KR20150086160A - Crystal of Glyceryl Phosphoryl Choline and Method for Preparing Thereof - Google Patents

Abstract

The present invention relates to novel crystal of glyceryl phosphoryl choline and a method for preparing the same. According to the method, the novel crystal can be obtained by adjusting crystal precipitation temperature and agitation time in a solvent environment. The method is easier than the prior method because a seeding process is not needed. The crystal is proven to have a melting point of 100°C or higher and to be a stable solid form without change over time based on result of analysis on thermal stability and polymorphism of the crystal, and thus is very useful in terms of formulation. Moreover, the crystal has: a profile of excellent moisture absorption properties as a result of moisture absorption result; proper bulk density (BD) and tap density (TD) proper to produce formulation; uniform particle distribution; and symmetrical characteristics of normalized distribution. Therefore, the crystal can be formulated in an easy manner. The crystal of glyceryl phosphoryl choline of the present invention can be used as an agent for improving brain function and an agent for treating dementia.

Description

Technical Field [0001] The present invention relates to a crystal of glyceryl phosphoryl choline and a method for producing the same,

The present invention relates to a L-α-glyceryl phosphoryl choline (GPC) crystal used as a therapeutic agent for dementia as a brain function improving agent and a method for producing the same.

L-α-glyceryl phosphorylcholine (GPC) was first reported to be important for rapid brain development in the late 1990s and is known as chloline alfoscerate.

L-α-glycerylphosphorylcholine was reported to be a suitable precursor of acetylcholine as an important compound for the production of new acetylcholine in the brain. Acetylcholine is an important neurotransmitter that includes muscle regulation, sleep and perception, and is known to decrease as the aging process progresses, leading to decreased perception, vascular dementia, or neurodegeneration seen in Alzheimer's disease.

L-α-glycerylphosphorylcholine is represented by the following formula (1), and normalizing the cranial nerve cell and cholinergic neuronal system enables brain functions to be used for treating brain dysfunction caused by cerebrovascular diseases such as senescence or dementia (2S) -2,3-dihydroxypropyl] 2-trimethylazanium ethyl phosphate ([(2S) -2,3-Dihydroxypropyl] 2-trimethylazanylethyl phosphate.

Formula 1

On the other hand, the production method of L-α-glycerylphosphorylcholine is largely known as a pure synthesis method and a method of extracting from lecithin, which is a by-product of soybean. For example, pure synthetic methods are described in European Patent No. 486,100, Italian Patent No. 1,243,724, Italian Patent No. 1,247,496, etc., and U.S. Patent No. 5,250,719, British Patent No. 2,058,792, European Patent No. 217,765, etc. A method of extracting from lecithin is described. Conventional GPCs produced in this manner are all obtained in a liquid state containing a significant amount of water.

For the method of crystallizing the liquid L-α-glycerylphosphoryl choline, see J. Am. Chem. Soc . 70, 1394-1399 (1948), which mentions that solid GPC produced by the pure synthesis method can be solidified in an alcohol solution, but no specific crystallization method or crystal structure is mentioned.

In Korean Patent No. 10-0262281, a GPC was prepared by carrying out a deacylation reaction by alcoholysis in a reactor containing a basic ion exchange resin, removing lipophilic impurities using a non-polar adsorptive resin , A method of dissolving the GPC in methanol, adding about 20-fold amount of n-butanol to the solution, concentrating it in vacuo, cooling and filtering to recover crystals of an anhydrous form, none.

On the other hand, Korean Patent No. 10-1287422 discloses an I-form crystal of glycerylphosphorylcholine, Korean Patent No. 10-1287423 discloses a type II crystal of glycerylphosphorylcholine, Korean Patent Publication No. 10-2013-0063520 Discloses a method for producing an I-form crystal of glycerylphosphorylcholine, and Korean Patent Laid-Open No. 10-2013-0063521 discloses a method for producing a II-form crystal of glycerylphosphorylcholine.

However, in the case of glycerylphosphorylcholine, the crystalline solid was almost unique in that the I-form crystal was almost unique (dissolution temperature (mp) 150 ° C.), and the π type crystal had a melting point of 70 ° C. or lower There is a problem in that it can not be used formally. That is, the crystal form having a melting point of at least 100 캜 which is a pharmaceutically significant crystalline form has the above-mentioned I-form crystal, but the I-form crystal can not be obtained without seeding.

