Anhydrous crystalline form of pheniramine glucuronate and process for its preparation

Abstract

This invention belongs to the field of pharmaceutical crystal form technology, specifically relating to an anhydrous crystal form of bengalantamine gluconate and its preparation method. The anhydrous crystal form of bengalantamine gluconate provided by this invention exhibits main peaks at 10.28, 10.61, 14.92, 16.38, and 22.21 degrees 2-θ (±0.2) in powder X-ray diffraction patterns. When evaluated by DSC and TGA, the weight loss of the anhydrous crystal form before melting is <0.5%. The water content of the anhydrous crystal form is <0.5% according to Karl Fischer titration. This novel anhydrous crystal form of bengalantamine gluconate possesses excellent stability, solubility, and high purity, which is more beneficial for the processing, storage, and transportation of downstream pharmaceutical formulations. Furthermore, the preparation method is simple to operate, has a high yield, and uses an environmentally friendly solvent system, making it suitable for scale-up production.

Description

Technical Field

[0001] This invention specifically relates to an anhydrous crystal form of benzalkonium gluconate and its preparation method, belonging to the field of pharmaceutical crystal form technology. Background Technology

[0002] Alzheimer's disease is a progressive neurodegenerative disease characterized by cognitive decline, memory loss, and impairment of daily living abilities. Acetylcholinesterase inhibitors are currently one of the first-line drugs for the treatment of mild to moderate Alzheimer's disease.

[0003] Galantamine is a classic acetylcholinesterase inhibitor. Extensive clinical data on its efficacy and safety have been accumulated, demonstrating its activity on multiple brain receptors, anti-inflammatory effects, and association with improved memory and attention, as well as a significant reduction in mortality risk. Among acetylcholinesterase inhibitors, galantamine is most effective in delaying cognitive decline and significantly reduces the risk of developing severe dementia.

[0004] Zunveyl gluconate, a prodrug of galantamine, is a known compound documented in the literature, and its structural formula is as follows: Through a unique design, it eliminates drug absorption in the gastrointestinal tract, remaining inert when taken orally through the stomach and effectively converting into the active ingredient of galantamine after passing through the gastrointestinal tract. Thus, it achieves the same therapeutic effect as galantamine while helping to prevent unpleasant side effects associated with galantamine (such as nausea, vomiting, loss of appetite, and insomnia).

[0005] Patent application CN116761612A discloses seven crystalline forms of benzalkonium gluconate (defined as crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, and crystalline form G). This application discloses characterization data for crystalline forms A to G, as well as the conditions for their interconversion. According to the information disclosed in the specification, crystalline form A is anhydrous, crystalline form B is tetrahydrate, crystalline form C is monohydrate, and crystalline form D is dihydrate. Under appropriate conditions, crystalline forms A, B, C, and D can interconvert. Crystalline form A is stable in environments below 43% RH, but in environments above 75% RH, the product significantly absorbs moisture and transforms into crystalline form B.

[0006] In summary, the existing amorphous form (crystalline form A) of benzalkonium gluconate suffers from high hygroscopicity and is prone to crystal form transformation under high humidity conditions. This crystal form instability may affect the storage stability, quality control, and uniformity of in vivo release behavior of the drug formulation. Therefore, developing a novel benzalkonium gluconate crystalline form with significantly lower hygroscopicity than the existing amorphous form and maintaining crystal form stability under different humidity conditions has significant practical application value and clinical significance. Summary of the Invention

[0007] This invention addresses the shortcomings of existing technologies by providing an anhydrous crystalline form of benzalkonium gluconate and its preparation method. This novel anhydrous crystalline form of benzalkonium gluconate exhibits excellent stability, solubility, and high purity, which is more beneficial for the processing, storage, and transportation of downstream pharmaceutical preparations, ensuring the safety and efficacy of the formulated products. Furthermore, the preparation method is simple to operate, has good reproducibility, high yield, high production efficiency, and uses an environmentally friendly solvent system, making it suitable for scale-up production.

