阅读说明：本技术 一种美金刚双羟萘酸盐晶体及其制备方法和应用 (Memantine pamoate crystal and preparation method and application thereof ) 是由 龚俊波 匡雯婕 吴送姑 林霞 杨子毅 候宝红 杨奕 张聪 于 2021-09-30 设计创作，主要内容包括：本发明提供了一种美金刚双羟萘酸盐晶体及其制备方法和应用,所述美金刚双羟萘酸盐晶体的分子式为C-(23.5)H-(28)NO-(3)；所述美金刚双羟萘酸盐晶体为Ⅲ晶型,以2θ表示的X-射线粉末衍射图谱在7.4±0.2、8.3±0.2、10.9±0.2、11.7±0.2、12.6±0.2、13.1±0.2、13.9±0.2、15.0±0.2、16.6±0.2、18.2±0.2、19.1±0.2度处有特征峰；该美金刚双羟萘酸盐晶体具有降低美金刚溶解度,进而可以实现缓控释的优点。(The invention provides a memantine pamoate crystal and a preparation method and application thereof, wherein the molecular formula of the memantine pamoate crystal is C 23.5 H 28 NO 3 (ii) a The memantine pamoate crystal is III crystal form, and the X-ray powder diffraction pattern expressed by 2 theta is 7.4 +/-0.2, 8.3 +/-0.2, 10.9 +/-0.2, 11.7 +/-0.2 and 12.Characteristic peaks exist at 6 +/-0.2, 13.1 +/-0.2, 13.9 +/-0.2, 15.0 +/-0.2, 16.6 +/-0.2, 18.2 +/-0.2 and 19.1 +/-0.2 degrees; the memantine pamoate crystal has the advantages of reducing the solubility of memantine and further realizing sustained and controlled release.)

1. A memantine pamoate crystal characterized in that the molecular formula of the memantine pamoate crystal is C_23.5H₂₈NO₃；

The memantine pamoate crystal is III crystal form, and an X-ray powder diffraction pattern expressed by 2 theta has characteristic peaks at 7.4 +/-0.2, 8.3 +/-0.2, 10.9 +/-0.2, 11.7 +/-0.2, 12.6 +/-0.2, 13.1 +/-0.2, 13.9 +/-0.2, 15.0 +/-0.2, 16.6 +/-0.2, 18.2 +/-0.2 and 19.1 +/-0.2 degrees.

2. The memantine pamoate crystal of claim 1, wherein the DSC profile of the memantine pamoate crystal is melting-while-decomposing.

3. The memantine pamoate crystal according to claim 1, wherein the crystal form of the memantine pamoate crystal is tetragonal system, space group is P-421 c;

preferably, the unit cell parameters of the memantine pamoate crystal include: axial length Axial angle α is 90.00 °, β is 90.00 °, γ is 90.00 °, and unit cell volume is

4. A method for preparing memantine pamoate crystals as claimed in any one of claims 1 to 3, characterized in that the preparation method comprises the steps of:

(1) adding the pamoate solution into the memantine hydrochloride solution, and reacting and crystallizing to obtain a memantine pamoate I type crystal;

(2) and (2) carrying out suspension crystallization on the type I crystal of the memantine pamoate obtained in the step (1) in an alcohol solvent to obtain a type III crystal of the memantine pamoate.

5. The method according to claim 4, wherein the pamoate solution of step (1) is prepared by a method comprising: adding alkali into the pamoic acid suspension, and reacting to obtain pamoate solution;

preferably, the pamoic acid suspension is a pamoic acid suspension in water;

preferably, the addition amount of the water is 29-66mL calculated by the addition amount of the pamoic acid being 1-5 g;

preferably, the molar ratio of the pamoic acid to the base is 1:1.8 to 1: 2.2;

preferably, the base comprises sodium hydroxide and/or potassium hydroxide;

preferably, the reaction temperature is 50-60 ℃, and the reaction time is 20-30 min;

preferably, the reaction is carried out under stirring conditions.

