KR101404836B1 - Co-crystals of agomelatine and preparation methods therof - Google Patents
Co-crystals of agomelatine and preparation methods therof Download PDFInfo
- Publication number
- KR101404836B1 KR101404836B1 KR1020140033531A KR20140033531A KR101404836B1 KR 101404836 B1 KR101404836 B1 KR 101404836B1 KR 1020140033531 A KR1020140033531 A KR 1020140033531A KR 20140033531 A KR20140033531 A KR 20140033531A KR 101404836 B1 KR101404836 B1 KR 101404836B1
- Authority
- KR
- South Korea
- Prior art keywords
- agomelatine
- crystal
- hydroquinone
- resorcinol
- crystals
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- Y10S514/00—
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides novel agomelatine co-crystals and processes for their preparation. The novel agomelatine co-crystals of the present invention exhibit excellent solubility, high dissolution rate in acidic and neutral media, and excellent stability.
Description
The present invention relates to a novel process for preparing agomelatine comprising agomelatine (N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide and aromatic polyhydric alcohol and a process for preparing the same. The novel co-crystals of the agomelatin of the present invention exhibit improved solubility, dissolution rate and stability.
Agomelatine is the first antidepressant to simultaneously work with receptor agonists of MT1 and MT2 melatonin and antagonists of 5-HT2C. Through both of these actions, agomelatine can be used as a new antidepressant treatment to restore the severely impaired biological rhythm in depressed patients. Agomelatine is a melatonin-induced antidepressant drug developed by Servier Pharmaceuticals, and its trade names are Valdoxan, Melitor, and Thymanax. Agomelatine is marketed for the treatment of major depressive disorders and has been reported to have low symptoms and sexual adverse effects after discontinuation compared to other antidepressants, and has been shown to have a positive effect on sleep. According to a new clinical study at the 31st Annual European College of Neuropsychopharmacology (ECNP), agomelatine showed better efficacy compared to the conventional SSRI (selective serotonin reuptake inhibitor) and SNRI (serotonin noradrenaline reuptake inhibitor) antidepressants do.
However, agomelatin exhibiting such excellent effects has low solubility and is not easy to exert its effect. Studies on the polymorph of agomelatin have also been conducted to improve the solubility, The crystalline polymorph of melanin alone does not exhibit sufficient solubility and, as a result, does not show sufficient elution in the body.
It is an object of the present invention to provide novel agomelatin co-crystals with improved solubility of agomelatin and improved dissolution rate in acidic and basic media.
It is an object of the present invention to provide a process for preparing a novel agomelatin crystal.
The present invention provides novel co-crystals of agomelatine, including N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide and aromatic polyhydric alcohols .
[Chemical Formula 1]
In the present invention, the co-crystal of agomelatine and aromatic polyhydric alcohol exhibits excellent solubility in comparison with the polymorphs of agomelatine or agomelatine, resulting in higher dissolution rates in acidic and neutral media .
According to the "Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals" published by the US Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) in April 2013, A crystal is defined as a crystalline solid material composed of two or more molecules in the same lattice. Thus, the crystallization is distinct from the solid phase polymorph of the drug (API). Generally speaking, unlike polymorphisms that contain only drug molecules in a crystal lattice, the co-crystals consist of a coformer component that is neutral to the drug in the crystal lattice. Similarly, unlike the salts in which the components in the crystal lattice are in the ionized state, the co-crystal components are present in a neutral state and thus are defined as nonionic interactions.
In the present invention, the aromatic polyhydric alcohol functions as a porogen. The aromatic polyhydric alcohol may be an aromatic polyhydric alcohol in a solid state at room temperature, and may preferably be benzodiol, and most preferably hydroquinone, resorcinol, or a mixture thereof.
In the present invention, the co-crystallization of agomelatin is carried out by dissolving agomelatine and the aromatic polyhydric alcohol in a linear or branched C1-C5 alcohol, ester, ether or a mixture thereof to prepare a solution, And removing the organic solvent.