[0008] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: an anhydrous crystal form of benzalkonium gluconate, wherein the anhydrous crystal form has main peaks at 10.28, 10.61, 14.92, 16.38 and 22.21 degrees 2-θ (±0.2) in the powder X-ray diffraction pattern; When the anhydrous crystalline form was evaluated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), the weight loss of the anhydrous crystalline form before melting began was <0.5%.

[0009] The anhydrous crystal form was tested for moisture content using Karl Fischer titration, and the moisture content of the anhydrous crystal form was <0.5%.

[0010] Furthermore, the anhydrous crystal form has one or more additional main peaks at 3.89, 7.80, 9.68, 13.28, 15.60, 16.00, 17.33, 18.07, 19.67, 20.14, 23.85, 25.16 and 25.88 degrees 2-θ (±0.2) in the powder X-ray diffraction pattern.

[0011] Preferably, the crystalline form has one or more additional main peaks at 9.68, 10.61, 15.60, 16.00, 17.33, 18.07, 19.67 and 23.85 degrees 2-θ (±0.2) in the powder X-ray diffraction pattern.

[0012] Furthermore, the anhydrous crystal form has peaks at 12.18 and / or 18.83 degrees 2-θ (±0.2) in the powder X-ray diffraction pattern.

[0013] Furthermore, the anhydrous crystal form has at least three main peaks selected from 3.89, 10.28, 10.61, 16.00 and 22.21 degrees 2-θ (±0.2).

[0014] Furthermore, the peaks were determined using powder X-ray diffraction analysis in transmission mode.

[0015] Furthermore, when evaluated using differential scanning calorimetry (DSC), the anhydrous crystal form began to melt at a temperature of 122–127 °C.

[0016] Furthermore, the anhydrous crystal form exhibits melting at a temperature of 123±0.2℃.

[0017] Furthermore, when the anhydrous crystal form was evaluated by DSC and TGA, the weight loss of the anhydrous crystal form before melting began was <0.3%.

[0018] This invention also provides a method for preparing the anhydrous crystalline form of benzalkonium gluconate, the method comprising: dispersing (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofurano[3a,3,2-ef][2]benzozaza-6-benzoate in a solvent, adding sodium D-gluconate, heating the system to 50~60℃, adjusting the pH, slowly cooling to 20~30℃, and crystallizing to obtain the anhydrous crystalline form of benzalkonium gluconate.

[0019] Furthermore, the solvent is at least one of alcohols, acetonitrile, and acetone.

[0020] Further, adjust the pH to 4-5.

[0021] Furthermore, the cooling rate is 3℃ / h to 8℃ / h.

[0022] The beneficial effects of this invention are: (1) The novel anhydrous crystalline form of benzalkonium gluconate provided by this invention has a much lower hygroscopicity than existing crystalline forms, and possesses excellent stability, solubility, and high purity. This is more conducive to the processing, storage, and transportation of downstream pharmaceutical preparations, ensuring the safety and efficacy of the preparation products.

[0023] (2) The method for preparing the anhydrous novel crystal form of benzalkonium gluconate provided by the present invention is simple to operate, has mild crystallization conditions, low cost, good reproducibility, high yield, high production efficiency, and a green and environmentally friendly solvent system, making it suitable for large-scale production. Attached Figure Description

[0024] Figure 1 The XRPD pattern of benzalkonium gluconate prepared in Example 1; Figure 2 The DSC spectrum of benzalkonium gluconate prepared in Example 1; Figure 3 The TGA spectrum of benzalkonium gluconate prepared in Example 1; Figure 4 The XRPD spectrum of the 3-month stability (75%RH, 40℃) of benzalkonium gluconate prepared in Example 1; Figure 5 The HPLC chromatogram of benzalantamine gluconate prepared in Example 1; Figure 6 The XRPD pattern of benzalantamine gluconate prepared in Comparative Example 1; Figure 7 The XRPD patterns of benzalkonium gluconate prepared in Example 1 and Comparative Example 1 are superimposed. Figure 8 XRPD spectrum of benzalkonium gluconate prepared in Comparative Example 1 after 1 month of stability (75%RH, 40℃). Detailed Implementation

[0025] The specific embodiments of the present invention will be described in detail below. The present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used is for describing particular embodiments only and is not intended to limit the invention.