6. The method according to claim 5, wherein the memantine hydrochloride is added in an amount of 1 to 3mol in the memantine hydrochloride solution of step (1) based on 1mol of the pamoic acid;

preferably, the temperature of the reaction crystallization in the step (1) is 25-60 ℃, and the time of the reaction crystallization is 5-15 min.

7. The preparation method according to claim 4, wherein the step (1) further comprises sequentially performing solid-liquid separation, washing and drying on the mixture obtained after the reaction crystallization;

preferably, the solid-liquid separation mode is filtration;

preferably, the cleaning solvent is water, and the cleaning times are 3-5 times;

preferably, the drying is carried out under vacuum conditions, the drying temperature is 50-70 ℃, the drying time is 18-24h, and the vacuum pressure is 0 MPa.

8. The method according to claim 4, wherein the alcoholic solvent of step (2) comprises any one of methanol, ethanol or isopropanol or a combination of at least two thereof;

preferably, the addition amount of the solvent in the step (2) is 1-5mL, wherein the addition amount of the memantine pamoate crystal form I is 0.5-5 g;

preferably, the temperature of the suspension crystallization is 5-60 ℃ and the time is 2-48 h.

9. A production method according to claim 4, wherein the step (2) further comprises subjecting the preform obtained after suspension crystallization to solid-liquid separation, washing and drying in this order;

preferably, the solid-liquid separation mode is filtration;

preferably, the drying is carried out under vacuum conditions, the drying temperature is 50-70 ℃, the drying time is 18-24h, and the vacuum pressure is 0 MPa.

10. Use of the crystalline memantine pamoate salt according to any one of claims 1-3 for the manufacture of a medicament for the treatment of alzheimer's disease.

Technical Field

The invention belongs to the technical field of medical crystallization, and relates to a memantine pamoate crystal and a preparation method and application thereof.

Background

The chemical name of memantine hydrochloride is 3, 5-Dimethyl-1-amino-adamantane hydrochloride (3, 5-Dimethyl-1-aminodiamantane hydrochloride), also known as 3,5-Dimethyl tricyclo [3.3.1.1.(3.7)]Decane-1-amino hydrochloride (3,5-Dimethyltricyclo (3.3.1.1(3,7)) can-1-amine hydrochloride). The molecular formula is C₁₂H₂₁N & HCl with a chemical structural formula:

memantine hydrochloride is the only NMDA receptor antagonist on the market for treating Alzheimer's disease and is the only drug for treating moderate to severe Alzheimer's disease, and is a low-medium affinity, non-competitive and strong voltage-dependent N-methyl-D-aspartate receptor antagonist which can block glutamate-induced N-methyl-D-aspartate receptor hyperexcitation and prevent intracellular calcium overload, thereby preventing the apoptosis of nerve cells and the progression of Alzheimer's disease. However, the administration frequency of the medicine on the market is from once to twice a day, the patient has poor medication compliance, and the medicine is easy to miss and refuse to take. Therefore, some measures are necessary to reduce the administration frequency and improve the treatment effect.

Pamoic acid (pamoic acid), also known as 2,2 ' -dihydroxy-3, 3 ' -diacid-1, 1 ' diacidNaphthyl methane; 4,4' -methylenebis (3-hydroxy-2-naphthoic acid), a dicarboxylic acid of formula C₂₃H₁₄O₆The structure is as follows:

pamoic acid is practically insoluble in water and in common organic solvents. It is an excipient approved by FDA for intramuscular injection, and can form insoluble salt with alkaline drugs to reduce solubility and further realize sustained release effect.

On the basis, the applicant finds that the memantine pamoate crystal form III and the preparation method thereof have the advantages that compared with the solubility of memantine hydrochloride, the solubility is reduced by at least 470 times, a new choice is provided for the preparation of the medicinal preparation, and the important significance is realized on the development of the medicament.

Disclosure of Invention

The invention aims to provide a memantine pamoate crystal and a preparation method and application thereof.

