KR101287423B1 - Crystalline form II of glyceryl phosphoryl choline - Google Patents

Abstract

The present invention relates to a type II crystal of glyceryl phosphoryl choline, and more particularly, after concentrating a conventional liquid L-α-glyceryl phosphoryl choline and dissolving it in an alcohol solution, the type II crystal is seed crystal It relates to type II crystals of L-α-glyceryl phosphoryl choline in monohydrate form obtained by feeding into (Seed crystal), aged and filtered.
The glyceryl phosphoryl choline type II crystal has an onset temperature of 62 ° C. and an endothermic peak of 66 ° C., an onset temperature of 141 ° C. and an endothermic peak of 145 ° C. in differential scanning calorimetry (DSC) analysis. In the powder X-ray diffraction (XRD) analysis, the 2θ diffraction angle is characterized by having a diffraction pattern of 10.3 ± 0.2 °, 12.2 ± 0.2 °, 13.4 ± 0.2 °, 14.8 ± 0.2 °, and 20.6 ± 0.2 °.

Description

Crystalline form II of glyceryl phosphoryl choline

The present invention relates to a type II crystal of glyceryl phosphoryl choline, and more particularly, after concentrating a conventional liquid L-α-glyceryl phosphoryl choline and dissolving it in an alcohol solution, the type II crystal is seed crystal ( Seed crystals), and a type II crystal of monohydrate form L-α-glyceryl phosphoryl choline obtained by aging and filtration.

L-α-glyceryl phosphoryl choline (hereinafter, also referred to as 'GPC') represented by Chemical Formula 1 is a known substance used as an agent for treating dementia as a brain function improving agent.

Conventionally known methods for producing L-α-glyceryl phosphoryl choline can be broadly classified into pure synthetic methods and extracting from lecithin, a byproduct of soybean. For example, the methods introduced in European Patent No. 486,100, Italian Patent No. 1,243,724, Italian Patent No. 1,247,496 and the like are pure synthetic methods, and are introduced in US Patent No. 5,250,719, UK Patent No. 2,058,792, and European Patent No. 217,765. Is a method of extraction from lecithin. Conventional GPCs produced in this way are all obtained in a liquid state containing a significant amount of water.

On the other hand, a method of crystallizing the liquid L-α-glyceryl phosphoryl choline is also known. First, J. Am. Chem. Soc. 70, 1394-1399 (1948) describes that hydrous GPC prepared by pure synthesis can be solidified in alcohol solution, but there is no mention of specific crystallization conditions or crystal structure.

In Korean Patent No. 262,281 (Dec. 29, 2000), GPC was prepared by deacylating reaction by alcoholicsis in a reactor containing a basic ion exchange resin, and using a nonpolar adsorbent resin to prepare a fat. After removal of the affinity impurities, the GPC is dissolved in methanol and concentrated in vacuo by adding about 20 times more n-butanol, followed by cooling and filtration to recover the anhydride crystals. However, in such a method, only a very hygroscopic fine crystal is reported to be formed, there is no mention of a specific crystal structure.

In addition, Korean Patent No. 966,627 (December 21, 2010) discloses a method for preparing GPC hydrochloride represented by the following Chemical Formula 2 using a crystallization solvent consisting of C1-C6 alcohol, C1-C6 ketone, and mixtures thereof. Although introduced, there is no mention of crystal structure either.

As described above, efforts have been made to crystallize GPC and the possibility has been suggested, but specific crystallization conditions and crystal structures are not mentioned. In addition, industrially available crystalline GPC raw materials have not been produced.

As described above, all GPC raw materials produced industrially so far are liquid, and currently commercially available GPC preparations are also limited to soft capsules using the liquid raw materials. However, these GPC soft capsules have the disadvantage that the active ingredient may dissolve the gelatinous coatings over time, require complex manufacturing facilities, use microbial anti-preservatives, and be inconvenient for patients to take. .

Accordingly, the present inventors have been researching powdered GPC to prepare GPC tablets that can replace GPC soft capsules, and the GPC crystals obtained by conventionally known crystallization methods are all polymorphic crystals. In addition to the crystals, it was confirmed that there are new crystal forms, Form I crystals and Form II crystals, which have completely different crystallographic characteristics. The present invention has been accomplished by optimizing the use of seed crystals and crystallization conditions to develop an effective method for industrially producing the type I crystals and the type II crystals.

It is an object of the present invention to provide Form II crystals of L-α-glyceryl phosphoryl choline.

Form II crystals of L-α-glyceryl phosphoryl choline according to the present invention have an onset temperature of 62 ° C. and an endothermic peak of 66 ° C., and an onset temperature of 141 ° C. in differential scanning calorimetry (DSC) analysis. And an endothermic peak of 145 ° C., and diffraction patterns having a 2θ diffraction angle of 10.3 ± 0.2 °, 12.2 ± 0.2 °, 13.4 ± 0.2 °, 14.8 ± 0.2 °, and 20.6 ± 0.2 ° in powder X-ray diffraction (XRD) analysis. It is characterized by having.

