KR101303803B1 - Preparation of co-crystals of various drug substances including cabamazepine-saccharin co-crystals by anti-solvent method - Google Patents

Abstract

PURPOSE: A method for preparing co-crystals of cabamazepine-saccharin is provided to improve solubility and release rate of the corresponding drugs. CONSTITUTION: A method for preparing co-crystals of cabamazepine-saccharin comprises the steps of: dissolving carbamazepine and saccharin in an organic solvent selected among methanol, ethanol, and acetone and preparing a solution; adding an anti-solvent to the solution; closing a cover and stirring the mixture; and filtering the mixture by reduced pressure and collecting crystallized particles. The composition has a property peak at 6.9 degrees and 14.9 degrees. The composition has differential scanning calorimetry (DSC) peak at 177.5°C.

Description

Preparation of co-crystals of various drug substances including cabamazepine-saccharin co-crystals by anti-solvent method}

The present invention relates to a carbamazepine-saccharin cocrystal, a method for preparing the same, and a pharmaceutical composition comprising the same, and to a method for preparing the same and a pharmaceutical composition comprising the same.

Co-crystals are very active in recent years because of their potential for improving important pharmaceutical properties, such as the dissolution rate of class-II drugs by the BCS. Subject (Hickey et al. 2007; McNamara et al. 2006).

In addition, the development of new co-crystal materials is recognized as a very promising strategy for securing intellectual property rights as new materials depending on their novelty, utility and innovation (Trask 2007; Bhatt et al. 2009). In response, several reviews or overview papers on drug co-decisions have recently been published in foreign literature (Qiao et al. 2011; Babu et al. 2011; Sekhon 2009; Aakeroy et al. 2007).

Firstly, pharmaceutical co-crystals are distinguished from salts in which hydrogen ions from organic acids to bases are transferred and ion-bonded, so that coformers and drug molecules that exist in the solid state at room temperature. It becomes a building block to form a crystal structure by secondary bonds such as hydrogen bonds (Aakeroy et al. 2007).

With the recent increase in interest and R & D efforts in drug co-determination and new drug formulations based on it, the US Food and Drug Administration (FDA) has issued industry guidelines for co-determination in early 2011 (FDA 2011). ).

Co-crystals can be prepared by various methods (Wishkerman et al. 2009). Major methods include solvent evaporation, cooling, slurry reaction and solid-state grinding. grinding). Among them, the solid phase grinding method has excellent co-crystal formation ability since the work was started in 2005 in the mortar and bowl in the state of pure solid (neat) and a small amount of liquid-assisted (Trask et al. 2005a). At the same time, it attracts a lot of attention as an environmentally friendly co-crystal manufacturing method.

In addition, a method of preparing a co-crystal using a supercritical fluid (Padrela et al. 2009) and an ultrasound-assisted method (Dhumal et al. 2009) have been reported.

Saccharin is a well-known drug additive substance and can be said to be a safe substance included in General Recognized as Safe Substance (GRAS). Saccharin is known to form cocrystals with numerous drugs such as indomethacin and carbamazepine (banerjee et al. 2005). It has been reported that co-crystals of carbamazepine-saccharin can be prepared by the solvent evaporation method, cooling method, slurry reaction method and solid phase grinding method as listed above (Basavoju et al. 2008).

Anti-solvent crystallization is known to be a very promising method for producing drug crystals that can control the desired particle size of drug powders and enable high production rates (Tung et al. 2009). It is also a process that enables semi-batch and continuous operations. Until now, a method of making a crystal powder of a drug by anti-solvent crystallization has been well known for a long time, but there have been few reports of a practical example of a method of preparing a co-crystal having two or more components. In the study of co-crystals of caffeine and maleic acid, there was a case of adding n-hexane as an antisolvent to seed-added chloroform / methanol solution (Trask et al. 2005b). There was no report of detailed data or analysis of the results.

In a recent study, a patent has been applied for a method of preparing indomethacin-saccharin cocrystal using purified water as an antisolvent in various organic solvents (Korean Patent Application No .: 10-2011-0146131; 2011/12/29 ). However, methyl acetate, which claims to have special results in this patent, is a combination of evaporation and antisolvent, not pure antisolvent. This is because a large amount of solvent evaporation was observed during the co-crystal formation reaction for 1 hour because the reactor was without a lid in the course of the production process. Therefore, it can be interpreted that the amount of solvent is greatly reduced as a considerable amount of methyl acetate is evaporated, thereby significantly including the effects of the evaporation method. In addition, since the natural evaporation of some of these solvents is greatly affected by various environmental conditions such as temperature, the industrial value of this method is considered to be quite limited.