In the present invention, the organic solvent may be a C1-C3 alcohol, a C3-C7 ester, a C2-C7 ether, or a mixture thereof. For example, the organic solvent may be methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, diethyl ether, methyl-tert-butyl ether or a mixture thereof.
In the present invention, the agomelatin co-crystals can be prepared by pulverizing agomelatine and the aromatic polyhydric alcohol.
The present invention provides novel co-crystals of Agomelatin comprising N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide and hydroquinone represented by the following formula (1)
[Chemical Formula 1]
The co-crystallization of agomelatine and hydroquinone can exhibit improved solubility and dissolution rate as compared to conventional polymorphs of agomelatine. For example, the co-crystals of agomelatine and hydroquinone show an increased specific elution rate (IDR) as compared to conventional agomelatine (type II polymorph), and specifically show that in both acidic and neutral media, 2 (IDR) < / RTI >
In the present invention, in the co-crystallization of agomelatine and hydroquinone, the hydroquinone functions as a coformant.
In the present invention, the co-crystals of agomelatine and hydroquinone may contain agomelatine and hydroquinone in a molar ratio of 1: 0.5 to 1: 3, preferably 1: 1, .
The novel agomelatin-hydroquinone co-crystals in the present invention are characterized in that the powder XRD rotational pattern is selected from 10.45, 17.05, 17.55, 18.10, 19.30, 20.15, 21.05, 21.35, 21.80, 22.15, 23.60, 24.25, 26.30 o 2 &thetas; (+/- 0.2 o ).
The co-crystallization of agomelatine-hydroquinone shows a powder XRD diffraction pattern of 2θ (± 0.2 ° ) and intensity (I) of the powder XRD rotation pattern shown in Table 1 below and the powder XRD diffraction pattern of the co- .
[Table 1]
In the present invention, the co-crystallization of agomelatine and hydroquinone exhibits one differential scanning calorimetry (DSC) endothermic peak at 96.5 to 99.5 ° C. at a heating rate of 10 ° C./min, preferably one at 98 ° C. (DSC) endothermic peak of < / RTI >
The co-crystallization of agomelatine and hydroquinone,
A liquid phase method in which a solution is prepared by dissolving agomelatine and hydroquinone in a linear or branched C1-C5 alcohol, ester or ether, and the organic solvent is removed from the solution.
In the present invention, the step of removing the organic solvent may be carried out by allowing the solution to stand at room temperature or at room temperature in consideration of the drying time and evaporating the organic solvent. The drying may be performed using a conventionally known drying method such as vacuum drying, It can also be added.
In the present invention, the organic solvent may be a C1-C3 alcohol, a C3-C7 ester, a C2-C7 ether, or a mixture thereof. For example, the organic solvent may be methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, diethyl ether, methyl-tert-butyl ether or a mixture thereof, preferably methanol and ethyl acetate.
The co-crystallization of agomelatine and hydroquinone,
Solid state agomelatine and solid state hydroquinone.
In the present invention, the grinding of agomelatine and hydroquinone may be carried out,
Hydroquinone, and milling balls into a milling pot and rotating the milling pot on the rollers.
The milling pot may be rotated on the roller at a speed of 250 rpm to 450 rpm, preferably at 350 rpm.
The present invention provides novel co-crystals of agomelatine comprising resorcinol, N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide,
[Chemical Formula 1]
In the present invention, the resorcinol functions as a coformant in the co-crystals of agomelatine and resorcinol.
In the present invention, the co-crystals of agomelatine and resorcinol may contain agomelatine and resorcinol in a molar ratio of 1: 0.5 to 1: 3, preferably in a molar ratio of 1: 1 .
In the present invention the novel agomelatine-resorcinol ball crystals The powder XRD rotation pattern 7.4, 8.05, 8.4, 14.55, 16.75, 17.45, 18.10, 19.15, 20.00, 21.40, 21.85, 22.65, 23.85, 24.50 o (+/- 0.2 o ) selected from the following equation.