[0027] The present invention provides an anhydrous crystal form of benzalantamine gluconate, wherein the anhydrous crystal form has characteristic peaks at 10.28, 10.61, 14.92, 16.38 and 22.21 degrees 2-θ (±0.2) in the powder X-ray diffraction pattern.

[0028] In some embodiments, the anhydrous crystal form provided by the present invention, when evaluated by DSC and TGA, has a weight loss of <0.5% before melting begins.

[0029] In some embodiments, the anhydrous crystal form provided by the present invention has a water content measured by Karl Fischer, and the water content of the anhydrous crystal form is <0.5%.

[0030] In some embodiments, the anhydrous crystalline form of benzalkonium gluconate provided by the present invention has characteristic peaks at 3.89, 10.28, 13.28, 14.92, 16.38, and 22.21 degrees 2-θ (±0.2) in its powder X-ray diffraction pattern, and, when evaluated by DSC and TGA, the anhydrous crystalline form has a weight loss of <0.5% before melting begins, and the moisture content of the anhydrous crystalline form is <0.5% after Karl Fischer testing.

[0031] Specifically, the powder X-ray diffraction pattern also has a characteristic peak at least at 3.89, 7.80, 9.68, 10.61, 13.28, 15.60, 16.00, 17.33, 18.07, 19.67, 20.14, 23.85, 25.16 and 25.88 degrees 2-θ (±0.2).

[0032] Specifically, the powder X-ray diffraction pattern shows peaks at 12.18 and / or 18.83 degrees 2-θ (±0.2).

[0033] Specifically, the powder X-ray diffraction pattern shows one or more additional main peaks at 9.68, 10.61, 15.60, 16.00, 17.33, 18.07, 19.67, and 23.85 degrees 2-θ (±0.2).

[0034] Preferably, the anhydrous crystal form has at least three main peaks selected from 3.89, 10.28, 10.61, 16.00 and 22.21 degrees 2-θ (±0.2).

[0035] Specifically, the peaks were determined using powder X-ray diffraction analysis in transmission mode.

[0036] Specifically, when evaluated using differential scanning calorimetry (DSC), the anhydrous crystal form begins to melt at a temperature of 122–127 °C.

[0037] Preferably, the anhydrous crystal form exhibits melting at a temperature of 123±0.2℃.

[0038] Preferably, when the anhydrous crystal form is evaluated by DSC and TGA, the weight loss of the anhydrous crystal form before melting begins is <0.3%.

[0039] This invention also provides a method for preparing the anhydrous crystalline form of benzalkonium gluconate, the method comprising: dispersing (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofurano[3a,3,2-ef][2]benzozaza-6-benzoate in a solvent, adding sodium D-gluconate, heating the system to 50~60℃, adjusting the pH, slowly cooling to 20~30℃, and crystallizing to obtain the anhydrous crystalline form of benzalkonium gluconate.

[0040] Specifically, the solvent is at least one selected from alcohols, acetonitrile, and acetone. Preferably, the alcohol solvent is one of ethanol and methanol.

[0041] Specifically, adjust the pH to 4-5.

[0042] Specifically, the cooling rate is 3℃ / h to 8℃ / h, preferably 5℃ / h.

[0043] Specifically, the molar ratio of (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofurano[3a,3,2-ef][2]benzozaza-6-benzoate to sodium D-gluconate is 1:(1.1~2), preferably 1:(1.2~1.6).

[0044] Specifically, the mass ratio of (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofurano[3a,3,2-ef][2]benzozaza-6-benzoate to solvent is 1:(5~12).

[0045] It should be noted that all solvents used in the preparation of the anhydrous crystal form of benzalkonium gluconate in this invention are of analytical grade.

[0046] In some embodiments, a 30% hydrochloric acid solution is used to adjust the pH of the reaction, but this does not mean that there is a limitation on the concentration of hydrochloric acid in this invention, as long as the purpose of adjusting the pH can be achieved.