In the present invention, in preparing a co-crystal of carbamazepine-saccharin, each reactor is sealed with a lid to block the evaporation of a volatile solvent, thereby preparing a method of producing by antisolvent in a pure sense and the result thereof. will be. As a result, it was confirmed that cocrystal with saccharin of particularly excellent properties can be obtained only when methanol, not methyl acetate, is used as a solvent.

An object of the present invention is to provide a production method for producing a co-crystal of carbamazepine-saccharin by the antisolvent method of methanol-purified water.

It is an object of the present invention to provide a pharmaceutical composition comprising a carbamazepine-saccharin cocrystal.

The present invention provides a co-crystal containing carbamazepine-saccharin in order to solve the above problems.

The cocrystal comprising carbamazepine-saccharin of the present invention is characterized by using methanol as a solvent among various organic solvents.

The difference between the cobalt containing carbamazepine-saccharin and the conventional carbamazepine of the present invention is particularly evident from the results of powder X-ray diffraction (PXRD) analysis and differential scanning calorimetry (DSC) analysis.

<Cavamazepine-Saccharin Cocrystal>

The carbamazepine-saccharin cocrystal of the present invention is characterized by having a powder X-ray diffraction pattern showing clear peaks at Bragg angles (2θ) of 6.9 ° and 14.9 °.

The carbamazepine-saccharin cocrystal of the present invention is characterized by showing a clear DSC peak at a temperature of 177 ° C.

The present invention comprises the steps of (i) dissolving carbamazepine and saccharin in a solvent selected from the group of organic solvents consisting of ethyl acetate, methyl acetate, ethanol, methanol and acetone to prepare a solution; And (ii) allowing the solution containing the carbamazepine and saccharin to be left at atmospheric pressure with natural agitation while stirring without closing the lid, followed by filtration under reduced pressure to obtain crystallized particles. Provided are methods for preparing saccharin cocrystals.

The present invention also provides a method for preparing a solution comprising: (i) dissolving carbamazepine and saccharin in a solvent selected from the group of organic solvents consisting of ethyl acetate, methyl acetate, ethanol, methanol, and acetone; (ii) adding anti-solvent of purified water to the solution of step (i); And (iii) sufficiently stirring the solution of step (ii) with the lid closed to induce cocrystallization, and filtering under reduced pressure to obtain crystallized particles, the method for preparing carbamazepine-saccharin cocrystal. to provide.

The antisolvent generally means a solvent having a large dissolution parameter with respect to a drug that is a solute, and the antisolvent is mainly used as an accelerator of crystal or cocrystal formation through the action of aggregation and precipitation. In the present invention, when ethyl acetate, methyl acetate, ethanol, methanol and acetone are used as solvents of carbamazepine and saccharin, purified water can be used as an antisolvent.

The present invention also provides a pharmaceutical composition comprising the carbamazepine-saccharin cocrystal according to the present invention in association with a pharmaceutically acceptable diluent or carrier.

The compositions of the present invention may be administered orally (eg, tablets, lozenges, capsules, suspensions, emulsions, dispersants or elixirs), topical administration (eg, creams, ointments, gels, suspensions, or aqueous and oily agents). Solutions), inhalation administration (e.g., fine powders or liquid aerosols), insufflation administration (e.g., fine powders) or parenteral administration (e.g., injections or rectal suppositories). Suitable form.

 Cobalt crystallization of carbamazepine-saccharin according to the present invention can significantly improve the solubility and dissolution rate of the drug compared to the conventional carbamazepine.

1 is a diagram showing the results of X-ray diffraction analysis of the indomethacin-saccharin cocrystal prepared in Example of the present invention and the conventional indomethacin.
Figure 2 is a diagram showing the results of DSC analysis of the indomethacin-saccharin cocrystal prepared in Example of the present invention and the conventional indomethacin.
Figure 3 is a view showing the results of performing the dissolution test for the indomethacin-saccharin cocrystal and the conventional indomethacin prepared in the embodiment of the present invention.
Figure 4 is a view showing the results of X-ray diffraction analysis of the carbamazepine-saccharin cocrystal and the conventional carbamazepine prepared in the embodiment of the present invention.
5 is a view showing the results of DSC analysis of the carbamazepine-saccharin cocrystal prepared in the embodiment of the present invention and the conventional carbamazepine.

Hereinafter, the present invention will be described in more detail by way of examples. However, the scope of the present invention is not limited by the following examples.

Example 1 Preparation of Carbamazepine-Saccharin Cocrystal Using Methyl Acetate

Dissolve 472 mg of carbamazepine and 366 mg of saccharin in 30 mL of methyl acetate using an appropriate reaction apparatus. This solution is then naturally evaporated with stirring at room temperature at 500 rpm. After all solvents were evaporated, the resulting co-crystal particles were dried at 40 ° C. for 24 hours and then stored at room temperature.