Accordingly, the present inventors have made efforts to develop a crystalline form of glycerylphosphorylcholine which is different from the crystalline form of glycerylphosphorylcholine and have pharmaceutically useful properties, as well as an easy method for the production process.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have made efforts to produce L-α-glyceryl phosphoryl choline (GPC) crystal form used as a therapeutic agent for dementia as a brain function improving agent. As a result, a novel crystal form of L-α-glyceryl phosphoryl choline (GPC) was prepared by controlling the crystallization temperature and stirring time in a solvent environment, and a thermodynamically aged time- It is a matastable solid form, has a good hygroscopic profile, is uniform in particle size, has a large bulk density (BD) and a large tap density (TD) And thus it can be produced by an easier method than the conventional method. Thus, the present invention has been completed.

Accordingly, an object of the present invention is to provide a glyceryl phosphoryl choline crystal characterized in that the crystalline form is III type.

Another object of the present invention is to provide a glyceryl phosphoryl choline crystal characterized in that the crystalline form is a type IV.

It is still another object of the present invention to provide a method for producing the above-described glyceryl phosphoryl choline crystal of the present invention.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, there is provided a powder X-ray diffraction (PXRD) analysis wherein the 2? Diffraction angles are 5.5 ± 0.2 ^° , 15.9 ± 0.2 ^° , 17.1 ± 0.2 ^° , 18.1 ± 0.2 ^° , 20.5 ± 0.2 ^° , 22.1 The peak is observed at ± 0.2 ^° and 23.2 ± 0.2 ^° C., and an endothermic peak at an endothermic onset temperature of 134 ° ± 2 ° C. and an endothermic temperature of 137 ° ± 2 ° C is observed in differential scanning calorimetry (DSC) analysis, (Glyceryl phosphoryl choline) crystals.

According to another aspect of the present invention, there is provided a powder X-ray diffraction (PXRD) analysis wherein the 2? Diffraction angles are 6.2 ± 0.2 ^° , 8.8 ± 0.2 ^° , 20.3 ± 0.2 ^° , 21.2 ± 0.2 ^° , 22.1 ± 0.2 ^° , And the endothermic peaks at ± 0.2 ^o , 25.2 ± 0.2 ^o, and 31.9 ± 0.2 ^o and endothermic start temperatures of 140 ° ± 2 ° C. and endothermic temperatures of 142 ° ± 2 ° C. in the differential scanning calorimetry (DSC) Type glyceryl phosphoryl choline crystals.

The present inventors have made efforts to produce L-α-glyceryl phosphoryl choline (GPC) crystal form used as a therapeutic agent for dementia as a brain function improving agent. As a result, a novel crystal form of L-α-glyceryl phosphoryl choline (GPC) was prepared by controlling the crystallization temperature and stirring time in a solvent environment, and a thermodynamically aged time- It is a matastable solid form, has a good hygroscopic profile, is uniform in particle size, has a large bulk density (BD) and a large tap density (TD) And thus it can be manufactured by an easier method than the conventional method.

The L-α-glyceryl phosphoryl choline (GPC) crystal of the present invention is a novel crystalline form through powder X-ray diffraction (PXRD) analysis and differential scanning calorimetry (DSC) Provides glyceryl phosphoryl choline crystals having crystalline forms III and IV.

According to one embodiment of the present invention, the glycerylphosphoryl choline crystals having a crystalline form of the crystalline form have a dissolution temperature of 137 ° C ± 2 ° C and the crystalline form of the glycerylphosphoryl choline crystals having a crystalline form has a dissolution temperature of 142 ° C ± 2 / RTI >

Hereinafter, the method of the present invention for producing glycerylphosphorylcholine crystals will be described in detail as follows:

(a) Dissolution and stirring of glycerylphosphorylcholine

First, the method of the present invention is a step of dissolving glycerylphosphorylcholine in a liquid phase in an organic solvent, adding a moisture absorbent thereto, and stirring.

According to another embodiment of the present invention, the glycerylphosphorylcholine of step (a) has a moisture content of 18% or less, more preferably a moisture content of 8-14%, and most preferably a moisture content of 10 -12%.

When the moisture content of the glycerylphosphorylcholine is out of the above range, undesired crystals may occur and the yield of crystallization may be greatly reduced.

The moisture absorber used in the step (a) can be selected from various moisture absorbers known in the art. Preferably, the moisture absorber is selected from the group consisting of calcium chloride (CaCl ₂ ), magnesium chloride (MgCl ₂ ), mica, diatomaceous earth, talc, zeolites, natural zeolites, magnesium oxide (MgO), iron oxide (Fe ₂ O _3), aluminum oxide (Al ₂ O _3), triethylamine, methyl cellulose, carboxymethyl cellulose, magnesium sulfate (MgSO _4), sodium sulfate (Na ₂ SO ₄ ), celite, 4 A (angstrom) molecular sieve (alkali metal aluminosilicate) or silica gel, and more preferably magnesium sulfate (MgSO ₄ ), sodium sulfate ₂ SO ₄ ), celite, 4 A (angstrom) molecular sieve (alkali metal aluminosilicate) or silica gel, and more preferably magnesium sulfate (MgSO ₄ ) or sodium sulfate Na ₂ SO _4), and most preferably sulfate Marg A syum (MgSO _4).