The co-crystal of agomelatine-resorcinol exhibits a 2θ (± 0.2 ° ) value and intensity (I) of the powder XRD rotation pattern in Table 2 below, and the powder XRD diffraction pattern of the co- .
[Table 2]
In the present invention, the co-crystallization of agomelatine and resorcinol exhibits two differential scanning calorimetry (DSC) endothermic peaks at 53 to 76 ° C. at a heating rate of 10 ° C./min, preferably 54.4 ° C. and (DSC) endothermic peak at < RTI ID = 0.0 > 74.5 C. < / RTI >
The co-crystals of agomelatine and resorcinol can be prepared,
And solid state agomelatine and solid state resorcinol.
In the present invention, the grinding of agomelatine and resorcinol can be carried out,
The agomelatine and resorcinol are added to the induction, followed by dry milling or mixing and grinding, or agomelatine and resorcinol are added to the induction and a small amount of linear or branched C1-C5 alcohol, ester or ether is added Or the like.
In the present invention, the organic solvent may be a C1-C3 alcohol, a C3-C7 ester, a C2-C7 ether, or a mixture thereof. For example, the organic solvent may be methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, diethyl ether, methyl-tert-butyl ether or a mixture thereof, preferably methanol and diethyl ether.
In the present invention, the grinding of agomelatine and resorcinol can be carried out,
The agomelatine, resorcinol, and milling balls can be prepared by injecting into a milling pot and rotating the milling pot on a roller.
The milling pot may be rotated on the roller at a speed of 250 rpm to 450 rpm, preferably at 350 rpm.
The co-crystals of agomelatine and resorcinol can be prepared,
Can be prepared by a liquid phase method in which a solution is prepared by dissolving agomelatine and resorcinol in a linear or branched C1-C5 alcohol, ester or ether, and the organic solvent is removed from the solution.
In the present invention, the step of removing the organic solvent may be carried out by allowing the solution to stand at room temperature or at room temperature in consideration of the drying time and evaporating the organic solvent. The drying may be performed using a conventionally known drying method such as vacuum drying, It can also be added.
In the present invention, the organic solvent may be a C1-C3 alcohol, a C3-C7 ester, a C2-C7 ether, or a mixture thereof. For example, the organic solvent may be selected from the group consisting of methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, diethyl ether, methyl-tert-butyl ether or mixtures thereof, preferably diethyl ether and methyl- Mixture, more preferably diethyl ether.
The present invention provides a pharmaceutical composition comprising the novel co-crystals of Agomelatin.
In the present invention, the novel co-crystals of agomelatine may be a co-crystal comprising agomelatine and an aromatic polyhydric alcohol. In the co-crystallization, the aromatic polyhydric alcohol may be an aromatic polyhydric alcohol which is solid at room temperature, preferably benzodiol, and more preferably hydroquinone, resorcinol, or a mixture thereof.
In the present invention, the pharmaceutical composition may be formulated by a conventional formulation method, including a carrier, adjuvant or diluent commonly used as an excipient together with the novel co-crystals of Agomelatin to be administered orally or parenterally .
In the present invention, the daily effective dose of the pharmaceutical composition is 1 mg to 3000 mg on an adult basis. The dose may be adjusted depending on the patient's age, weight, sex, dosage form, health condition, It may be administered once to several times per day.
The co-crystals of agomelatine of the present invention are superior in both solubility and dissolution rate in acidic and neutral media compared to conventional agomelatin (type II polymorph) and exhibit high stability, indicating that agomelatine The therapeutic effect can be maximized.
Fig. 1 is a graph showing the results obtained by the method according to the present invention. Fig. 1 is a graph showing the results obtained by using the evaporation method according to the present invention (Example 1, Example 2) (the upper graph in Fig. 1) and the ball milling (Example 3) X-ray diffraction (XRD) pattern of latin-hydroquinone co-crystals. In FIG. 1, both of the co-crystals according to the two manufacturing methods show the same XRD pattern, and compared with the X-ray diffraction pattern of Agomelatin (FIG. 2) and the hydroquinone X-ray diffraction pattern (FIG. 3) It can be seen that there is no quinone component. Thus, Figure 1 shows that a new agomelatin-hydroquinone co-crystal of high purity has been formed.