In order to achieve the purpose, the invention adopts the following technical scheme:

one of the objects of the present invention is to provide a memantine pamoate crystal having a molecular formula of C_23.5H₂₈NO₃；

The memantine pamoate crystal is in a crystal form I, and an X-ray powder diffraction pattern expressed by 2 theta has characteristic peaks at 7.4 +/-0.2, 8.3 +/-0.2, 10.9 +/-0.2, 11.7 +/-0.2, 12.6 +/-0.2, 13.1 +/-0.2, 13.9 +/-0.2, 15.0 +/-0.2, 16.6 +/-0.2, 18.2 +/-0.2 and 19.1 +/-0.2 degrees.

Preferably, the DSC profile of the memantine pamoate crystal is melting while decomposing, so that its melting point cannot be accurately measured.

Preferably, the crystal form of the memantine pamoate crystal is a tetragonal crystal system, and the space group is P-42₁c。

Preferably, the unit cell parameters of the memantine pamoate crystal include:

axial lengthAxial angle α is 90.00 °, β is 90.00 °, γ is 90.00 °, and unit cell volume is

A second object of the present invention is to provide a method for producing a memantine pamoate crystal according to the first object, the method comprising the steps of:

(1) adding the pamoate solution into the memantine hydrochloride solution, and reacting and crystallizing to obtain a memantine pamoate I type crystal;

(2) and (2) carrying out suspension crystallization on the type I crystal of the memantine pamoate obtained in the step (1) in an alcohol solvent to obtain a type III crystal of the memantine pamoate.

Preferably, the preparation method of the pamoate solution in step (1) comprises the following steps: adding alkali into the pamoic acid suspension, and reacting to obtain pamoate solution;

preferably, the pamoic acid suspension is a pamoic acid suspension in water;

preferably, the addition amount of the water is 29-66mL calculated by the addition amount of the pamoic acid being 1-5 g;

preferably, the molar ratio of the pamoic acid to the base is 1:1.8 to 1: 2.2;

preferably, the base comprises sodium hydroxide and/or potassium hydroxide;

preferably, the reaction temperature is 50-60 ℃, and the reaction time is 20-30 min;

preferably, the reaction is carried out under stirring conditions.

Preferably, the addition amount of memantine hydrochloride in the memantine hydrochloride solution in the step (1) is 1-3mol based on 1mol of the pamoic acid;

preferably, the temperature of the reaction crystallization in the step (1) is 25-60 ℃, and the time of the reaction crystallization is 5-15 min.

Preferably, the step (1) further comprises the steps of sequentially carrying out solid-liquid separation, washing and drying on the mixture obtained after the reaction crystallization;

preferably, the solid-liquid separation mode is filtration;

preferably, the cleaning solvent is water, and the cleaning times are 3-5 times;

preferably, the drying is carried out under vacuum conditions, the drying temperature is 50-70 ℃, the drying time is 18-24h, and the vacuum pressure is 0 MPa.

Preferably, the alcoholic solvent in step (2) comprises any one of methanol, ethanol or isopropanol or a combination of at least two thereof;

preferably, the addition amount of the solvent in the step (2) is 1-5mL, wherein the addition amount of the memantine pamoate crystal form I is 0.5-5 g;

preferably, the temperature of the suspension crystallization is 5-60 ℃ and the time is 2-48 h.

Preferably, the step (2) further comprises the steps of sequentially carrying out solid-liquid separation, cleaning and drying on the preform obtained after suspension crystallization;

preferably, the solid-liquid separation mode is filtration;

preferably, the drying is carried out under vacuum conditions, the drying temperature is 50-70 ℃, the drying time is 18-24h, and the vacuum pressure is 0 MPa.

The invention also aims to provide the application of the memantine pamoate crystal in the preparation of the medicine for treating the Alzheimer disease.

Compared with the prior art, the invention has the following beneficial effects:

the memantine pamoate provided by the invention has the advantages of reducing the solubility of memantine and further possibly realizing sustained and controlled release, and solves the problems of high solubility, quick release and multiple administration of the existing memantine hydrochloride.