[0047] This invention provides an anhydrous crystalline form of benzalantamine gluconate, characterized by powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The parameters used in these methods can be set according to conventional procedures in the field and can be adjusted or varied as needed based on the specific physicochemical properties of the substance being tested.

[0048] In this invention, the method parameters for powder X-ray diffraction are as follows: Test instrument: Powder X-ray diffractometer; Instrument model: EMPYREAN; Start angle: 3°; End angle: 60°; Scanning speed: 0.167° / s; Sampling step width: 0.039; High voltage setting: 40kV; Current: 40mA; Power: 1.6kW.

[0049] In this invention, the method parameters for differential scanning calorimetry are as follows: Test instrument: thermogravimetric analyzer; temperature range: 30~420℃; heating rate: 10℃ / min.

[0050] In this invention, the method parameters for TGA are: Test instrument: thermogravimetric analyzer; temperature range: 50~600℃; heating rate: 10℃ / min.

[0051] In this invention, impurities and purity are detected using high-performance liquid chromatography (HPLC). The chromatographic conditions are as follows: octadecylsilane-bonded silica gel (Waters XBridge BEH C18) is used as the packing material; 20 mmol / L ammonium acetate solution-acetonitrile (95:5) is used as mobile phase A; acetonitrile is used as mobile phase B; the detection wavelength is 230 nm; the column temperature is 40 °C; the flow rate is 0.8 mL per minute; and the injection volume is 5 μL.

[0052] To better illustrate the embodiments of the present invention, the present invention will be further described in detail below through specific examples.

[0053] Example 1

[0054] This embodiment describes the preparation of an anhydrous crystal form of benzalkonium gluconate, including the following steps: (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofurano[3a,3,2-ef][2]benzozaza-6-benzoate (20.00 g, 0.05 mol) was dispersed in acetonitrile (160.00 g), and sodium D-gluconate (13.37 g, 0.06 mol) was added. The system was heated to 50-60 °C, and the pH was adjusted to 4-5 by adding 30% hydrochloric acid solution dropwise. The temperature was then slowly lowered to 20-30 °C at a rate of 5 °C / h, and crystallization was allowed to occur for 6-10 h. The mixture was filtered, the filter cake was washed with acetonitrile, and the product was dried under vacuum to obtain 28.4 g of anhydrous crystalline form of benzalkonium gluconate, with a yield of 94.8%.

[0055] The XRPD pattern of benzalkonium gluconate prepared in Example 1 is as follows: Figure 1 As shown.

[0056] The DSC spectrum of benzalkonium gluconate prepared in Example 1 is as follows: Figure 2 As shown.

[0057] The TGA spectrum of benzalkonium gluconate prepared in Example 1 is as follows: Figure 3 As shown.

[0058] The XRPD spectrum of the 3-month stability (75%RH, 40℃) of benzolantamine gluconate prepared in Example 1 is shown below. Figure 4 As shown.

[0059] Depend on Figure 4 It can be seen that the new crystal form of benzalkonium gluconate obtained in Example 1 of the present invention has good stability after 3 months, and the crystal form has not changed much.

[0060] The HPLC chromatogram of benzalkonium gluconate prepared in Example 1 is as follows: Figure 5 As shown in Table 1 below, the detection data is as follows.

[0061] Table 1 Chromatographic detection data of Example 1

[0062] Example 2

[0063] This embodiment describes the preparation of an anhydrous crystal form of benzalkonium gluconate, including the following steps: (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofurano[3a,3,2-ef][2]benzozaza-6-benzoate (20.00 g, 0.05 mol) was dispersed in acetone (200.00 g), and sodium D-gluconate (17.83 g, 0.08 mol) was added. The system was heated to 50-60 °C, and the pH was adjusted to 4-5 by adding 30% hydrochloric acid solution dropwise. The temperature was then slowly lowered to 20-30 °C at a rate of 5 °C / h, and crystallization was allowed to occur for 6-10 h. The mixture was filtered, the filter cake was washed with acetone, and the product was dried under vacuum to obtain 27.2 g of anhydrous crystalline form of benzalkonium gluconate, with a yield of 92.4%.