In addition, the method for producing L-α-glyceryl phosphoryl choline type II crystals according to the present invention, A) water content of 15-18% liquid L-α-glyceryl phosphoryl choline concentrated at a temperature of 45 ~ 65 ℃ To reduce the moisture content to 6-12%; B) dispersing the concentrated L-α-glyceryl phosphoryl choline obtained in step A) in an alcohol solution of 1 to 5 times, and cooling to a temperature of 5 ~ 20 ℃; C) To the alcohol solution of L-α-glyceryl phosphoryl choline obtained in step B), 0.1-0.5 mol% of L-α-glyceryl phosphoryl choline II crystal is added as a seed crystal and stirred. After aging for 2-5 hours without filtering the precipitated crystals; And a control unit.

L-α-glyceryl phosphoryl choline type II crystals according to the present invention is higher in purity than conventional liquid L-α-glyceryl phosphoryl choline raw material, and is easy to change the dosage form or dosage of pharmaceutical formulations of patients There is an effect that can produce a variety of high compliance formulations.

In addition, the type II crystal has excellent storage stability and easy handling in the formulation process, because the hygroscopicity of absorbing moisture in the air is very low compared to the conventional polymorphic crystal.

1 is an X-ray diffraction spectrum of a GPC type II crystal of the present invention,
2 is an X-ray diffraction spectrum of a conventional GPC polymorph crystal,
3 is a differential scanning calorie spectrum of a GPC type II crystal of the present invention,
4 is a differential scanning calorimetry spectrum for a conventional GPC polymorph crystal,
5 is a micrograph of a GPC type II crystal of the present invention,
6 is a micrograph of a conventional GPC polymorph crystal,
7 is a graph comparing the moisture content of GPC type I and type II and polymorphic crystals,
8 is an IR spectrum for GPC type I and II and polymorph crystals.

Form II crystals of L-α-glyceryl phosphoryl choline according to the present invention are monohydrate and have an onset temperature of 62 ° C. and an endothermic peak of 66 ° C. and an initiation of 141 ° C. in differential scanning calorimetry (DSC) analysis. Temperature (onset) and endothermic peak of 145 ° C, and 2θ diffraction angles in powder X-ray diffraction (XRD) analysis were 10.3 ± 0.2 °, 12.2 ± 0.2 °, 13.4 ± 0.2 °, 14.8 ± 0.2 °, 20.6 ± 0.2 ° It is characterized by having a diffraction pattern of.

In addition, the type II crystal of L-α-glyceryl phosphoryl choline is a hexagonal polyhedral form, the size of crystal grains is uniform about 200 ~ 300㎛, the melting temperature is about 66 ℃ (1 degree / min) to be. In addition, the hygroscopicity is lower than that of the conventional polymorphic crystal, so that the initial moisture content of 6.5% is almost maintained even when the raw material having moisture content, that is, the moisture content is 6.5% is left for about 10 hours under the condition of 30% humidity.

For reference, in the case of conventional polymorphic crystals, when the raw material having a moisture content of 2.9% is left under a humidity of 30% under relatively high hygroscopicity, the moisture content is 4.2% after 10 hours by absorbing moisture in the air as time passes. To rise. If such hygroscopicity is large, special handling is necessary because the weight and physical properties may change during raw material storage or formulation.

The method for preparing L-α-glyceryl phosphoryl choline type II crystals consists of the following three steps.

A) liquid L-α- glyceryl Concentration step of phosphoryl choline

First, the conventional liquid L-α-glyceryl phosphoryl choline is concentrated at a temperature of 45-65 ° C. to reduce the water content to 6-12%. At this time, when the concentration temperature is less than 45 ℃ or more than 65 ℃ occurs a flexible material occurs in the purification process. And if the water content after concentration is less than 6% undesired polymorphic crystals can occur, on the contrary 12% or more is not preferable because the crystallization yield is greatly reduced.

For reference, the conventional liquid L-α-glyceryl phosphoryl choline raw material has a water content, that is, a water content of about 15 to 18%, but the liquid L-α-glyceryl phosphoryl choline raw material may be used as it is without concentration. In this case, since the crystallization yield is low, in the present invention, it is preferable to concentrate the water content of the liquid L-α-glyceryl phosphoryl choline raw material to 6-12%.

When using liquid L-α-glyceryl phosphoryl choline having a water content of 15 to 18% as a starting material, the water content is reduced to 6 to 12% by concentrating at a temperature of 45 to 65 ° C for 8 to 10 hours.

