Method for controlling the crystallization process and online monitoring of the crystallization process of carbamazepine induced by self-assembled films

Abstract

The application belongs to the field of chemical engineering crystallization, and particularly relates to a self-assembled membrane induced carbamazepine crystal form control method and an online monitoring method of a crystallization process. The method comprises the following steps: S1: self-assembled membrane preparation: immersing a treated gold film substrate into a mercapto self-assembled membrane solution to form a film; the mercapto self-assembled membrane solution is an SH-R-R' solution, wherein R is an aromatic group or an alkyl group, and R' is COOH, OH or H; S2: solution cooling crystallization; the method provides a functionalized interface to induce the carbamazepine solution crystallization process, utilizes the interaction between the groups modified on the substrate surface and the drug molecules to induce the crystal nucleus formation process of the system, and through a program temperature control device to obtain different drug crystal forms. The self-assembled membrane modification on the surface of a quartz crystal microbalance crystal microvibration piece can further provide the function of accurately monitoring the crystal nucleus induction point change occurring in the induced carbamazepine process online.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical engineering crystallization, and particularly relates to a method for controlling the crystal form of carbamazepine induced by self-assembled membrane and an online monitoring method for crystallization process. BACKGROUND

[0002] Polymorphism is widespread, more than half of the APIs exist in polymorphs. Since the 1970s, the research on polymorphism of drugs has gradually attracted extensive attention of pharmacists at home and abroad. It is found that there may be a very large difference in clinical efficacy of polymorphic solid chemical drugs. Different crystal forms of drugs may have significant differences in appearance, solubility, dissolution rate, melting point, biological activity, etc. Due to the difference in lattice energy, polymorphic drugs have different melting points, solubility, dissolution rate, stability, and biological activity. It is because a solid drug may have multiple crystal forms, and only one or more can produce the best clinical therapeutic effect, that is, the so-called "dominant drug crystal form" concept, that is, in the case of multiple crystal forms of solid chemical drugs, the dominant drug crystal form is the crystal form state that meets the requirements of pharmaceutical stability, has the best clinical therapeutic effect, the highest safety, and is most suitable for the preparation of pharmaceutical products.

[0003] Carbamazepine (CBZ for short), a clinically common psychotropic drug, is a white or nearly white powder, and is mainly used for treating epilepsy. This drug is one of the six effective antiepileptic drugs recognized by WHO, and can also be used for anticonvulsant, antidepressant and antineuralgia. Therefore, the drug has a broad market prospect. However, similar to other polymorphic molecules of drugs, carbamazepine also exists in other crystal forms and hydrates. However, the participation of water molecules often makes its drug efficacy worse, and water molecules usually exist as a component of carbamazepine dihydrate crystal structure, and this product is not worth expecting. Therefore, there is an urgent need for an efficient method to regulate other crystal forms to improve its drug efficacy.

[0004] Chinese patent CN106117141A discloses a synthesis method of carbamazepine bulk drug, the synthesis technology adopts imino stilbene, benzene and triphosgene synthesis reaction to obtain imino stilbene carbonyl chloride, and then is treated by liquid nitrogen and decolorization, finally obtains carbamazepine bulk drug, the process is also relatively complex, the yield is low, the energy consumption is high, only stable crystal form III is obtained. Chinese patent CN108863933A also discloses a preparation method of carbamazepine bulk drug, on the basis of the previous one, the consumption of other reagents is reduced, the production cost is reduced and the production efficiency is improved, the method takes imino dibenzyl and chlorobenzene as raw materials, and obtains carbamazepine bulk liquid through acyl chloride, bromination and amination processes, and the whole process adopts a new type of closed equipment, however, the process is still relatively complex, and the obtained raw material is only stable crystal form III, the method cannot obtain other crystal forms of carbamazepine, and cannot screen the best drug effect of crystal form. Chinese patent CN112457252 discloses a preparation method of template-induced carbamazepine metastable crystal form II, under the action of stirring, carbamazepine stable crystal form III is dissolved in an alcohol solvent, a template agent is added, and the crystal is cooled and crystallized under continuous stirring, finally, the crystal product of carbamazepine metastable crystal form II is obtained, although the method successfully induces different drug crystal forms, the induction process is relatively complicated, and the key is that the crystal product is difficult to separate from the template agent quickly, thereby increasing the cost.

