Amorphous NADP solvate and preparation method thereof

Abstract

The invention relates to an amorphous NADP solvate and a preparation method thereof. The amorphous NADP solvate disclosed by the invention is an NADP diethanol solvate or an NADP diisopropanol solvate. The preparation method comprises the following steps: adding an NADP aqueous solution with specific concentration and pH into an alcohol solvent with specific temperature, stirring, crystallizing, carrying out suction filtration, and carrying out vacuum drying to obtain the amorphous NADP solvate. The amorphous NADP solvate disclosed by the invention solves the problems of stability and fluidity, and meanwhile, the method is simple to operate, the process is easy to control, and the method is suitable for industrialization.

Description

Technical fields:

[0001] This invention belongs to the field of drug crystallization technology, specifically relating to an amorphous NADP solvate and its preparation method. Background technology:

[0002] Oxidized β-nicotinamide adenine dinucleotide phosphate (NADP) is a crucial nucleotide coenzyme, structured as shown in Formula I. It consists of nicotinamide adenine dinucleotide (NAD) linked to a phosphate molecule via an ester bond. NADP participates in various anabolic reactions, such as the synthesis of lipids, fatty acids, and nucleotides. In vivo, NADP acts not only as a hydrogen transfer carrier but also as a medium for phosphate transfer in various synthetic reactions. Furthermore, NADP is widely used as an additive in food and cosmetics, finding applications in scientific research, food, and cosmetic fields.

[0003]

[0004] The polymorphic state of drugs is an important aspect of drug evolution, and most drugs exhibit polymorphism. This polymorphism directly affects drug stability, solubility, bioavailability, safety, efficacy, and formulation processing performance. Amorphous forms, in particular, possess better in vitro dissolution and in vivo absorption properties and may lead to better clinical efficacy; therefore, related research is receiving increasing attention.

[0005] Patent CN104876993B discloses a purification method for oxidized β-nicotinamide adenine dinucleotide phosphate. The purified NADP solution is concentrated to 100-150 g / L by nanofiltration using a membrane concentration device (hollow fiber membrane with a molecular weight cutoff of 200). Then, it is freeze-dried in a vacuum freeze dryer to obtain a freeze-dried product with a purity greater than 99%. The total yield can reach 91.4%. The cost of using freeze-drying technology is relatively high. Summary of the Invention:

[0006] The purpose of this invention is to address the shortcomings of existing technologies by providing a new NADP solvate and its preparation method.

[0007] On the one hand, the present invention provides an amorphous NADP solvate.

[0008] Furthermore, the amorphous NADP solvates described in this invention are amorphous NADP diethanol solvates and amorphous NADP diisopropanol solvates.

[0009] Furthermore, the X-ray powder diffraction pattern of the amorphous NADP diethanol solvate described in this invention is essentially as follows: Figure 2 As shown, its characteristic is that the X-ray powder diffraction spectrum, expressed in terms of diffraction angle 2θ, does not contain characteristic peaks of the crystal form.

[0010] Furthermore, the TGA spectrum of the amorphous NADP-diethanol solvate of the present invention is attached. Figure 3 As shown, the weight loss due to water evaporation is 20–140℃, and the weight loss due to ethanol evaporation is 140–200℃.

[0011] Furthermore, the X-ray powder diffraction pattern of the amorphous NADP diisopropanol solvate described in this invention is essentially as follows: Figure 6 As shown, its characteristic is that the X-ray powder diffraction spectrum, expressed in terms of diffraction angle 2θ, does not contain characteristic peaks of the crystal form.

[0012] Furthermore, the TGA spectrum of the amorphous NADP-diisopropanol solvate of the present invention is attached. Figure 7 As shown, the weight loss due to water evaporation is 20–150℃, and the weight loss due to isopropanol evaporation is 150–220℃.

[0013] On the other hand, the present invention provides a method for preparing amorphous NADP solvates.

[0014] The preparation method of the NADP solvate of the present invention is as follows: First, the NADP aqueous solution is premixed with an alcohol solvent, and then the premixed solution is adjusted to a specific concentration and pH and added to an alcohol solvent at a specific temperature for stirring and crystallization. After filtration and vacuum drying, the amorphous NADP solvate is obtained.