According to another embodiment of the present invention, the weight ratio of the glycerylphosphorylcholine and the hygroscopic agent in the step (a) is 1: 0.5-5, more preferably 1: 0.5-3, 1: 1-2.

According to another embodiment of the present invention, the glycerylphosphorylcholine of step (a) is 1-10% (w / v) based on the volume of the organic solvent of step (a), more preferably 3- 7% (w / v), even more preferably 4-6% (w / v).

According to another embodiment of the present invention, the organic solvent of step (a) is selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene, acetone, methyl acetate, ethyl acetate, methylene chloride More preferably methanol, ethanol, isopropyl alcohol or acetone, more preferably methanol, ethanol, isopropyl ether, benzene, ethylene glycol, propylene glycol, butylene glycol and acetonitrile, Or ethanol, and most preferably methanol.

According to another embodiment of the present invention, the stirring of step (a) is carried out at a temperature of 20-25 ° C for 10 minutes to 3 hours, more preferably at a temperature of 22-25 ° C for 30 minutes to 90 minutes , Still more preferably at a temperature of 23-25 ° C for 50 minutes to 70 minutes.

(b) Addition of organic solvent and filtration under reduced pressure

Then, the method of the present invention includes the step of adding an organic solvent to the result of the step (a), stirring, and then filtrating under reduced pressure.

According to another embodiment of the present invention, the organic solvent of step (b) is selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene, acetone, methyl acetate, ethyl acetate, More preferably methanol, ethanol, isopropyl alcohol or acetone, still more preferably methanol or ethanol, or more preferably methanol or ethanol, more preferably methanol, ethanol, isopropyl alcohol or acetone, more preferably methanol, Ethanol, most preferably methanol.

According to another embodiment of the present invention, the organic solvent of the step (b) is 1-4 times, more preferably 2-3 times, the volume of the organic solvent of the step (a) Is 2.2-2.6 times.

According to another embodiment of the present invention, the stirring of step (b) is carried out for 1-10 minutes, more preferably for 3-7 minutes.

(c) Vacuum concentration at 30-60 < 0 > C

In the method of the present invention, the filtrate obtained in step (b) is subjected to vacuum concentration at a temperature of 30-60 ° C.

The reason for the vacuum concentration in the above-mentioned temperature range is to reduce the water content of glycerylphosphorylcholine in consideration of the desired crystal and crystallization yield.

According to another embodiment of the present invention, the temperature for vacuum concentration is 40-50 캜, more preferably 43-47 캜.

(d) Addition of an organic solvent and vacuum concentration at a temperature of 30-60 DEG C

Then, the method of the present invention includes the step of adding an organic solvent to the resultant concentrated in step (c) and concentrating in vacuo at a temperature of 30-60 ° C.

One of the features of the present invention is that the crystallization yield is improved by performing two vacuum concentration steps.

According to another embodiment of the present invention, the temperature for vacuum concentration is 40-50 캜, more preferably 43-47 캜.

According to another embodiment of the present invention, the organic solvent of step (d) is 0.5-2 times, more preferably 0.7-1.5 times, the volume of the organic solvent of step (a) 0.8-1.2 times.

According to another embodiment of the present invention, the organic solvent of step (d) is selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene, acetone, methyl acetate, ethyl acetate, methylene chloride , More preferably toluene, acetone, methyl acetate, methylene chloride or acetonitrile, more preferably from the group consisting of chloroform, ether, petroleum ether, benzene, ethylene glycol, propylene glycol, butylene glycol and acetonitrile, Preferably acetone, methyl acetate or acetonitrile, and most preferably acetonitrile.

(e) Addition of an organic solvent and stirring at a temperature of 23-25 DEG C for 6 hours to 5 days

The process of the present invention is then followed by the step of adding an organic solvent to the resultant concentrated in step (d) and stirring for 6 to 5 days at a temperature of 23-25 ° C.

According to another embodiment of the present invention, the organic solvent of the step (e) is 0.5-2 times, more preferably 0.7-1.5 times, the volume of the organic solvent of the step (a) 1.0-1.4 times.

According to another embodiment of the present invention, the organic solvent of step (e) is selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene, acetone, methyl acetate, ethyl acetate, methylene chloride Is selected from the group consisting of chloroform, ether, petroleum ether, benzene, ethylene glycol, propylene glycol, butylene glycol and acetonitrile and is methanol, ethanol, methyl acetate or ethyl acetate, more preferably ethyl acetate and methanol, More preferably ethyl acetate in an amount of 0.8 to 1.3 times and methanol in an amount of 0.1 to 0.5 times the volume of the organic solvent in the step (a), even more preferably ethyl acetate in a volume ratio of 3-7: 1 and methanol to be.