[0005] In summary, most of the existing preparation methods of carbamazepine are mainly based on synthesis, and the obtained crystal form is stable crystal form III; only one report about crystal form induction induces metastable crystal form II, and there is no report about other efficient induction crystal form methods to obtain different crystal forms. SUMMARY

[0006] The purpose of the present application is to overcome the shortcomings in the prior art, and provide a self-assembled membrane-induced carbamazepine crystal form control method and an online monitoring method of a crystallization process.

[0007] To achieve the above purpose, the technical scheme adopted by the present application is as follows:

[0008] A self-assembled membrane-induced carbamazepine crystal form method, comprising the following steps:

[0009] S1: preparation of a self-assembled membrane: immerse a treated gold film substrate into a mercapto self-assembled membrane solution to form a film; the mercapto self-assembled membrane solution is an SH-R-R' solution, wherein R is an aromatic group or an alkyl group, and R' is COOH, OH or H;

[0010] S2: solution cooling crystallization: the raw material of carbamazepine in crystal form III is added into a crystallizer of ethanol / water mixed solvent, and then the self-assembled film prepared in S1 is added into the crystallizer, and heating is performed to form a 0.03-0.0325 g / mL carbamazepine solution; then the water bath temperature is controlled to be decreased at a rate of 0.7-0.9 ℃ / min to 5-10 ℃;

[0011] S3: the crystal formed in S2 is characterized.

[0012] The thiol self-assembled film solution in S1 is 11-mercaptoundecanoic acid, mercaptobenzothiazole solution, 11-mercaptoundecanol, and the concentration thereof is 1 mmol / L.

[0013] The temperature in S2 is heated to 70-80 ℃.

[0014] The ratio of ethanol / water in the ethanol / water mixed solvent in step S2 is 80 / 20 vol.%.

[0015] The treatment process of the gold film substrate in step S1 is that the gold film substrate is immersed in a piranha solution for surface cleaning, then washed with distilled water, and then dried by blowing high-purity N2.

[0016] The gold film substrate in step S1 is from the surface of a quartz crystal microbalance crystal microcantilever.

[0017] Compared with the prior art, the method has the following beneficial effects:

[0018] The method provides a functionalized interface to induce the carbamazepine solution crystallization process, utilizes the interaction force between the groups modified on the substrate surface and the drug molecules to induce the crystal nucleus formation process of the system, and achieves different drug crystal forms through a program-controlled temperature device. The different crystal forms are due to the great difference in the arrangement between the molecules in the system. The functionalized interface with different groups induces the internal arrangement of the drug crystal through the intermolecular interaction force in the process of the drug forming crystal nucleus, so that different crystal nucleus of different crystal forms is formed, and the program-controlled temperature device is used to control the supersaturation of the system, so that more target molecules continue to grow into the crystal of the same crystal form as the crystal nucleus based on the crystal nucleus.

[0019] The method has a simple process, and the key is the preparation and modification of the self-assembled film to stably induce the metastable crystal form of carbamazepine. The new crystallization means overcomes the defects of the traditional drug screening conditions, such as poor controllability and poor stability, can better control the crystal crystallization process, greatly enriches the crystal form control method, and greatly shortens the exploration period of the drug crystal form.

[0020] As a preferred, the self-assembled film is modified on the surface of an in-line electrochemical component, a quartz crystal microbalance gold film crystal oscillator wafer, which is a sensitive component plated with gold in the center of the surface, not only can be used as a physical support for the self-assembled film, but also can provide a gold film for the formation of a gold-sulfur bond, and further provide a function of accurately monitoring the change of the crystal nucleus induction point in the process of inducing carbamazepine on different functional interfaces due to the piezoelectric effect. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 Ramam spectrum, XRPD spectrum, electron microscope image and particle size diagram of the carbamazepine metastable crystal form II product prepared in Example 1 are shown.