[0015] Furthermore, the concentration of the NADP aqueous solution described in this invention is 5% to 50%, preferably 10% to 30%.

[0016] Furthermore, the pH value of the NADP aqueous solution described in this invention is 1.5 to 6.5, preferably 2.0 to 4.0.

[0017] Furthermore, the alcohol solvents described in this invention are selected from methanol, ethanol, and isopropanol, with ethanol and isopropanol being preferred.

[0018] Furthermore, the weight ratio of the alcohol solvent to the NADP aqueous solution in this invention is 5:1 to 30:1, preferably 10:1 to 20:1.

[0019] Furthermore, the temperature described in this invention is selected from -5 to 5°C.

[0020] Furthermore, the stirring and crystallization process described in this invention is selected for 1 to 48 hours, preferably 10 to 24 hours.

[0021] The beneficial effects of this invention are that it discloses novel NADP diethanol solvates and NADP diisopropanol solvates. The amorphous NADP solvates disclosed in this invention solve the stability and flowability problems, while the method is simple to operate, the process is easy to control, and it is suitable for industrial application. Attached image description:

[0022] Appendix Figure 1 NADP diethanol solvate 1 H-NMR spectrum

[0023] Appendix Figure 2 XPRD spectrum of NADP diethanol solvate

[0024] Appendix Figure 3 TGA spectrum of NADP diethanol solvate

[0025] Appendix Figure 4 HPLC chromatogram of NADP diethanol solvate

[0026] Appendix Figure 5 NADP diisopropanol solvate 1 H-NMR spectrum

[0027] Appendix Figure 6 XPRD pattern of NADP diisopropanol solvate

[0028] Appendix Figure 7 TGA spectrum of NADP diisopropanol solvate

[0029] Appendix Figure 8 HPLC chromatogram of NADP diisopropyl solvate Detailed implementation method:

[0030] The technical content of the present invention will be further described below with reference to specific embodiments, in order to better understand the content of the present invention, but the scope of protection of the present invention is not limited thereto.

[0031] The X-ray powder diffraction (XPRD) pattern shown in this invention was obtained using a Rigaku X-ray powder diffractometer from Japan. The detection conditions were: Cu-Kα ray radiation; graphite monochromator; tube voltage 40 kV; tube current 40 mA; 2-theta scanning range 3–45°; scanning rate 5° / min; step size 0.02°.

[0032] The TGA spectra of this invention were obtained using a Q500 thermogravimetric analyzer (TA Instruments, USA). Detection conditions: sample volume: 5–10 mg; gas: nitrogen; gas flow rate: 50 ml / min; heating rate: 10 °C / min; initial temperature: 20–30 °C; measurement temperature range: 30–350 °C. Example 1: Preparation of amorphous NADP-diethanol solvate.

[0033] Take 100g of 10% NADP aqueous solution, add 50g of ethanol for premixing, and adjust the pH to 2.0. Add 1000g of ethanol to a three-necked flask, set up a mechanical stirrer, thermometer, and water bath, and control the internal temperature at -5℃ using the water bath. Add the NADP aqueous solution dropwise, and after the addition is complete, stir and crystallize for 24 hours. Filter and vacuum dry to obtain 11.2g of white solid, which is the NADP diethanol solvate. 1 HNMR spectra as follows Figure 1 As shown, the XPRD map is as follows Figure 2 As shown, the TGA spectrum is as follows: Figure 3 As shown. By Figure 3 The TGA curves show that the weight loss was 6.383% at temperatures between 20 and 140°C, attributed to water evaporation, and 9.423% at temperatures between 140 and 200°C, attributed to ethanol evaporation. The HPLC chromatogram for liquid chromatography is shown below. Figure 4 The moisture content was 5.90%, and the ethanol residue was 100,978 ppm.