One of the greatest features of the present invention is that the desired glycerylphosphoryl choline crystals are generated by controlling the agitation time at a temperature of 23-25 ° C.

According to another embodiment of the present invention, the stirring of step (e) is carried out for 6 to 24 hours, and by controlling the agitation time, a crystalline type III glyceryl phosphoryl choline crystal can be generated.

According to another embodiment of the present invention, stirring of the step (e) is carried out for 3 to 5 days, and by controlling the agitation time, a crystal type IV type glycerylphosphoryl choline crystal can be generated.

(f) Vacuum drying and obtaining glycerylphosphoryl choline crystals

Finally, the process of the present invention comprises vacuum drying the result of step (e) at a temperature of 40-70 DEG C for 12-24 hours to obtain glycerylphosphorylcholine crystals.

The vacuum drying is preferably carried out at a temperature of 50-60 ° C, more preferably at a temperature of 53-57 ° C, and more preferably at a temperature of 54-56 ° C.

The glycerylphosphorylcholine crystals obtained by vacuum drying at the above-mentioned temperature and time have a moisture content of 1% or less.

When the stirring time is adjusted to 6 hours to 24 hours in the step (e), the glycerylphosphorylcholine crystal of the step (f) is a crystalline type III glyceryl phosphoryl choline crystal, and the crystalline type III glyceryl Phosphoryl choline crystals were analyzed by powder X-ray diffraction (PXRD) analysis at 2θ diffraction angles of 5.5 ± 0.2 ^° , 15.9 ± 0.2 ^° , 17.1 ± 0.2 ^° , 18.1 ± 0.2 ^° , 20.5 ± 0.2 ^° , 22.1 ± 0.2 ^° and 23.2 ± And a peak at 0.2 ^o and an endothermic peak at an endothermic onset temperature of 134 ° C ± 2 ° C and an endothermic temperature of 137 ° C ± 2 ° C in differential scanning calorimetry (DSC) analysis.

On the other hand, when the agitation time is adjusted to 3 days to 5 days in the step (e), the glycerylphosphorylcholine crystal of the step (f) is a crystalline type IV glycerylphosphoryl choline crystal, The glycerylphosphoryl choline crystals were analyzed by powder X-ray diffraction (PXRD) analysis at 2? Diffraction angles of 6.2 ± 0.2 ^° , 8.8 ± 0.2 ^° , 20.3 ± 0.2 ^° , 21.2 ± 0.2 ^° , 22.1 ± 0.2 ^° , 23.7 ± 0.2 ^° , 25.2 ± 0.2 ^° and 31.9 ± 0.2 ^° . In differential scanning calorimetry (DSC) analysis, an endothermic peak at 140 ° ± 2 ° C and an endothermic temperature of 142 ° ± 2 ° C is observed.

In this way, a crystalline form of L-α-glyceryl phosphorylcholine (GPC) used as a therapeutic agent for dementia can be produced as a brain function improving agent.

The features and advantages of the present invention are summarized as follows:

(a) L-α-glyceryl phosphoryl choline (GPC) crystal form (Forms III and IV) used as a therapeutic agent for dementia as a brain function improving agent and a method for producing the same.

(b) The glycerylphosphoryl choline crystals of the present invention can be obtained by controlling the crystal precipitation temperature and stirring time in a solvent environment in the production of the novel crystals, and a seeding process is unnecessary, The manufacturing process is easier than that.

(c) The crystals of the present invention are found to be a stable solid form having a dissolution temperature of 100 ° C or higher and thermodynamic time-dependent changes do not occur through analysis of thermal stability and crystal polymorphism, and thus they are very useful for formulation.

(d) In addition, the hygroscopicity test results show that it has a good hygroscopic profile, and BD (bulk density) and TD (tap density) are suitable values for formulation and have a very uniform particle distribution and a symmetrical property of normal distribution, .