[0022] Figure 2 Ramam spectrum, XRPD spectrum, electron microscope image and particle size diagram of the carbamazepine metastable crystal form II product prepared in Example 2 are shown.

[0023] Figure 3 Ramam spectrum, XRPD spectrum, electron microscope image and particle size diagram of the carbamazepine metastable crystal form I product prepared in Example 3 are shown.

[0024] Figure 4 Ramam spectrum, XRPD spectrum, electron microscope image and particle size diagram of the carbamazepine metastable crystal form II product prepared in Example 4 are shown.

[0025] Figure 5 Ramam spectrum, XRPD spectrum, electron microscope image and particle size diagram of the carbamazepine metastable crystal form II product prepared in Example 5 are shown.

[0026] Figure 6 Ramam spectrum, XRPD spectrum, electron microscope image and particle size diagram of the carbamazepine metastable crystal form II product prepared in Example 6 are shown.

[0027] Figure 7 Ramam spectrum, XRPD spectrum, electron microscope image and particle size diagram of the carbamazepine metastable crystal form I product prepared in Example 7 are shown.

[0028] Figure 8 Ramam spectrum, XRPD spectrum, electron microscope image and particle size diagram of the carbamazepine metastable crystal form I product prepared in Example 8 are shown.

[0029] Figure 9 Ramam spectrum, XRPD spectrum, electron microscope image and particle size diagram of the carbamazepine dihydrate crystal form product prepared in Comparative Example 1 are shown.

[0030] Figure 10 The figure shows the real-time monitoring of the crystal growth process of the MUA modified QCM.

[0031] Figure 11Figure 2 shows the real-time monitoring of crystal growth process by QCM modified with 2MBT.

[0032] Figure 12 Figure 3 shows the real-time monitoring of crystal growth process by QCM modified with MUOH.

[0033] Figure 13 Figure 4 shows the real-time monitoring of crystal growth process by QCM. DETAILED DESCRIPTION

[0034] In order to make the skilled in the art better understand the technical solutions of the present application, the present application will be further described in detail below in combination with the drawings and the best mode.

[0035] Example 1: A method for inducing the crystal form of carbamazepine by self-assembled film, comprising the following steps: (1) immerse the gold-coated substrate in piranha solution (3:1 = H2SO4 / H2O2) for about 30 s; (2) rinse with distilled water, followed by purging and drying with high-purity N2; (3) immerse the treated gold-coated substrate in 1 mmol / L 11-mercaptoundecanoic acid solution for 12 h; (4) rinse off the excess solution with ethanol and dry with high-purity N2; (5) prepare a 0.03 g / mL carbamazepine solution in ethanol / water mixed solvent (80 / 20 vol.%) using water bath heating at 70°C; (6) keep the prepared self-assembled film in the above solution at 70°C for 15 min; (7) control the temperature of the circulating water bath to reduce the temperature of the solution to 5°C at a rate of 0.813°C / min, and then maintain the constant temperature for 30 min; (8) characterize the obtained crystal by Raman, PXRD, SEM, etc., and the results, as shown in Figure 1 Figure 5, are carbamazepine metastable crystal form II. 9) The main particle size of the product is 309.644 μm, the purity is 99.80%, and the crystal morphology is rectangular.