B) concentrated L-α- glyceryl Dissolution Step of Phosphoryl Choline

Next, the L-α-glyceryl phosphoryl choline concentrated in the step A) was added to an alcohol solution at a temperature of 45 to 65 ° C. to dissolve, filtered through a membrane filter to remove foreign substances, and then a temperature of 5 to 20 ° C. Cool to.

In this case, ethanol and isopropyl alcohol may be used as the alcohol solution used as the crystallization solvent, and the amount thereof is 1 to 5 times, preferably 2 to 5 times the concentration of L-α-glyceryl phosphoryl choline. If the amount of the alcohol solution is out of the above range, the crystallization efficiency is lowered, resulting in a lower yield and purity.

In addition, if the cooling temperature of the alcohol solution is less than 5 ℃ has a problem that the crystal formation is rapidly accelerated and the size of the crystal grains do not grow sufficiently, on the contrary, if the temperature is 20 ℃ or more, GPC remains in the remaining water and alcohol after concentration, crystal yield This causes a decrease.

C) crystallization step

Finally, 0.1-0.5 mol% of Form II crystals of L-α-glyceryl phosphoryl choline are added to the alcohol solution of L-α-glyceryl phosphoryl choline obtained in step B) as seed crystal, After aging for 2 to 5 hours without stirring, the precipitated crystals were filtered to obtain monohydrate form L-α-glyceryl phosphoryl choline II crystals.

According to the experimental results of the present inventors, although it is possible to obtain a type II crystal without adding the seed crystal (Seed crystal), in this case it takes a aging time more than 24 hours, the problem that the crystal size does not grow sufficiently Occurs. Seed crystals first used in the preparation of Form II crystals according to the present invention used those prepared in this manner.

In the present invention, the crystal grain size is grown to about 200 ~ 300㎛ around the type II seed crystal (Seed crystal) during the aging process. As the crystal grains grow in this way, the surface area of the whole powder particles decreases, so that the hygroscopicity is relatively reduced. In addition, if the agitation in the aging process may be precipitated because I-type crystals may be precipitated.

Hereinafter, preferred examples will be described to aid in understanding the present invention. However, the following examples do not limit the scope of the present invention.

Liquid L-α-glyceryl phosphoryl choline (1.5 kg) having a water content of 18% was vacuum concentrated at a temperature of 50 ° C. for 9 hours to reduce the water content to about 9%. 3 liters of ethanol was added thereto, stirred while maintaining a temperature of 50 ° C., and then dissolved sufficiently, and then filtered through a 1.0 μm membrane filter to remove foreign substances.

Next, the L-α-glyceryl phosphoryl choline solution was cooled to 10 ° C., and 2.0 g of L-α-glyceryl phosphoryl choline II crystal was added thereto as seed crystals, and then aged for 4 hours without stirring. The precipitated crystals were filtered and dried in vacuo to obtain 1.02 kg (yield: 83%) of L-α-glyceryl phosphoryl choline II crystal having a water content of 6.5%.

A liquid L-α-glyceryl phosphoryl choline (1.5 kg) having a water content of 18% was vacuum concentrated at a temperature of 50 ° C. for 8 hours to confirm that the water content was about 11%. 3 liters of ethanol was added thereto, stirred while maintaining a temperature of 50 ° C., and then dissolved sufficiently, and then filtered through a 1.0 μm membrane filter to remove foreign substances.

Next, the L-α-glyceryl phosphoryl choline solution was cooled to 9 ° C., and 2.0 g of L-α-glyceryl phosphoryl choline II crystal was added thereto as seed crystals, and then aged for 3 hours without stirring. . The precipitated crystals were filtered and dried in vacuo to obtain 1.01 kg (yield: 82%) of L-α-glyceryl phosphoryl choline II crystal having a water content of 6.5%.

[Comparative Example]

Liquid L-α-glyceryl phosphoryl choline (30 g) having a water content of 18% was vacuum concentrated at a temperature of 50 ° C. for 8 hours, and azeotropy with 60 g ethanol to confirm that the water content was 4%. It was. After cooling to 5 ° C, the resulting crystals were aged for 1 hour, and the precipitated crystals were filtered and dried in vacuo to obtain 17 g (yield: 69%) of L-α-glyceryl phosphoryl choline polymorph crystal having a water content of about 2.9%. Got it.

For reference, the comparative example is described in J. Am. Chem. Soc. The manufacturing method described in 70, 1394-1399 (1948) and Korean Patent No. 262,281 was carried out.

[Crystal Analysis and Property Test]

end. Powder X-ray diffraction ( XRD ) analysis

Powder X-ray diffraction (XRD) analysis of the GPC type II crystals obtained in the above examples showed that the 2θ diffraction angles were 10.3 ± 0.2 °, 12.2 ± 0.2 °, 13.4 ± 0.2 °, and 14.8. Peaks were seen at ± 0.2 ° and 20.6 ± 0.2 °, respectively.