Drawings

FIG. 1 is an X-ray diffraction pattern of crystal form I of memantine pamoate prepared in preparation example.

Fig. 2 is a thermogravimetric TGA of crystalline form I of memantine pamoate prepared in preparation example.

Fig. 3 is a differential scanning calorimetry DSC diagram of crystalline form I of memantine pamoate prepared in preparation example.

FIG. 4 is a single crystal X-ray diffraction pattern of crystalline form I of memantine pamoate prepared in preparation example.

FIG. 5 is an X-ray diffraction pattern of crystalline form III of memantine pamoate salt prepared in example 1.

Figure 6 is a TGA plot of the thermal weight loss of crystalline form iii of memantine pamoate prepared in example 1.

Figure 7 is a differential scanning calorimetry DSC of crystalline form iii of memantine pamoate prepared in example 1.

Figure 8 is a single crystal X-ray diffraction pattern of crystalline form iii of memantine pamoate salt prepared in example 1.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

It is noted that in X-ray powder diffraction spectroscopy, the diffraction pattern obtained from a crystalline compound tends to be characteristic for a particular crystalline form, where the relative intensities of characteristic peaks may vary due to the dominant orientation effect resulting from differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of the crystal form in question. When judging whether the crystal form is the same as the known crystal form, the relative positions of the peaks rather than the relative intensities are more important. Furthermore, for any given crystallization, the position of the peaks may deviate somewhat due to equipment and operating conditions, and characteristic peaks within the error range may be considered to be the same characteristic peak, as is also well known in the crystallography art. For example, the position of the peak may shift due to a change in temperature when analyzing the sample, sample movement, calibration of the instrument, or the like, and the measurement error of the 2 θ value is sometimes about ± 0.2 °. Therefore, this error should be taken into account when determining each crystal structure. For the same crystal form of the same compound, the peak positions of PXRD spectrums have similarity on the whole, and the relative intensity error is likely to be larger.

(1) PXRD test instrument: x-ray powder diffractometer

The instrument model is as follows: rigaku D/max-2500, Japan;

the test method comprises the following steps: Cu-Kalpha radiation of copper targetThe voltage is 40kV, the current is 100mA, the test angle is 2-40 degrees, the step length is 8 degrees/min, the exposure time is 0.2s, the test temperature is room temperature (25 ℃), the width of the light tube slit is 1mm, and the width of the detector slit is 2.7 mm.

(2) DSC instrument: differential calorimetric scanner

The instrument model is as follows: mettler Toledo DSC1/500 from Mettler Toledo company;

the test method comprises the following steps: the sample amount is 5-10mg, the heating rate is 10 ℃/min, and the flow rate of protective gas nitrogen is 50 mL/min.

(3) Instrument for SXRD test: single crystal X-ray diffractometer

The instrument model is as follows: bruker D8 Venture, germany;

the test method comprises the following steps: with Mo KaFor rays, data was collected over a range of 4.04deg to 56.564 deg.

Preparation example

4.669g of pamoic acid raw material is placed in 32ml of water and stirred at 60 ℃ to prepare pamoic acid suspension, 0.3mol/L of NaOH solution is dripped into the pamoic acid suspension while stirring, and after the NaOH solution is dripped completely, the stirring is continued for 5 minutes and the ultrasonic treatment is carried out for 5 minutes. If insoluble precipitate still remains, stirring is continued, and NaOH solution is added dropwise until the pamoic acid is completely dissolved, so as to obtain clear pamoic acid solution. 5.1785g of memantine hydrochloride raw material is placed in 300ml of water, stirred at room temperature, the clarified pamoic acid solution is dripped into the memantine water solution, and stirring is continued for 5min after dripping is finished, so that milk white powder is obtained, namely the memantine pamoate crystal I crystal form.

FIG. 1 is a powder X-ray diffraction pattern of the crystals of memantine pamoate prepared as described above, and it can be seen from FIG. 1 that: diffraction angle 2 theta shows that the crystal has characteristic peaks at 6.7, 11.9, 14.0, 16.1, 17.4, 20.3, 21.0 and 22.0 degrees, and the crystal is in the I crystal form.