[0064] Example 3

[0065] This embodiment describes the preparation of an anhydrous crystal form of benzalkonium gluconate, including the following steps: (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofurano[3a,3,2-ef][2]benzozaza-6-benzoate (20.00 g, 0.05 mol) was dispersed in ethanol (160.00 g), and sodium D-gluconate (13.37 g, 0.06 mol) was added. The system was heated to 50-60 °C, and the pH was adjusted to 4-5 by adding 30% hydrochloric acid solution dropwise. The temperature was then slowly lowered to 20-30 °C at a rate of 5 °C / h, and crystallization was allowed to occur for 6-10 h. The mixture was filtered, the filter cake was washed with ethanol, and the product was dried under vacuum to obtain 28.0 g of anhydrous crystalline form of benzalkonium gluconate, with a yield of 93.3%.

[0066] Comparative Example 1 The preparation of amorphous form A of benzalkonium gluconate, disclosed in patent application CN116761612A, includes the following steps: (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuran[3a,3,2-ef][2]benzozaza-6-benzoate (20.00 g, 0.05 mol) was dispersed in aqueous tetrahydrofuran (200.00 g), and D-gluconolactone (13.65 g, 0.07 mol) was added. The mixture was heated to 50-60 °C until it dissolved completely. The temperature was then slowly lowered to 20-30 °C, and seed crystals were added. Solid precipitated out. The crystals were cultured for 10-15 h, filtered, and the filter cake was washed with tetrahydrofuran. The crystals were then dried under vacuum to obtain 25.0 g of benzogalantamine gluconate, with a yield of 83.4%.

[0067] The XRPD pattern of benzalkonium gluconate prepared in Comparative Example 1 is as follows: Figure 6 As shown.

[0068] The XRPD spectra of benzalkonium gluconate prepared in Example 1 and Comparative Example 1 are as follows: Figure 7 As shown.

[0069] The XRPD spectrum of the 1-month stability (75% RH, 40℃) of benzalkonium gluconate prepared in Comparative Example 1 is shown below. Figure 8 As shown.

[0070] Depend on Figure 4 and Figure 8 The comparison shows that the new crystalline form of benzalkonium gluconate obtained in this invention exhibits good stability after 3 months, with virtually no change in crystalline form. However, Figure 8 In the existing technology, the anhydrous form A of benzalkonium gluconate exhibits poor stability and changes in crystal form only after one month.

[0071] The solubility of the novel anhydrous benzalkonium gluconate crystal form obtained in Example 1 of this invention and crystal form A in Comparative Example 1 were tested in water. The results showed that the novel anhydrous benzalkonium gluconate crystal form obtained in this invention has higher solubility in water between 25°C and 50°C (at 25°C, the solubility of the novel crystal form in water is 145 mg / mL, and the solubility of crystal form A in water is 123 mg / mL; at 50°C, the solubility of the novel crystal form in water is 167 mg / mL, and the solubility of crystal form A in water is 149 mg / mL).

[0072] Comparative Example 2 This comparative example uses the same method as the examples to prepare an anhydrous crystal form of benzalkonium gluconate, except that tetrahydrofuran solvent is used instead of acetonitrile. The specific steps include: (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuran[3a,3,2-ef][2]benzozaza-6-benzoate (20.00 g, 0.05 mol) was dispersed in tetrahydrofuran (200.00 g), and sodium D-gluconate (13.37 g, 0.06 mol) was added. The system was heated to 50-60 °C, and the pH was adjusted to 4-5 by adding 30% hydrochloric acid solution dropwise. The temperature was then slowly lowered to 20-30 °C at a rate of 5 °C / h, and crystallization was allowed to occur for 6-10 h. The mixture was filtered, the filter cake was washed with tetrahydrofuran, and the product was dried under vacuum to obtain 25.8 g of anhydrous crystalline form A of benzogalantamine gluconate, with a yield of 86.0%.

[0073] The results showed that in tetrahydrofuran solvent, the crystal form A reported in the original patent was obtained, rather than the anhydrous benzoyl benzoate crystal form provided in this invention.