In addition, powder X-ray diffraction (XRD) analysis was performed on the GPC polymorph crystal obtained in the comparative example, and as shown in FIG. 2, the 2θ diffraction angles were 9.8 ± 0.2 °, 10.3 ± 0.2 °, 12.0 ± 0.2 °, Peaks were observed at 12.2 ± 0.2 °, 13.4 ± 0.2 °, 14.3 ± 0.2 °, 14.8 ± 0.2 °, 15.8 ± 0.2 °, and 19.6 ± 0.2 °, respectively. The measurement conditions of the powder X-ray diffraction (XRD) spectrum are as follows.

1) Device: PANalytical, X 'Pert-Pro / X Source: Cu

2) Tube voltage: 40 kV / Tube current: 30 mA

3) Divergence Slit: 1/2 ° / Scattering Slit: 1/2 ° / Light Receiving Slit: 0.15 mm

4) Scanning range: 5 to 40 ° 2θ / Sampling interval: 0.02 °

5) Scan Speed: 0.02 ° / sec

I. Differential scanning calories ( DSC ) analysis

As a result of differential scanning calorimetry (DSC) analysis on the GPC type II crystal obtained in the above example, as shown in FIG. 3, an onset temperature of 62 ° C., an endothermic peak of 66 ° C., and an initiation temperature of 141 ° C. ( onset) and an endothermic peak at 145 ° C. Further, as a result of differential scanning calorimetry (DSC) analysis on the GPC polymorph crystal obtained in the comparative example, as shown in FIG. 4, the starting temperature at 60 ° C., the endothermic peak at 60.4 ° C., the starting temperature at 62 ° C., and 64 ° C. The endothermic peak at, the end temperature at 143 ° C, the endothermic peak at 146 ° C, the start temperature at 147 ° C, and the endothermic peak at 149 ° C. In this case, the measurement conditions of the differential scanning calorimeter (DSC) spectrum is as follows.

1) Device: Mettler DSC 1102-R081, X

2) Measuring range: 50 to 200 ° C / Temperature interval: 1 ° C / min

3) N2 speed: 50ml / min

All. Microscopic photography

5 and 6 are micrographs (100 magnifications) of GPC type II crystals and polymorphic crystals, respectively. Form II crystal of the present invention is a hexagonal polyhedral form, as shown in Figure 5, the particle size is uniformly grown to about 200 ~ 300㎛ form a smooth particle surface, while the conventional polymorphic crystal is shown in Figure 6 As described above, crystal grains having a size of 20 to 25 µm are agglomerated with each other to form a mass having a size of 150 to 160 µm, and rough unevenness is formed on the surface.

la. Hygroscopicity ( Hygroscopicity ) exam

FIG. 7 is a graph showing changes in moisture content over time when GPC type I crystals, type II crystals, and polymorphic crystals are left at 30% humidity for 10 hours. X-axis is the elapsed time (T), and Y-axis is the moisture content ( %). The type I crystals and the type II crystals showed very low hygroscopicity after almost 10 hours after maintaining the initial moisture content.

In the case of polymorphic crystals, however, the water content was initially 2.9%, but as time passed, the water content was absorbed and the water content rose to 4.2% after 10 hours. As shown in FIG. 5 and FIG. 6, the polymorphic crystal exhibits high hygroscopicity, which is presumably because the crystal surface is rougher and there are more irregularities than the I-type and II-type crystals.

hemp. Infrared absorption ( IR A) spectrum

Finally, FIG. 8 shows infrared absorption (IR) spectra of GPC type I crystals, type II crystals, and polymorph crystals, respectively. It can be seen that it has both characteristics of type and type II crystals. In this case, the measurement conditions of the infrared absorption (IR) spectrum is as follows.

1) Device: FT / IR-4100 (Jasco)

2) Measuring range: 4000 to 650 cm-1

3) Resolution: 4.00 cm-1

4) Scan count: 36

Claims (5)

1) In the differential scanning calorimetry (DSC) analysis, it has an onset temperature of 62 ° C. and an endothermic peak of 66 ° C., an onset temperature of 141 ° C. and an endothermic peak of 145 ° C.,
2) In the powder X-ray diffraction (XRD) analysis, the 2θ diffraction angle shows a diffraction pattern of 10.3 ± 0.2 °, 12.2 ± 0.2 °, 13.4 ± 0.2 °, 14.8 ± 0.2 °, and 20.6 ± 0.2 °,
3) The crystal structure is a hexagonal polyhedron, the particle size is 200 ~ 300㎛,
4) Form II crystals of glyceryl phosphoryl choline, characterized by a dissolution temperature of 66 ° C. and a monohydrate. delete delete delete delete

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