[0036] Example 2: A method for inducing a crystal form of carbamazepine using a self-assembled monolayer, comprising the following steps: (1) Immersing a gold-coated substrate in an arowana solution (3:1 = H2SO4 / H2O2) for about 30 s; (2) rinsing with distilled water, followed by drying with high-purity N2. (3) Immersing the treated gold-coated substrate in a 1 mmol / L mercaptobenzothiazole solution for up to 12 h. (4) Rinsing off the excess solution with ethanol and drying with high-purity N2. (5) Preparing a 0.03 g / mL carbamazepine solution in an ethanol / water mixed solvent (80 / 20 vol.%) using water bath heating at 70 °C; (6) Keeping the prepared self-assembled monolayer in the above solution at 70 °C for 15 min; (7) Controlling the temperature of the circulating water bath to reduce the temperature of the solution to 5 °C at a rate of 0.813 °C / min, and then keeping the temperature constant for 30 min. (8) Characterizing the obtained crystals using Raman, PXRD, SEM, etc., and the results, as shown in Figure 2 , are carbamazepine metastable crystal form II. (9) The main particle size of the product is 246.186 μm, the purity is 99.63%, and the crystal morphology grows in a needle shape.

[0037] Example 3: A method for inducing a crystal form of carbamazepine using a self-assembled monolayer, comprising the following steps: (1) Immersing a gold-coated substrate in an arowana solution (3:1 = H2SO4 / H2O2) for about 30 s; (2) rinsing with distilled water, followed by drying with high-purity N2. (3) Immersing the treated gold-coated substrate in a 1 mmol / L 11-mercaptoundecanol solution for up to 13 h. (4) Rinsing off the excess solution with ethanol and drying with high-purity N2. (5) Preparing a 0.0325 g / mL carbamazepine solution in an ethanol / water mixed solvent (80 / 20 vol.%) using water bath heating at 80 °C; (6) Keeping the prepared self-assembled monolayer in the above solution at 80 °C for 15 min; (7) Controlling the temperature of the circulating water bath to reduce the temperature of the solution to 8 °C at a rate of 0.813 °C / min, and then keeping the temperature constant for 30 min. (8) Characterizing the obtained crystals using Raman, PXRD, SEM, etc., and the results, as shown in Figure 3 , are carbamazepine metastable crystal form I. (9) The main particle size of the product is 282.068 μm, the purity is 99.82%, and the crystal morphology grows in a rectangular shape.

[0038] Example 4: A method for inducing a crystal form of carbamazepine by self-assembled monolayers, comprising the following steps: (1) immerse the gold-coated substrate in an arowana solution (3:1 = H2SO4 / H2O2) for about 30 s; (2) rinse with distilled water, followed by drying with high-purity N2; (3) immerse the treated gold-coated substrate in a 1 mmol / L 11-mercaptoundecanoic acid solution for 13 h; (4) rinse off the excess solution with ethanol and dry with high-purity N2; (5) prepare a 0.027 g / mL carbamazepine solution in an ethanol / water mixed solvent (80 / 20 vol.%) at 80°C using a water bath; (6) control the temperature of the circulating water bath to reduce the temperature of the solution to 50°C at a rate of 0.813°C / min; (7) immerse the previously prepared 11-mercaptoundecanoic acid self-assembled monolayer into the solution that is in the process of temperature reduction, and continue to program the temperature reduction of the solution; (8) control the temperature of the circulating water bath to bring the temperature of the solution to 5°C, and then maintain the temperature for 30 min; (9) characterize the obtained crystals by Raman, PXRD, SEM, etc., and the results, as shown in Figure 4 , are a metastable crystal form II of carbamazepine. (6) The main particle size of the product is 308.464 μm, and the purity is 99.68%, and the crystal morphology is rectangular.

[0039] Example 5: A method for inducing a crystal form of carbamazepine by self-assembled monolayers, comprising the following steps: (1) immerse the gold-coated substrate in an arowana solution (3:1 = H2SO4 / H2O2) for about 30 s; (2) rinse with distilled water, followed by drying with high-purity N2; (3) immerse the treated gold-coated substrate in a 1 mmol / L 11-mercaptoundecanoic acid solution for 13 h; (4) rinse off the excess solution with ethanol and dry with high-purity N2; (5) prepare a 0.0325 g / mL carbamazepine solution in an ethanol / water mixed solvent (80 / 20 vol.%) at 80°C using a water bath; (6) immerse the prepared self-assembled monolayer in the above solution at 80°C for 15 min; (7) after immersing the specific self-assembled monolayer, adjust the temperature reduction rate of the temperature reduction process to 0.5°C / min, so that the temperature of the solution reaches 5°C, and then maintain the temperature for 30 min; (8) take out the self-assembled monolayer substrate from the solution to obtain a metastable crystal form II of carbamazepine product. (9) The main particle size of the product is 408.359 μm, the purity is 99.92%, the crystal morphology is short rectangular, and the test results are as shown in Figure 5 .