FIG. 1 shows the results of a powder X-ray diffraction (PXRD) analysis of glyceryl phosphoryl choline crystal type III according to an embodiment of the present invention.
FIG. 2 shows the results of differential scanning calorimetry (DSC) analysis of glyceryl phosphoryl choline crystal type III according to an embodiment of the present invention.
FIG. 3 is a graph showing the results of analysis of glyceryl phosphoryl choline crystal type III (New form (NF) -I) and conventional crystalline type I and II type powder X-ray diffraction (PXRD) analysis according to an embodiment of the present invention 2 &thetas; diffraction angles.
FIG. 4 shows the results of powder X-ray diffraction (PXRD) analysis of glyceryl phosphoryl choline crystal Form IV according to another embodiment of the present invention.
FIG. 5 shows the results of differential scanning calorimetry (DSC) analysis of glyceryl phosphoryl choline crystal Form IV according to another embodiment of the present invention.
FIG. 6 is a graph showing the results of analysis of glyceryl phosphoryl choline crystal type IV (New form (NF) -II) according to another embodiment of the present invention and conventional crystalline type I and II type powder X-ray diffraction (PXRD) 2 &thetas; diffraction angles.
FIG. 7 shows a result of powder X-ray diffraction (PXRD) analysis for confirming the transfer of a crystalline polymorphism after storing glyceryl phosphoryl choline crystal type III at 120 ° C. for 4 weeks according to an embodiment of the present invention.
8 is a graph showing the results of differential scanning calorimetry (DSC) analysis for confirming the transfer of the crystalline polymorphism after storing glyceryl phosphorylcholine choline type III at 120 ° C for 4 weeks according to an embodiment of the present invention.
9 is a graph showing the results of powder X-ray diffraction (PXRD) analysis for confirming whether a crystalline polymorphism is transferred after storing glyceryl phosphoryl choline crystal Form IV at 120 ° C for 4 weeks according to another embodiment of the present invention.
FIG. 10 shows the results of differential scanning calorimetry (DSC) analysis for confirming the transfer of the crystal polymorphism after storing glyceryl phosphoryl choline crystal Form IV at 120 ° C for 4 weeks according to another embodiment of the present invention.
11 shows the particle size distribution (PSD) of glyceryl phosphoryl choline crystal type III according to one embodiment of the present invention.
12 shows a particle diagram of a glyceryl phosphoryl choline crystal Form IV according to another embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Example 1: Preparation of crystalline form III (New form (NF) -I)

55 g of L-α-glycerylphosphoryl choline (GPC-12% moisture) liquid was dissolved in 275 ml of methanol at 24 ° C., then 82.5 g of MgSO ₄ was added and stirred at room temperature for 1 hour. Then, 660 ml of methanol was further added thereto, followed by stirring for 5 minutes. Then 5.5 g of celite was filtered through a packed filter and washed with 55 ml of methanol. A filtrate was obtained and concentrated in vacuo at a water bath temperature of 45 캜 until crystals precipitated. Thereafter, 275 ml of acetonitrile was further added, and the mixture was concentrated in vacuo at a water bath temperature of 45 캜 to obtain white crystals. 275 ml of ethyl acetate and 55 ml of methanol were added thereto, followed by stirring at 24 DEG C for 6 to 24 hours. Thereafter, the mixture was filtered under reduced pressure (washing with 55 ml of ethyl acetate) and vacuum-dried at 55 ° C for 12 hours to 24 hours to obtain 46.8 g of L-α-glycerylphosphorylcholine crystalline Form III (New form (NF) Yield: 85%).

Powder X-ray diffraction (PXRD) analysis

Powder X-ray diffraction (PXRD) analysis of the crystalline Form III revealed that the 2? Diffraction angles were 5.5 ± 0.2 ^° , 15.9 ± 0.2 ^° , 17.1 ± 0.2 ^° , 18.1 ± 0.2 ^° , 20.5 ± 0.2 ^° , 22.1 ± 0.2 ^° and 23.2 ^° 0.0 > 0 < / RTI > ^o (Fig. 1).

The scanning range was 5 to 40 ^° , 2?, And the scanning speed was 5 deg / min.

Differential scanning calorimetry (DSC) analysis

As a result of the differential scanning calorimetry (DSC) analysis of crystal form III, an endothermic peak was observed at an endothermic initiation temperature of 134 캜 2 캜 and an endothermic temperature of 137 캜 2 캜 (Fig. 2). The temperature raising range was 20-160 占 폚, and the temperature raising rate was 10 占 폚 / min.

Example 2: Preparation of crystalline Form IV

55 g of L-α-glycerylphosphorylcholine (GPC-12% moisture) liquid was dissolved in 275 ml of methanol at 24 ° C., and then 82.5 g of MgSO ₄ was added and stirred at room temperature for 1 hour. Then, 660 ml of methanol was further added thereto, followed by stirring for 5 minutes. Then 5.5 g of celite was filtered through a packed filter and washed with 55 ml of methanol. A filtrate was obtained and concentrated in vacuo at a water bath temperature of 45 캜 until crystals precipitated. Thereafter, 275 ml of acetonitrile was further added, and the mixture was concentrated in vacuo at a water bath temperature of 45 캜 to obtain white crystals. 275 ml of ethyl acetate and 55 ml of methanol were added thereto, followed by stirring at 24 DEG C for 3 to 5 days. Thereafter, the mixture was filtered under reduced pressure (washing with 55 ml of ethyl acetate) and vacuum-dried at 55 ° C for 12 hours to 24 hours to obtain 48.4 g of L-α-glycerylphosphoryl choline crystal form IV (New form (NF) (Yield: 88%).

