafenib obtained in Examples 1 to 4 with different ligands. Figure 7 It is evident that, compared to dry conditions, the systems exhibit more significant differences in physical stability under humid and hot conditions. Amorphous sorafenib (Comparative Example 2) and the sorafenib-proline co-amorphous system are more prone to crystallization transformation; while the sorafenib-L-phenylalanine system and the sorafenib-indomethacin system demonstrate superior physical stability. After 6 months of storage at 25℃ / 60% RH, their PXRD patterns still primarily show broad, diffuse peaks, and after 3 months of storage at 40℃ / 75% RH, they retain their amorphous characteristics, with only partial crystallization signals detected after 6 months of storage. These results indicate that... Figure 7 The main difference between the topmost sample and the products of Examples 1 to 4 is that the system composition is different. The former is a single-component amorphous sorafenib control, while the latter is a binary co-amorphous system formed after the introduction of different ligands. The purpose of setting up this control is to compare the effect of the introduction of co-formed compounds on the physical stability of the amorphous form of sorafenib under humid and hot storage conditions.

[0107] comprehensive Figure 6 and Figure 7 It is known that the sorafenib co-amorphous system constructed in this invention can inhibit drug recrystallization to varying degrees under different storage conditions. Among them, the system with L-phenylalanine and indomethacin as co-formants has relatively better anti-recrystallization ability and long-term storage stability.

[0108] In Examples 5-12, the ball milling speed and ball milling time of sorafenib and the co-formed product were adjusted respectively. Figure 1 PXRD characterization results showed that the samples obtained in Examples 5-12 generally exhibited similar diffraction characteristics to those in Examples 1-4, with diffuse peaks dominating and no obvious crystalline characteristic peaks observed. This indicates that within the ratio and process parameters defined in this invention, sorafenib and the co-formed products can form a co-amorphous system. These results further demonstrate that the method of this invention has good repeatability and process applicability.

[0109] As can be seen from the test results of Examples 1 to 12 and Comparative Examples 1 to 5, the present invention overcomes the technical difficulties existing in the existing sorafenib solid modification technologies, including salt-forming modification and polymer solid dispersions. It effectively solves the technical contradiction of difficulty in achieving both high solubility and high physical stability, the problem of large drug volume caused by low drug loading, and the risk of failure due to pH-dependent disproportionation in vivo.

[0110] Compared with existing "salt-forming modification technology" (Comparative Example 4), the present invention has the following characteristics:

[0111] 1) The fundamental difference in the degree of solubility increase:

[0112] While Comparative Example 4 improved solubility through salt formation, it was dependent on a specific pH environment. According to the description of Comparative Example 4, the equilibrium solubility of the prepared sorafenib α-aminobutyrate was only 19.3 μg / mL in strongly acidic simulated gastric juice (pH 1.0), the environment most favorable for its solubility. In contrast, Example 4 of this invention (the sorafenib-indomethacin co-amorphous system) achieved an equilibrium solubility as high as 57.6 μg / mL in neutral physiological medium (pH 6.8), the environment where the drug is least soluble. Even in the neutral intestinal environment where the drug is least soluble, the solubility of the system of this invention is nearly three times that of existing salt formation techniques in the most soluble acidic environment (pH 1.0). This indicates that the solubilizing effect brought about by the disruption of lattice energy through the co-amorphization strategy of this invention is significantly superior to simple ionic bond salt formation modification.

[0113] 2) Avoid the risk of disproportionation in the body:

[0114] Comparative Example 4, upon entering the neutral intestinal environment (pH 6.8), readily undergoes a disproportionation reaction due to pH changes, leading to the precipitation of free alkali and thus the loss of its solubility advantage. In contrast, the co-amorphous system of this invention utilizes a "spring-parachute" effect, maintaining a supersaturated state for an extended period in a pH 6.8 medium (e.g., Figure 4 As shown in the figure, it effectively overcomes the problem of pH-dependent solubility drop.