[0040] Example 6: A method for inducing a crystal form of carbamazepine by self-assembled monolayers, comprising the following steps: (1) immerse the gold-coated substrate in an arowana solution (3:1 = H2SO4 / H2O2) for about 30 s; (2) rinse with distilled water, followed by drying with high-purity N2; (3) immerse the treated gold-coated substrate in 1 mmol / L mercaptobenzothiazole for 13 h; (4) rinse off the excess solution with ethanol and dry with high-purity N2; (5) prepare a 0.0325 g / mL carbamazepine solution in an ethanol / water mixed solvent (80 / 20 vol.%) using water bath heating at 80°C; (6) keep the prepared self-assembled monolayer in the above solution at 80°C for 15 min; (7) control the temperature of the circulating water bath to reduce the temperature at a rate of 0.727°C / min, constantly reduce the final temperature of the solution, and keep the temperature constant at the final temperature for 30 min; (8) take the self-assembled monolayer substrate out of the solution to obtain a carbamazepine metastable crystal form II product; (9) the main particle size of the product is 411.285 μm, the purity is 99.83%, the crystal morphology is short rectangular, and the test results are as shown in Figure 6 .

[0041] Example 7: A method for inducing a crystal form of carbamazepine by self-assembled monolayers, comprising the following steps: (1) immerse the gold-coated substrate in an arowana solution (3:1 = H2SO4 / H2O2) for about 30 s; (2) rinse with distilled water, followed by drying with high-purity N2; (3) immerse the treated gold-coated substrate in 1 mmol / L 11-mercaptoundecanol for 13 h; (4) rinse off the excess solution with ethanol and dry with high-purity N2; (5) prepare a 0.0325 g / mL carbamazepine solution in an ethanol / water mixed solvent (80 / 20 vol.%) using water bath heating at 80°C; (6) keep the prepared self-assembled monolayer in the above solution at 80°C for 15 min, and open the stirrer to keep the solution in a stirred state; (7) control the temperature of the circulating water bath to reduce the temperature at a rate of 0.813°C / min, while the stirrer is stirred at 200 rpm; (8) when the temperature is reduced to 5°C, a carbamazepine metastable crystal form I product is obtained at the interface of the self-assembled monolayer; (9) the main particle size of the product is 211.494 μm, the purity is 99.65%, the crystal morphology is short rectangular, and the test results are as shown in Figure 7 .

[0042] Example 8: A method for inducing a crystal form of carbamazepine by self- assembled membrane, comprising the following steps: (1) immerse the gold-coated substrate in an arowana solution (3:1 = H2SO4 / H2O2) for about 30 s; (2) rinse with distilled water, followed by drying with high-purity N2. (3) immerse the treated gold-coated substrate in 1 mmol / L 11-mercaptoundecanol for 13 h. (4) rinse off the excess solution with ethanol and dry with high-purity N2. (5) prepare a 0.0325 g / mL carbamazepine solution in an ethanol / water mixed solvent (80 / 20 vol.%) at 80°C using a water bath heater; (6) keep the prepared self-assembled membrane in the above solution at 80°C for 15 min, and turn on the stirrer to keep the solution in a stirred state; (7) control the temperature of the circulating water bath to reduce the temperature at a rate of 0.5°C / min, while the stirrer is stirred at 200 rpm. (8) When the temperature is reduced to 5°C, the carbamazepine metastable crystal form I product is obtained at the interface of the self-assembled membrane. (9) The main particle size of the product is 213.221 μm, the purity is 99.89%, the crystal morphology is short rectangular, and the test results are shown in Figure 8 .