Powder X-ray diffraction (PXRD) analysis

Powder X-ray diffraction (PXRD) analysis of crystal type IV revealed that the 2? Diffraction angles were 6.2 ± 0.2 ^° , 8.8 ± 0.2 ^° , 20.3 ± 0.2 ^° , 21.2 ± 0.2 ^° , 22.1 ± 0.2 ^° , 23.7 ± 0.2 ^° , 25.2 0.0 > 0.2 < / RTI > ^o and 31.9 + 0.2 ^o (Fig. 4). The scanning range was 5 to 40 ^° , 2?, And the scanning speed was 5 deg / min.

Differential scanning calorimetry (DSC) analysis

As a result of DSC analysis of the crystalline form IV, an endothermic peak was observed at an endothermic start temperature of 140 ° C ± 2 ° C and an endothermic temperature of 142 ° C ± 2 ° C (FIG. 5). The temperature raising range was 40-160 占 폚, and the temperature raising rate was 10 占 폚 / min.

Test example:

One of the most important factors in considering the effectiveness of the new crystalline form is that it should not cause a polymorphic transition due to aging changes in the process or storage of the formulation. When a crystal type transition occurs, the characteristics of the material itself may be changed, which may also affect the profile of the finished product. In the case of a crystalline form having a relatively low melting point, transition to a more stable crystalline form thermodynamically under certain conditions may occur. On the other hand, the most thermodynamically stable crystalline form of the formulation is not the optimum active active ingredient (API), and metastable crystalline forms, which generally meet the various properties required in the formulation, are often optimized active active ingredients do. Therefore, metastable crystalline polymorphism, which does not cause the transition of the polymorphism in a specific condition, such as the process or storage condition of the preparation, is very useful for pharmaceuticals. The present inventors have conducted the following experiments in this respect.

Test Example 1: Thermodynamic stability

Were stored at 60, 80, 100 and 120 ° C for 4 weeks for L-α-glycerylphosphorylcholine crystalline Form III and IV (New form (NF) -I, Type II) prepared in Examples 1 and 2, respectively , And thermodynamic stability.

The stability was measured by the residual ratio (%) with respect to the initial content of the active ingredient. The results are summarized in Table 1 below. The residual ratio was determined by quantitative determination of the compound. 300 mg of each compound was precisely measured, 5 ml of acetic anhydride and 45 ml of anhydrous acetic acid, and titrated with 0.1 mol / L perchloric acid.

- Early 60 ° C 80 ℃ 100 ℃ 120 DEG C Example 1 100% 99.8% 100% 99.5% 100.3% Example 2 100% 100.2% 99.9% 100.4% 99.7%

In addition, XRD and DSC were measured in order to confirm whether the crystal polymorphism was transferred in the case of the sample stored at 120 ° C. for 4 weeks. The results are summarized in FIGS. 7 to 10 below.

1 to 3 show the results of measurement of XRD and DSC of the L-α-glycerylphosphoryl choline type III (New form (NF) -I) prepared in Example 1 at 120 ° C. for 4 weeks before storage 4 to 6 show XRD and DSC measurements of the L-α-glycerylphosphoryl choline type IV (New form (NF) -II) prepared in Example 2 at 120 ° C. for 4 weeks before storage Results are shown.

As a result of the analysis of the thermal stability results and the crystal polymorphism, the L-α-glycerylphosphorylcholine crystalline Form III, IV (New form (NF) -I, Ⅱ form) prepared in Examples 1 and 2 exhibited thermodynamic time- It is confirmed that it is a stable solid form which does not occur.

Test Example 2: Hygroscopicity

Hygroscopicity tests of L-α-glycerylphosphorylcholine crystalline Form III and IV (New form (NF) -I, Type II) prepared in Examples 1 and 2 were conducted. In the case of the conventional known crystal form, when the raw material having a moisture content of 2.9% is left in a condition of relative humidity of 30% due to the relatively high hygroscopicity, moisture is absorbed in the air as time elapses and after a lapse of 10 hours, % (Refer to Korean Patent No. 10-1287422). However, if the hygroscopicity is large, special handling is necessary because the weight and physical properties may change during the raw material storage or formulation.

Thus, the L-α-glycerylphosphorylcholine I-form crystal of an anhydride described in Korean Patent No. 10-1287422 was used as Comparative Example 1, and the hygroscopicity comparative test was carried out as follows. On the other hand, the L-α-glycerylphosphoryl choline type II crystal described in Korean Patent No. 10-1287423 is a monohydrate type crystal having a moisture content of about 7% and a melting point of about 70 ° C. Were excluded from the experiment.