2 is an X-ray diffraction (XRD) pattern of conventional agomelatine (Type II polymorph,? 99.85%, Changzhou ruiming Pharmaceutical Co., Changzhou, China).
3 is an X-ray diffraction (XRD) pattern of hydroquinone (≥99%, Sigma Aldrich, St. Louis, Mo., USA). 1 to 3, the horizontal axis is 2? (Brag angle), and the vertical axis is the intensity (cps) of the X-ray.
FIG. 4 is a graph showing the differential scanning calorimetry (DSC) endotherms of the agomelatine-hydroquinone co-crystals produced by the evaporation liquid method (top view of FIG. 4) and the ball milling method (bottom view of FIG. 4) It is a peak.
5 is a differential scanning calorimetry (DSC) endothermic peak of conventional agomelatine (Type II polymorph, ≥99.85%, Changzhou ruiming Pharmaceutical Co., Changzhou, China).
6 is a differential scanning calorimetry (DSC) endothermic peak of hydroquinone (≥99%, Sigma Aldrich, St. Louis, Mo., USA). 4 to 6, the horizontal axis represents the temperature (占 폚), and the vertical axis represents the heat flux (mW).
In FIG. 4, both the liquid phase method according to the present invention and the endothermic peak of the agomelatine-hydroquinone co-crystal by the solid phase method occurred at around 98 ° C. Compared with the endothermic peak at 108 ° C and 175 ° C, respectively, seen in the case of melanatin (FIG. 5) and hydroquinone (FIG. 6), the crystallization according to the present invention is a new It can be seen that one agomelatine-hydroquinone co-crystal.
7 is a thermogravimetric analysis (TGA) graph of the agomelatine-hydroquinone co-crystal according to the present invention.
Figure 8 is a thermogravimetric analysis (TGA) graph of conventional agomelatine (Type II polymorph). 7 and 8, the abscissa represents the temperature (占 폚) and the ordinate represents the weight (mg) of the sample. Figures 7 and 8 clearly show that the co-determination according to the invention is significantly different from agomelatine.
FIG. 9 shows the dissolution rates of the conventional agomelatine and the agomelatine-hydroquinone co-crystal according to the present invention in acidic and neutral media, respectively. In FIG. 9, the horizontal axis represents time (minute) and the vertical axis represents concentration (mg / ml) of agomelatine. As a result, the dissolution rate of the agomelatine-hydroquinone co-crystals according to the present invention in both acidic and neutral media was significantly higher than that of conventional agomelatine.
Figure 10 shows the thermal stability of the agomelatine-hydroquinone co-crystal according to the invention. It can be confirmed that the X-ray diffraction pattern of the co-crystal powder heat-treated under the conditions shown in Experimental Example 6 is very stable as compared with the powder pattern before the heat treatment.
Fig. 11 is a graph showing the results of measurement of agomelatine-resorcinol (hereinafter referred to as " agomelatin-resorcinol ") prepared by the liquid phase method (Example 4) Fig. 5 is a diagram showing an X-ray diffraction (XRD) pattern of a crystal ball. In Fig. 11, both of the manufacturing methods showed the same XRD pattern and the comparison of the XRD pattern (Fig. 2) of existing agomelatine and the XRD pattern of resorcinol (Fig. 12) It can be seen that there is no crystal. Thus, Figure 11 shows that a high purity new agomelatine-resorcinol crystal was formed.
Figure 12 shows an X-ray diffraction (XRD) pattern of resorcinol (≥99%, Sigma Aldrich, St. Louis, Mo., USA). 11 and 12, the horizontal axis is 2? (Brag angle), and the vertical axis is the intensity (cps) of the X-ray.
13 shows the differential scanning calorimetry (DSC) of agomelatine-resorcinol co-crystals produced by the liquid phase method (top view of FIG. 13) and the ball milling (bottom view of FIG. 13) Endothermic peak.