[0074] Comparative Example 3 This comparative example uses the same method as the examples to prepare an anhydrous crystal form of benzalkonium gluconate, except that the temperature is lowered to 20-30°C at a higher cooling rate than specified in this invention, at 10°C / h. Specifically, the following steps are included: (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofurano[3a,3,2-ef][2]benzozaza-6-benzoate (20.00 g, 0.05 mol) was dispersed in acetonitrile (160.00 g), and sodium D-gluconate (13.37 g, 0.06 mol) was added. The system was heated to 50-60 °C, and the pH was adjusted to 4-5 by adding 30% hydrochloric acid solution dropwise. The temperature was then lowered to 20-30 °C at a rate of 10 °C / h, and crystallization was allowed to occur for 6-10 h. The mixture was filtered, the filter cake was washed with acetonitrile, and then dried under vacuum.

[0075] The results showed that the anhydrous form of the obtained benzalkonium gluconate was amorphous compared with that in Example 1, which may be due to the excessively fast crystallization rate and incomplete crystal nucleation.

[0076] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are exhaustively listed. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0077] For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention, and these modifications and improvements are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the appended claims.

Claims

1. An anhydrous crystalline form of pheniramine glucuronate, characterized by, The anhydrous crystal form exhibits main peaks at 10.28, 10.61, 14.92, 16.38, and 22.21 degrees 2-θ (±0.2) in the powder X-ray diffraction pattern; When the anhydrous crystalline form was evaluated by differential scanning calorimetry and thermogravimetric analysis, the weight loss of the anhydrous crystalline form before melting began was <0.5%; The anhydrous crystal form was tested for moisture content using Karl Fischer titration, and the moisture content of the anhydrous crystal form was <0.5%.

2. The crystalline form of anhydrous pheniramine gluconate according to claim 1, characterized in that, The anhydrous crystal form has one or more additional main peaks at 3.89, 7.80, 9.68, 13.28, 15.60, 16.00, 17.33, 18.07, 19.67, 20.14, 23.85, 25.16 and 25.88 degrees 2-θ (±0.2) in the powder X-ray diffraction pattern.

3. The anhydrous crystalline form of pheniramine glucuronate of any one of claims 1-2, characterized by, The anhydrous crystal form has peaks at 12.18 and / or 18.83 degrees 2-θ (±0.2) in the powder X-ray diffraction pattern.

4. The anhydrous crystal form of benzalkonium gluconate according to claim 2, characterized in that, The anhydrous crystal form has at least three main peaks selected from 3.89, 10.28, 10.61, 16.00 and 22.21 degrees 2-θ (±0.2).

5. The anhydrous crystal form of benzalkonium gluconate according to claim 1, characterized in that, The peaks were determined using powder X-ray diffraction analysis in transmission mode.

6. The anhydrous crystal form of benzalkonium gluconate according to claim 1, characterized in that, When evaluated using differential scanning calorimetry, the anhydrous crystal form begins to melt at a temperature of 122–127 °C.

7. The anhydrous crystal form of benzalkonium gluconate according to claim 6, characterized in that, The anhydrous crystal form exhibits melting at a temperature of 123±0.2℃.

8. The anhydrous crystal form of benzalkonium gluconate according to claim 1, characterized in that, When the anhydrous crystalline form was evaluated by differential scanning calorimetry and thermogravimetric analysis, the weight loss of the anhydrous crystalline form before melting began was <0.3%.

9. A method for preparing the anhydrous crystalline form of benzalkonium gluconate according to any one of claims 1-8, characterized in that, The preparation method includes: dispersing (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofurano[3a,3,2-ef][2]benzozaza-6-benzoate in a solvent, adding sodium D-gluconate, heating the system to 50~60℃, adjusting the pH, slowly cooling to 20~30℃, and crystallizing to obtain the anhydrous crystal form of benzalantamine gluconate.

10. The method for preparing the anhydrous crystal form of benzalkonium gluconate according to claim 9, characterized in that, The solvent is at least one of alcohols, acetonitrile, and acetone; Adjust the pH to 4-5 and the cooling rate to 3℃ / h-8℃ / h.

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