Fig. 2 is a TGA diagram of the crystals of memantine pamoate prepared as described above, and from fig. 2, it can be seen that there is no weight loss in the solvent, indicating that the salt is obtained as a non-solvate.

FIG. 3 is a DSC chart of the crystal of memantine pamoate prepared as described above, and it can be seen from FIG. 3 that the substance shows a characteristic endothermic peak at 210 ℃.

Fig. 4 is an X-ray single crystal diffraction pattern of the memantine pamoate crystal prepared as described above, and as can be seen from fig. 4, the crystal form of the substance is a monoclinic system, the space group is Cc, the basic unit of memantine pamoate crystal form I includes 2 memantine ions and 1 pamoate ion, and the unit cell parameters: axial length The axial angle α is 90.00 °, β is 90.116(4 °), γ is 90.00 °, and the unit cell volume is

Example 1

0.5g of memantine pamoate crystal form I raw material (prepared in preparation example) is placed in 1ml of methanol for suspension crystallization, filtration is carried out after 6h-48h to obtain milk white crystals, and the crystals are dried at 50 ℃ for 12h to obtain memantine pamoate crystal form III.

FIG. 5 is a powder X-ray diffraction pattern of the crystals of memantine pamoate prepared as described above, and it can be seen from FIG. 5 that: diffraction angle 2 theta indicates that the crystal has characteristic peaks at 7.4, 8.3, 10.9, 11.7, 12.6, 13.1, 13.9, 15.0, 16.6, 18.2 and 19.1 degrees, and the crystal is in a III crystal form.

Fig. 6 is a TGA diagram of the memantine pamoate crystal prepared as described above, and as can be seen from fig. 6, the memantine pamoate crystal is a non-solvate.

Fig. 7 is a DSC chart of the memantine pamoate crystal prepared as described above, and as can be seen from fig. 7, this substance decomposes while melting, and therefore the melting point cannot be accurately measured.

Fig. 8 is an X-ray single crystal diffraction pattern of the memantine pamoate crystal prepared as described above, and as can be seen from fig. 8, the crystal form of the substance is tetragonal system, space group is P-421c, the basic unit of memantine pamoate crystal form iii includes 1 memantine ion and 1 pamoate ion, unit cell parameters:

axial lengthAxial angle α is 90.00 °, β is 90.00 °, γ is 90.00 °, and unit cell volume is

Solubility tests were carried out on the memantine pamoate salt type III crystals prepared as described above, and it was found that: solubility in PBS buffer was about 0.039mg/mL at 37 deg.C, and the solubility of memantine hydrochloride was 18.40mg/mL, which was at least a 470-fold decrease compared to the solubility of memantine hydrochloride.

Example 2

0.5g of memantine pamoate crystal form I raw material (prepared in preparation example) is placed in 1ml of ethanol for suspension crystallization, filtration is carried out after 6h-48h to obtain milk white crystals, and the crystals are dried at 50 ℃ for 12h to obtain memantine pamoate crystal form III.

The product obtained in example 2 was subjected to the crystallographic test, the test results being the same as in example 1.

The product obtained in example 2 was subjected to PXRD test, which revealed that: the diffraction angle 2 theta indicates that the crystal has characteristic peaks at 7.4, 8.5, 10.7, 11.8, 12.5, 13.2, 13.9, 15.2, 16.4, 18.4 and 19.3.

The DSC test of the product obtained in example 2 revealed that: the melting point of the product cannot be accurately measured because the product is melted and decomposed.

Solubility tests were carried out on the memantine pamoate salt type III crystals prepared as described above, and it was found that: solubility in PBS buffer was about 0.039mg/mL at 37 deg.C, and the solubility of memantine hydrochloride was 18.40mg/mL, which was at least a 470-fold decrease compared to the solubility of memantine hydrochloride.