14 is a differential scanning calorimetry (DSC) endothermic peak of resorcinol. 13 and 14, the horizontal axis indicates the temperature (占 폚) and the vertical axis indicates the heat flux (mW). The endothermic peaks in FIG. 13 occurred in the vicinity of 54 ° C. and 75 ° C. in both of the two production methods according to the present invention. However, the endothermic peak in FIG. 13 occurred at 108 ° C. in the agomelatin crystal form (FIG. 5) Peak. Thus, it can be confirmed that a new agomelatine-resorcinol-containing co-crystal not containing these two components is formed in Fig.
BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to explain the present invention more fully to those skilled in the art to which the present invention belongs.
Example 1 Preparation of Agomelatin-Hydroquinone Co-Crystal by Evaporation
0.552 grams of gum (g) and hydroquinone (≥99%, Sigma aldrich, st. Louis, MO) of agomelatine (type II polymorph, ≥99.85%, Changzhou ruiming pharmaceutical co., Changzhou, China) ) Were precisely weighed and placed in a 250 mL beaker. To this, 100 mL of ethyl acetate was added, the cap of the beaker was covered, and agomelatine and hydroquinone were fully dissolved while stirring at room temperature for 30 minutes. After sufficiently dissolving agomelatine and hydroquinone, the lid of the beaker containing the stable ethyl acetate solution was removed, and the ethyl acetate was allowed to spontaneously evaporate. The remaining solid was recovered in a beaker sufficiently dried with ethyl acetate within 20 hours, and then connected to a vacuum pump and dried under reduced pressure to obtain the agomelatin-hydroquinone co-crystal of the present invention.
Example 2 Preparation of Agomelatin-Hydroquinone Co-Crystal by Evaporation
Except that methanol was used in place of ethyl acetate in Example 1 and the remaining conditions were the same as in Example 1 to obtain the agomelatin-hydroquinone co-crystal of the present invention.
Example 3 Preparation of Agomelatin-Hydroquinone Co-Crystal by Ball Mill
0.552 grams of gum (g) and hydroquinone (≥99%, Sigma aldrich, st. Louis, MO) of agomelatine (type II polymorph, ≥99.85%, Changzhou ruiming pharmaceutical co., Changzhou, China) ) Were precisely weighed and placed in a milling pot of 250 mL zirconia. A zirconia ball was put thereinto and then tightly sealed. This was put on a roller and milled at a rotation speed of 350 rpm. After milling for 48 hours, the powder in the pot was recovered to obtain agomelatin-hydroquinone co-crystals.
Example 4 Preparation of Agomelatin-Resorcinol Crystalline Crystals by Evaporation
1.52 grams of agomelatine (type II polymorph, ≥99.85%, Changzhou ruiming pharmaceutical co., Changzhou, China) and 0.552 grams of resorcinol (≥99%, Sigma aldrich, St. Louis, MO) g) were precisely weighed and placed in a 250 mL beaker. 100 mL of diethyl ether was added thereto, the beaker was capped, and agomelatine and resorcinol were sufficiently dissolved while stirring at room temperature for 30 minutes. Agomelatine and resorcinol were sufficiently dissolved and the lid of the beaker containing the solution was removed to allow the diethyl ether to spontaneously evaporate. After 24 hours, the solid remaining in the beaker sufficiently dried with diethyl ether was recovered and dried under reduced pressure to obtain the agomelatin-resorcinol crystal of the present invention. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis results of the obtained agomelatine-resorcinol co-crystals are shown in FIGS. 11 and 13, respectively.