[0115] Compared with existing "polymer solid dispersion technology" (Comparative Example 5), the present invention has the following characteristics:

[0116] 1) Significant advantages in drug loading capacity and administration volume:

[0117] Comparative Example 5, in maintaining its amorphous state, heavily relies on the spatial barrier effect of the polymer carrier, resulting in a significantly low drug loading. According to the formulation of Example 1 in the comparative document (100 mg sorafenib, 200 mg crospovidone, 200 mg povidone K30), its drug loading is only 20%, meaning that patients need to take a bulky formulation to achieve the therapeutic dose, severely reducing compliance. In contrast, the present invention eliminates the dependence on a large polymer carrier by tightly binding the drug to the small molecule ligand through intermolecular forces. Taking Example 1 as an example, the two are combined in a 1:1 molar ratio, and the calculated drug loading is as high as approximately 73.8% (based on the molecular weight of sorafenib 464.82 and the molecular weight of L-phenylalanine 165.19). At the same effective dose, the formulation volume of the present invention is only about one-third of the comparative technology, significantly improving patient compliance.

[0118] 2) Physical stability mechanism and moisture resistance:

[0119] Comparative Example 5 primarily relied on the physical steric hindrance of povidone polymers (PVP K30 and cross-linked povidone) to inhibit crystallization. However, these polymers are highly hygroscopic, easily absorbing water during storage, leading to a decrease in the system's Tg, which in turn triggers drug molecule migration and recrystallization. In contrast, this invention abandons the highly hygroscopic polymer barrier strategy and instead induces the spontaneous formation of a specific intermolecular hydrogen bond network between the drug and ligands through mechanical ball milling. This strong intermolecular interaction significantly restricts the migration barrier of drug molecules at the molecular level. Therefore, even under extremely challenging high temperature and high humidity conditions (40℃ / 75% RH), this invention still exhibits excellent resistance to hygroscopic recrystallization, and its long-term storage stability is significantly better than that of highly hygroscopic polymer solid dispersions.

[0120] 3) The green and environmentally friendly nature of the preparation process:

[0121] In terms of preparation process, Comparative Example 5 typically relies on complex fluidized bed equipment and requires the use of toxic organic solvents such as methanol-dichloromethane, facing serious risks of solvent residue and environmental pollution. This invention employs a room-temperature dry mechanical ball milling process, utilizing pure mechanical energy to break the crystal lattice, achieving solvent-free green manufacturing, completely avoiding the problem of organic solvent residue, and significantly improving the safety of the production process while reducing environmental costs.

[0122] Compared with the simple physical mixing of Comparative Example 3, the present invention has the following characteristics:

[0123] 1) Crystal structure disruption and molecular-level mixing:

[0124] The low-energy milling in Comparative Example 3 only brought sorafenib and its ligand into contact at the macroscopic particle scale, without disrupting their original crystal lattices, thus resulting in a simple physical mixture. In contrast, the high-energy mechanical ball milling process employed in this invention generates intense impact and shear forces that completely break down the original crystal lattices of both sorafenib and its ligand raw materials. Under this high-energy state, the drug and ligand are forced into a homogeneous mixture at the molecular level.

[0125] 2) The establishment of strong intermolecular interactions:

[0126] After completely disrupting the crystal lattice and achieving molecular-level contact, the method of this invention induces the spontaneous formation of a strong intermolecular hydrogen bond network between the hydrogen bond donor and acceptor groups of sorafenib and the corresponding groups in the ligand molecules. This intermolecular interaction, induced by high-energy mechanical processes, is the main driving force for maintaining the monolithic homogeneity and high physical stability of the co-amorphous system. This is confirmed by the significant shift or broadening of characteristic peaks in the FTIR results, while the physical mixture of Comparative Example 3 did not exhibit such significant spectroscopic changes in intermolecular interactions.

[0127] PXRD characterization results show that the samples from Examples 5-12, prepared using different process parameters, all exhibit typical broadly diffuse amorphous characteristics. This objectively confirms that the original crystalline lattice of sorafenib has been effectively destroyed. Since the core thermodynamic mechanism of solubilization in a co-amorphous system lies in eliminating the lattice dissociation energy during drug dissolution, Examples 5-12, which are completely transformed into an amorphous phase, also possess the physicochemical basis to overcome the dissolution rate limitations of poorly soluble drugs, thus producing a superior solubilization effect compared to sorafenib crystalline raw material.