Example 3

0.5g of memantine pamoate crystal form I raw material (prepared in preparation example) is placed in 1ml of isopropanol for suspension crystallization, filtration is carried out after 6h-48h to obtain milk white crystals, and the crystals are dried for 12h at 50 ℃ to obtain memantine pamoate crystal form III.

The product obtained in example 3 was subjected to the crystallographic test, the test results being the same as in example 1.

The product obtained in example 3 was subjected to PXRD test, which revealed that: the diffraction angle 2 theta indicates that the crystal has characteristic peaks at 7.2, 8.1, 11.0, 11.5, 12.8, 13.3, 14.0, 15.2, 16.4, 18.4 and 19.3.

The DSC test of the product obtained in example 3 revealed that: the product is melted and decomposed, so that the melting point cannot be accurately measured.

Solubility tests were carried out on the memantine pamoate salt type III crystals prepared as described above, and it was found that: solubility in PBS buffer was about 0.039mg/mL at 37 deg.C, and the solubility of memantine hydrochloride was 18.40mg/mL, which was at least a 470-fold decrease compared to the solubility of memantine hydrochloride.

Example 4

5g of memantine pamoate crystal form I raw material (prepared in preparation example) is placed in 5ml of methanol for suspension crystallization, filtration is carried out after 6-48 h to obtain milk white crystals, and the crystals are dried at 50 ℃ for 12h to obtain memantine pamoate crystal form III.

The product obtained in example 4 was subjected to the crystallographic test, the test results being the same as in example 1.

The product obtained in example 4 was subjected to PXRD test, which revealed that: the diffraction angle 2 theta indicates that the crystal has characteristic peaks at 7.4, 8.2, 10.8, 11.7, 12.5, 13.3, 13.9, 15.1, 16.8, 18.4 and 19.1.

The DSC test of example 4 revealed that: the melting point of the product cannot be accurately measured because the product is melted and decomposed.

Solubility tests were carried out on the memantine pamoate salt type III crystals prepared as described above, and it was found that: solubility in PBS buffer was about 0.039mg/mL at 37 deg.C, and the solubility of memantine hydrochloride was 18.40mg/mL, which was at least a 470-fold decrease compared to the solubility of memantine hydrochloride.

Comparative example 1

Preparing a 0.1mol/L aqueous solution of sodium oleate and a 0.1mol/L aqueous solution of memantine hydrochloride, dropwise adding the aqueous solution of memantine hydrochloride into the aqueous solution of sodium oleate under stirring at 75 ℃, centrifuging for 10min at 10000r/min, collecting the upper oily viscous liquid, washing for 3 times by hot water, and carrying out vacuum drying on the obtained oily viscous liquid for 24h at 40 ℃ to obtain the memantine oleate.

Solubility measurement of the memantine oleate obtained in comparative example 1 was carried out, and the solubility in PBS buffer was 0.90mg/mL and the solubility of the memantine pamoate of the present invention was 0.039mg/mL at 37 ℃. The memantine pamoate salt of the present invention is lower than memantine oleate.

Comparative example 2

The only difference from comparative example 1 is that the aqueous solution of sodium oleate in comparative example 1 was replaced with the aqueous solution of sodium stearate, and the remaining preparation method was the same as in comparative example 1.

Solubility of the memantine stearate obtained in comparative example 2 was measured, and the solubility in PBS buffer was 0.7017mg/mL at 37 ℃ and 0.08mg/mL with the memantine pamoate salt of example 1 of the present invention. The memantine pamoate salt of the present invention is lower than memantine stearate.

Comparative example 3

The only difference from comparative example 1 is that the aqueous solution of sodium oleate of comparative example 1 was replaced with an aqueous solution of sodium palmitate, and the remaining preparation method was the same as in comparative example 1.

Solubility of the memantine palmitate obtained in comparative example 3 was measured and found to be 0.6972mg/mL in PBS buffer at 37 ℃ and 0.08mg/mL as compared to memantine pamoate in example 1 of the present invention. The memantine pamoate salt of the present invention is lower than memantine palmitate.

The applicant declares that the above description is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be understood by those skilled in the art that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are within the scope and disclosure of the present invention.