[0043] Comparative Example 1: A method for inducing a crystal form of carbamazepine by self- assembled membrane, comprising the following steps: (1) immerse the gold-coated substrate in an arowana solution (3:1 = H2SO4 / H2O2) for about 30 s; (2) rinse with distilled water, followed by drying with high-purity N2. (3) prepare a 0.0278 g / mL carbamazepine solution in an ethanol / water mixed solvent (80 / 20 vol.%) at 75°C using a water bath heater; (4) keep the bare gold substrate in the above solution at 75°C for 15 min; (5) control the temperature of the circulating water bath to reduce the temperature of the solution to 6°C at a rate of 0.713°C / min, and then keep the temperature constant for 30 min. (6) The obtained crystals are characterized by Raman, PXRD, SEM, etc., and the results are shown in Figure 5 , which is a carbamazepine dihydrate crystal form. (7) The main particle size of the product is 492.372 μm, the purity is 99.43%, and the crystal morphology is plate-shaped.

[0044] Examples 9-12: Examples 9-12 are the same as Example 8, except that a quartz crystal microbalance gold film crystal oscillator substrate surface is used as a gold substrate, and then MUA (11- mercaptoundecanoic acid, Example 9), 2MBT (mercaptobenzothiazole, Example 10), MUOH (11- mercaptoundecanol, Example 11), and a bare QCM without mercapto compound modification (Example 12) are used as substrates, respectively; Figure 10-13 correspond to the crystal growth process diagram of the crystal form controllable crystallization process induced by the quartz crystal microbalance gold film crystal vibrator plate modified by the self-assembled film. The results show that the surface of the gold film crystal vibrator plate of the crystal microbalance can not only provide physical support for the formation of the self-assembled film, but also provide the gold film for the formation of the S-Au bond of the self-assembled film; and the piezoelectric effect thereof is used to monitor the process of crystal growth in real time in situ.

[0045] The above only describes the preferred embodiments of the present application, and it should be noted that those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A method of controlling the induction of a carbamazepine crystal form by a self-assembled film, characterized by, The method comprises the following steps: S1: Preparation of self-assembled film: immerse the treated gold film substrate into a solution of self-assembled film to form a film; the solution of self-assembled film is a solution of SH-R-R', wherein R is an aromatic group or an alkyl group, and R' is COOH, OH or H; the treatment of the gold film substrate is as follows: immerse the gold film substrate into a solution of Otocinclus for surface cleaning, then rinse with distilled water, and then dry by blowing with high-purity N2; S2: Solution cooling crystallization: add raw carbamazepine of crystal form III into a crystallizer of ethanol / water mixed solvent, then add the self-assembled film prepared in S1 into the crystallizer, heat to form a solution of carbamazepine with a concentration of 0.027-0.0325 g / mL, then control the temperature of water bath to reduce the temperature to 5-10 ℃ at a cooling rate of 0.7 ℃ / min-0.9 ℃ / min; S3: Characterize the crystal formed in S2.

2. The method of claim 1, wherein the self-assembled film induces the control of the crystalline form of carbamazepine. The solution of self-assembled film in S1 is 11-mercaptoundecanoic acid, mercaptobenzothiazole or 11-mercaptoundecanol.

3. The method of claim 1, wherein the self-assembled film induces the control of the crystalline form of carbamazepine. The concentration of the solution of self-assembled film in S1 is 0.5 mmol / L-2 mmol / L.

4. The method of claim 1, wherein the self-assembled film induces the control of the crystalline form of carbamazepine. The temperature in S2 is heated to 70-80 ℃.

5. The method of claim 1, wherein the self-assembled film induces the control of the crystalline form of carbamazepine. The ratio of ethanol / water in the ethanol / water mixed solvent in S2 is 80 / 20 vol.%.

6. A method for on-line monitoring of a crystallization process, characterized by, The method comprises the control method of any one of claims 1-5, and the gold film substrate in S1 is from the surface of a quartz crystal microbalance gold film crystal oscillator piece.

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