[0128] This invention relates to the amorphous drug form of sorafenib, which can be used to prepare oral pharmaceutical formulations that improve the oral bioavailability of sorafenib. Oral pharmaceutical formulations refer to pharmaceutical formulations administered orally, including types such as oral solid dosage forms and oral liquid dosage forms; this invention preferably uses oral solid dosage forms. Oral solid dosage forms are selected from tablets, capsules, granules, or powders. Oral solid dosage forms contain the amorphous drug form of sorafenib and pharmaceutically acceptable excipients, including one or more of fillers, disintegrants, flow aids, and lubricants; wherein, the filler can be selected from one or more of lactose, mannitol, microcrystalline cellulose, starch, or pregelatinized starch; the disintegrant can be selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, or low-substituted hydroxypropyl cellulose; the flow aid can be selected from one or more of colloidal silica or talc; and the lubricant can be selected from one or more of magnesium stearate, calcium stearate, sodium stearate fumarate, or polyethylene glycol.

[0129] Oral solid dosage forms are prepared by directly compressing, encapsulating, or granulating a mixture of sorafenib co-amorphous drug and excipients. Compared with existing oral sorafenib formulations, the oral solid dosage form of sorafenib prepared in this invention can improve the oral administration performance of sorafenib by utilizing its higher solubility and dissolution rate, and inhibit phase separation or recrystallization during storage by leveraging its better physical stability. This helps to improve the quality stability and dosing consistency of the formulation, and solves the problems of slow dissolution, insufficient absorption, and poor stability of existing oral sorafenib formulations.

[0130] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A sorafenib co-amorphous drug, characterized in that, The co-amorphous drug is composed of the active ingredient sorafenib and a ligand; the ligand is selected from any one of L-phenylalanine, L-proline, L-arginine and indomethacin; the sorafenib and the ligand form a single homogeneous amorphous structure through intermolecular interactions; the molar ratio of sorafenib to the ligand is 1:

1.

2. The sorafenib co-amorphous drug according to claim 1, characterized in that, The X-ray powder diffraction pattern of the amorphous drug does not show sharp crystalline diffraction peaks of sorafenib and its ligand raw materials, but rather broad and diffuse amorphous diffraction peaks.

3. The sorafenib co-amorphous drug according to claim 1, characterized in that, The co-amorphous drug has a single glass transition temperature Tg in differential scanning calorimetry.

4. The sorafenib co-amorphous drug according to claim 3, characterized in that, When the ligand is L-phenylalanine, the Tg of the coamorphous drug is 90.88℃; when the ligand is L-proline, the Tg of the coamorphous drug is 87.65℃; when the ligand is L-arginine, the Tg of the coamorphous drug is 91.20℃; and when the ligand is indomethacin, the Tg of the coamorphous drug is 64.38℃.

5. The method for preparing sorafenib co-amorphous drug according to any one of claims 1 to 4, characterized in that, Sorafenib was mixed with the ligand at a molar ratio of 1:1 and placed in the ball mill jar of a planetary ball mill. The mixture was subjected to high-energy mechanical ball milling at room temperature, and the product was collected.

6. The method for preparing sorafenib co-amorphous drug according to claim 5, characterized in that, The ball mill operates at a speed of 350-450 rpm for 150-210 minutes.

7. The method for preparing sorafenib co-amorphous drug according to claim 5, characterized in that, The mass of sorafenib prepared in a single high-energy mechanical ball milling process is 200-500 mg.

8. The use of the sorafenib co-amorphous drug according to any one of claims 1 to 4 in the preparation of oral pharmaceutical formulations that improve the oral bioavailability of sorafenib.

9. The use of the sorafenib co-amorphous drug according to claim 8 in the preparation of oral pharmaceutical formulations with improved oral bioavailability of sorafenib, characterized in that, The oral pharmaceutical preparation is an oral solid dosage form; the oral solid dosage form is selected from one of tablets, capsules, granules and powders.

10. The use of the sorafenib co-amorphous drug according to claim 8 in the preparation of oral pharmaceutical formulations with improved oral bioavailability of sorafenib, characterized in that, The oral solid dosage form comprises the sorafenib co-amorphous drug and pharmaceutically acceptable excipients; the excipients include one or more of fillers, disintegrants, glidants and lubricants; the oral solid dosage form is prepared by directly compressing, encapsulating or granulating the sorafenib co-amorphous drug with the excipients.

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