The test was carried out in a chamber having a relative humidity of 20, 30 and 40% at room temperature (25 캜), and the crystal form of Comparative Example 1, Examples 1 and 2 was added and the moisture was checked at each time point. Moisture was measured by Kahl Fisher.

- Comparative Example 1 Example 1 Example 2 Relative humidity
time 40% 30% 20% 40% 30% 20% 40% 30% 20% 0 hr 0.15% 0.15% 0.15% 0.22% 0.22% 0.22% 0.14% 0.14% 0.14% 1 hr 0.23% 0.19% 0.16% 0.28% 0.24% 0.23% 0.17% 0.17% 0.14% 2 hr 0.37% 0.22% 0.16% 0.31% 0.31% 0.23% 0.26% 0.20% 0.14% 3 hr 0.41% 0.29% 0.16% 0.39% 0.37% 0.24% 0.33% 0.22% 0.14% 4 hr 0.56% 0.38% 0.16% 0.47% 0.41% 0.24% 0.38% 0.30% 0.14% 5 hr 0.68% 0.42% 0.17% 0.53% 0.42% 0.26% 0.46% 0.33% 0.16% 6 hr 0.81% 0.47% 0.18% 0.77% 0.51% 0.26% 0.61% 0.44% 0.16% 7 hr 0.92% 0.53% 0.17% 0.83% 0.55% 0.26% 0.75% 0.46% 0.16% 8 hr 1.02% 0.64% 0.19% 0.92% 0.60% 0.26% 0.89% 0.51% 0.19% 9 hr 1.25% 0.68% 0.20% 1.01% 0.66% 0.28% 0.93% 0.54% 0.19% 10 hr 1.44% 0.73% 0.23% 1.03% 0.71% 0.28% 1.02% 0.66% 0.19%

As can be seen from Table 2 above, when the relative humidity of less than 1%, which is the reference humidity of the solid powder of a conventional active active ingredient (API), is used, the moisture content of Comparative Example 1 is 20% and 30% , But 40% shows humidification outside the reference humidity after 7 hours, whereas Examples 1 and 2 show similar water-solubility at relative humidity of 20 and 30%, but show better hygroscopicity than Comparative Example 1 at 40% Of the total population. Unlike Comparative Example 1, in which the pattern of humidification increases with time, in Examples 1 and 2, it was found that the particles saturate after a certain period of time. The characteristic of such a crystalline polymorph means that it has a more stable hygroscopic profile under normal working conditions.

Test Example 3: Ease of Preparation

In the case of solid powder, mixing with the excipient at the time of tableting, flow rate of the particles, uniformity of the particles and the like are very important. This is because the particles are homogeneously distributed on the particle size distribution, and the larger the bulk density (BD) and the tap density (TD) are, the better the fluidity and the saturation are.

BD (Bulk density of powder) and TD (Powder tap density) were measured for crystalline Forms III and IV (New Form (NF) -I, Type II) of Examples 1 and 2, BD and TD were prepared by accurately weighing 10 g of powder in a measuring cylinder and measuring the particle size distribution (PSD) using a particle size analyzer (Malvern) The Mastersizer 2000 was placed in the standard mode and measured.

- Example 1 Example 2 Bulk density (BD) 0.43 g / ml 0.45 g / ml TD (tap density) 0.63 g / ml 0.66 g / ml

Generally, in the case of a solid powder having a BD of 0.3 or less and a TD of 0.4 or less, there is a disadvantage in that the tablet has a disadvantage in that the tablets are bulky when the tablets are tableted due to severe electrostatic discharge or scattering. However, The BD and TD values of crystalline Forms III and IV (New Form (NF) -I, Type II) showed values suitable for formulation. As can be seen in Figures 11 and 12, the crystalline forms of Examples 1 and 2 are PSD It was confirmed that the powder is an ideal powder with very homogeneous particle distribution and symmetrical property of normal distribution.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (17)