Example 2 Preparation of Carbamazepine-Saccharin Cocrystal by Adding Purified Water to Methanol Solution

Dissolve 472 mg of carbamazepine and 732 mg of saccharin in 30 mL of methanol using an appropriate reaction apparatus. Then, add 50 mL of anti-solvent purified water to the solution, close the lid, and stir for 20 minutes at a speed of 300 rpm at room temperature. After confirming that a significant amount of solid crystalline was produced, the particles were collected via reduced pressure filtration. The collected particles were dried at 40 ° C. for 24 hours and then stored at room temperature.

Experimental Example 1 X-ray diffraction analysis of carbamazepine cocrystal

To determine the difference in crystal structure between the carbamazepine-saccharin cocrystal and the conventional carbamazepine prepared by the same procedure as in <Example 1> and <Example 2>, it was analyzed by X-ray diffraction method. The results are shown in FIG.

1 shows four X-ray diffraction patterns. (A) is saccharin, (b) is carbamazepine, (c) is co-crystal prepared by evaporation method using methyl acetate of <Example 1>, and (d) is <Example 2> The X-ray diffraction pattern of the co-crystal prepared by the anti-solvent method using methanol as a solvent is shown.

Both carbamazepine-saccharin cocrystals shown in (c) and (d) in FIG. 1 show strong diffraction peaks at Bragg angles of 6.9 ° and 14.9 °, unlike saccharin or carbamazepine. Since the peak cannot be observed at the position corresponding to the Bragg angle, it can be seen that only pure crystals are formed.

In detail comparing the X-ray diffraction pattern of the co-crystal prepared by the two methods in Figure 1, it can be seen that the peak of (d) as a whole larger than (c). This means that the crystallinity of the carbamazepine-saccharin cocrystal formed by the antisolvent method is higher. That is, the carbamazepine-saccharin cocrystal having better crystallinity than the evaporation method can be produced by the antisolvent method using methanol as a solvent.

Experimental Example 2 DSC Analysis of Carbamazepine Cocrystal

 The carbamazepine-saccharin cocrystals and the two components, respectively, were prepared to compare thermal properties of the carbamazepine-saccharin cocrystals prepared in <Example 1> to <Example 2>, respectively. 5 mg each of the platinum pan was started at 30 ° C. and scanned at 300 ° C. at a rate of 10 ° C./min to perform DSC analysis. The results are shown in FIG. 2.

2 shows all four DSC thermograms. (A) is saccharin, (b) is carbamazepine, (c) is co-crystal prepared by evaporation method using methyl acetate of <Example 1>, and (d) is <Example 2> DSC thermograms for cocrystals prepared by using methanol as a solvent and prepared by an antisolvent method are shown.

Both carbamazepine-saccharin cocrystals shown in (c) and (d) in FIG. 2 show strong melting point peaks at 177.5 ° C, unlike saccharin or carbamazepine, and temperatures corresponding to the melting point of carbamazepine or saccharin. Since the peak cannot be observed at, it can be seen that pure cocrystal was formed purely.

In detail comparing the DSC profile of the co-crystal prepared by the two methods in Figure 2, it can be seen that the peak of (d) as a whole larger than (c). This means that the crystallinity of the carbamazepine-saccharin cocrystal formed by the antisolvent method is higher. This observation is exactly the same as the observation from the previous X-ray diffraction analysis. Therefore, it was confirmed that the carbamazepine-saccharin cocrystal having better crystallinity than the evaporation method can be produced by the antisolvent method using methanol as a solvent.

The scope of the present invention is not limited to the embodiments described above, but is defined by the claims, and various changes and modifications can be made by those skilled in the art within the scope of the claims. It is self evident.

Claims (4)

(i) dissolving carbamazepine and saccharin in a solvent selected from an organic solvent consisting of ethanol, methanol and acetone to prepare a solution;
(ii) adding an anti-solvent to the solution of step (i); And
(iii) stirring the solution of step (ii) with the lid closed, and filtering under reduced pressure to obtain crystallized particles, characterized in that the Bragg angles (2θ) have characteristic peaks at 6.9 ° and 14.9 °. A method for producing a carbamazepine-saccharin cocrystal having an X-ray powder diffraction pattern showing a differential scanning calorimeter (DSC) peak at 177.5 ° C. The method of claim 1,
The antisolvent is purified water carbamazepine-saccharin cocrystal production method. The method of claim 2,
The organic solvent is a method for producing a carbamazepine-saccharin cocrystal. A composition comprising the carbamazepine-saccharin cocrystal according to claim 3 and an acceptable excipient.

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