[0034] Example 2 Preparation of amorphous NADP-diisopropanol solvate

[0035] Take 100g of 30% NADP aqueous solution, add 50g of isopropanol for premixing, and adjust the pH to 4.0. Add 3000g of isopropanol solvent to a three-necked flask, set up a mechanical stirrer, thermometer, and water bath, and control the internal temperature at 5℃ using the water bath. Add the NADP aqueous solution dropwise, and after the addition is complete, stir and crystallize for 10 hours. Filter and vacuum dry to obtain 31.7g of white solid, which is the NADP diisopropanol solvate. 1 H-NMR spectrum as follows Figure 5 As shown, the XPRD map is as follows Figure 6 As shown, the TGA spectrum is as follows: Figure 7 As shown in the TGA curve, the weight loss was 8.747% at temperatures between 20 and 150°C, due to water evaporation, and 10.62% at temperatures between 150 and 220°C, due to isopropanol evaporation. The HPLC chromatogram for liquid chromatography is shown below. Figure 8 The moisture content was 8.98%, and the isopropanol residue was 175,117 ppm.

[0036] Example 3: Preparation of amorphous NADP

[0037] Take 100g of 10% NADP aqueous solution and adjust the pH to 2.0 for later use. Add 1000g of methanol to a three-necked flask, set up a mechanical stirrer, thermometer and water bath, and control the internal temperature at 0℃ with water bath. Add NADP aqueous solution dropwise, and stir to crystallize for 24h after the addition is complete. Filter and vacuum dry to obtain 10.2g of white solid.

[0038] Headspace GC analysis showed that the methanol residue was 1.3%, which is relatively low and indicates that it is a non-solvent.

[0039] Comparative Experiment 1: Preparation of Amorphous NADP

[0040] Take 100g of 10% NADP aqueous solution and adjust the pH to 2.0 for later use. Add 1000g of ethanol to a three-necked flask, set up a mechanical stirrer, thermometer and water bath, control the internal temperature of the water bath at 15℃, add NADP aqueous solution dropwise, stir and crystallize for 24h after the addition is complete, filter and vacuum dry to obtain 10.5g of white solid.

[0041] Headspace GC analysis showed that the ethanol residue was 3.2%, which is relatively low and indicates that the product is NADP.

[0042] Comparative Experiment 2: Preparation of Amorphous NADP

[0043] Take 100g of 30% NADP aqueous solution and adjust the pH to 4.0 for later use. Add 3000g of isopropanol solvent to a three-necked flask, set up a mechanical stirrer, thermometer and water bath, control the internal temperature of the water bath at 25℃, add NADP aqueous solution dropwise, stir and crystallize for 10h after the addition is complete, filter and vacuum dry to obtain 10.4g of white solid.

[0044] Headspace GC analysis showed that the residual isopropanol was 2.9%, which is relatively low, indicating that it is a non-solvent. Therefore, the product is NADP.

[0045] Example 4 Stability Study Data

[0046] The NADP ethanol solvate, NADP isopropanol solvate, and NADP amorphous lyophilized product were tested at 5±3℃, and the data obtained are shown in the table below.

[0047]

Claims

1. An amorphous NADP solvate, characterized in that, The NADP solvate is either NADP diethanol solvate or NADP diisopropanol solvate, and X-ray powder diffraction analysis shows that it exists in an amorphous form.

2. The amorphous NADP solvate as described in claim 1, characterized in that, The X-ray powder diffraction pattern of the amorphous NADP diethanol solvate is basically shown in Figure 2, and the X-ray powder diffraction pattern of the amorphous NADP diisopropanol solvate is basically shown in Figure 5.

3. The amorphous NADP solvate as described in claim 1, characterized in that, The TGA spectrum of the amorphous NADP diethanol solvate is shown in Figure 3, and the TGA spectrum of the amorphous NADP diisopropanol solvate is shown in Figure 7.

4. The method for preparing amorphous NADP solvates according to any one of claims 1-3, characterized in that, The process includes the following steps: premixing an aqueous NADP solution with ethanol or isopropanol, adjusting the pH to 2.0–4.0, adding it to ethanol or isopropanol, stirring and crystallizing for 10–24 h at a temperature of -5–5 °C, filtering and vacuum drying to obtain an amorphous NADP solvate.

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