In the powder X-ray diffraction (PXRD) analysis, peaks at 2θ diffraction angles of 5.5 ± 0.2 ^° , 15.9 ± 0.2 ^° , 17.1 ± 0.2 ^° , 18.1 ± 0.2 ^° , 20.5 ± 0.2 ^° , 22.1 ± 0.2 ^° and 23.2 ± 0.2 ^° And a glyceryl phosphoryl choline crystal characterized by having an endothermic peak at an endothermic start temperature of 134 ° C ± 2 ° C and an endothermic temperature of 137 ° C ± 2 ° C in a differential scanning calorimetry (DSC) analysis, .
In the powder X-ray diffraction (PXRD) analysis, the 2? Diffraction angles were 6.2 ± 0.2 ^° , 8.8 ± 0.2 ^° , 20.3 ± 0.2 ^° , 21.2 ± 0.2 ^° , 22.1 ± 0.2 ^° , 23.7 ± 0.2 ^° , 25.2 ± 0.2 ^°, 0.2 ^° , and showed an endothermic peak at an endothermic onset temperature of 140 ° C ± 2 ° C and an endothermic temperature of 142 ° C ± 2 ° C in a differential scanning calorimetry (DSC) analysis, and the crystal form was of the type IV, glycerylphosphorylcholine (glyceryl phosphoryl choline) crystals.
A process for preparing a glyceryl phosphoryl choline crystal comprising the steps of:
comprising the steps of: (a) dissolving glyceryl phosphoryl choline in the liquid phase in an organic solvent, and thereto was added magnesium sulfate (MgSO ₄₎ or sodium sulfate (Na ₂ SO ₄₎ as an absorbent and stirred;
(b) adding an organic solvent to the resultant product of step (a), stirring the mixture, and then subjecting the mixture to reduced pressure filtration;
(c) vacuum-concentrating the resultant filtered in step (b) at a temperature of 30-60 ° C;
(d) adding acetonitrile as an organic solvent to the resultant concentrated in step (c) and concentrating in vacuo at a temperature of 30-60 ° C;
(e) adding ethyl acetate and methanol as an organic solvent in a volume ratio of 3-7: 1 to the resultant concentrated in step (d) and stirring at a temperature of 23-25 ° C for 6 hours to 5 days; And
(f) vacuum drying the result of step (e) at a temperature of 40-70 ° C for 12-24 hours to obtain glycerylphosphoryl choline crystals.
4. The method of claim 3 wherein the glyceryl phosphoryl choline in step (a) has a moisture content of 18% or less.
4. The method according to claim 3, wherein the glycerylphosphoryl choline and the hygroscopic agent in step (a) have a weight ratio of 1: 0.5-5.
4. The method according to claim 3, wherein the glycerylphosphorylcholine of step (a) is 1-10% (w / v) based on the volume of the organic solvent of step (a).
The method according to claim 3, wherein the stirring of step (a) is carried out at a temperature of 20-25 ° C for 10 minutes to 3 hours.
4. The method according to claim 3, wherein the organic solvent in step (b) is 1-4 times the volume of the organic solvent in step (a).
4. The method according to claim 3, wherein the organic solvent in step (d) is 0.5-2 times the volume of the organic solvent in step (a).
4. The method according to claim 3, wherein the organic solvent in step (e) is 0.5-2 times the volume of the organic solvent in step (a).
4. The method of claim 3, wherein the organic solvent in step (a) and (b) is selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene, acetone, methyl acetate, ethyl acetate, , An organic solvent selected from the group consisting of chloroform, ether, petroleum ether, benzene, ethylene glycol, propylene glycol, butylene glycol and acetonitrile.
4. The method according to claim 3, wherein the stirring of step (e) is carried out for 6 to 24 hours.
13. The method according to claim 12, wherein the glycerylphosphorylcholine crystal of step (f) is a crystalline type III glyceryl phosphoryl choline crystal.
14. The method according to claim 13, wherein the crystal type III glyceryl phosphoryl choline crystals have a 2? Diffraction angle of 5.5 ± 0.2 ^° , 15.9 ± 0.2 ^° , 17.1 ± 0.2 ^° and 18.1 ± 0.2 ^° in powder X-ray diffraction (PXRD) , 20.5 ± 0.2 ^{° C} , 22.1 ± 0.2 ^{° C} and 23.2 ± 0.2 ^° C, and showed an endothermic peak at an endothermic onset temperature of 134 ° C ± 2 ° C and an endothermic temperature of 137 ° C ± 2 ° C in differential scanning calorimetry (DSC) Lt; / RTI >
4. The method according to claim 3, wherein the stirring of step (e) is carried out for 3 to 5 days.
16. The method according to claim 15, wherein the glycerylphosphoryl choline crystal in step (f) is a crystalline type IV glyceryl phosphoryl choline crystal.
The crystal type IV type glyceryl phosphoryl choline crystal according to claim 16, wherein the 2? Diffraction angles in the powder X-ray diffraction (PXRD) analysis are 6.2 ± 0.2 ^° , 8.8 ± 0.2 ^° , 20.3 ± 0.2 ^° , 21.2 ± 0.2 ^° , 22.1 ± 0.2 ^{° C} , 23.7 ± 0.2 ^{° C} , 25.2 ± 0.2 ^{° C} and 31.9 ^{° C} ± 0.2 ^{° C} , respectively. In the differential scanning calorimetry (DSC) analysis, an endothermic onset temperature of 140 ° C ± 2 ° C and an endothermic temperature of 142 ° C ± 2 ° C Wherein an endothermic peak is observed.

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