Example 5 Production of Agomelatine-Resorcinol Co-Crystal by Ball Mill
0.544 grams of resorcinol (≥99%, Sigma aldrich, st. Louis, MO), 2.44 grams of agomelatine (type II polymorph, ≥99.85%, Changzhou ruiming pharmaceutical co., Changzhou, China) g) were precisely weighed and placed in a milling pot of 250 mL zirconia material. A zirconia ball was put thereinto and then tightly sealed. This was put on a roller and milled at a rotation speed of 350 rpm. After milling for 72 hours, the powder in the pot was recovered to obtain agomelatin-resorcinol co-crystals. X-ray diffraction (XRD) analysis results of the obtained agomelatine-resorcinol co-crystals are shown in FIG. 11 and Table 2, and the results of differential scanning calorimetry (DSC) analysis are shown in FIG.
Experimental Example 1 X-ray diffraction (XRD) analysis
Agomelatin-hydroquinone co-crystals, agomelatine crystals and hydroquinone crystals obtained in Examples 1 to 3 were subjected to powder X-ray diffraction (XRD) analysis.
The powder XRD diffraction pattern was obtained by using a Rigaku DMAX-2200 X-ray diffraction analyzer using Cu-K ?, 0.154 nm as a solid phase detector under the condition of 40 kV / 40 mA.
200 mg of each sample powder was weighed to a flat surface on a silica mount prepared beforehand and Bragg angles (2θ) in the range of 5 to 35 ° were measured under the conditions of a step size of 0.05 ° and a goniometer speed of 3 seconds per step .
The X-ray diffraction (XRD) analysis results of the agomelatine-hydroquinone co-crystals obtained in Examples 1 to 3 are shown in FIG. 1 and Table 1 above.
XRD pattern analysis results of agomelatin crystal type (type II polymorph, ≥99.85%, Changzhou ruiming pharmaceutical co., Changzhou, China) and hydroquinone crystal type (≥99%, Sigma aldrich, St. Louis, MO) Are shown in Figs. 2 and 3.
As can be seen from FIGS. 1 to 3 and Table 1, the agomelatine-hydroquinone co-crystals synthesized in Examples 1 to 3 have a unique diffraction pattern different from agomelatine and hydroquinone , And it was found that the agomelatin-hydroquinone co-crystal was synthesized.
The XRD patterns of the agomelatine-resorcinol co-crystals and the resorcinol of Examples 4 and 5 were also analyzed. The results are shown in FIGS. 11, 12 and Table 2. As can be seen from FIGS. 11, 12 and Table 2, it can be seen that the agomelatine-resorcinol co-crystals have a unique diffraction pattern different from agomelatine and resorcinol from which agomelatine - resorcinol co-crystal was synthesized.
<Experimental Example 2> Analysis of differential scanning calorimetry (DSC)
The endothermic properties of the agomelatine-hydroquinone co-crystals, agomelatine and hydroquinone obtained in Example 1 were measured using a DSC-60 (Shimadzu, Japan) analyzer.
5 mg of each sample powder was placed in an aluminum container, and the DSC value was measured with an empty aluminum container as a reference. The DSC measurement was carried out at a temperature raising rate of 10 占 폚 / min under a nitrogen atmosphere at a temperature range of 30 to 300 占 폚.
The results of the DSC measurement of the agomelatin-hydroquinone co-crystals of Example 1 are shown in FIG. 4, and the DSC results of agomelatine and hydroquinone are shown in FIGS. 5 and 6, respectively.
As can be seen from the DSC measurement results, the agomelatine-hydroquinone co-crystals synthesized in Example 1 of the present invention showed one endothermic peak at about 98 ° C, and agomelatine and hydroquinone were 108 And an endothermic peak at 175 ° C. From this, it was found that pure agomelatine-hydroquinone co-crystals differing from agomelatine and hydroquinone were obtained.
On the other hand, the endothermic characteristics of the agomelatine-resorcinol crystal and resorcinol crystal form of Examples 4 and 5 were analyzed in the same manner, and the results are shown in FIG. 13 and FIG. As can be seen from Figs. 13 and 14, agomelatine-resorcinol co-crystals occurred at about 54 DEG C and 75 DEG C, whereas agomelatin crystal form (Fig. 5) ) Shows an endothermic peak at around 107 DEG C, so that it can be confirmed that a new agomelatine-resorcinol co-crystal not containing these two components is formed in Fig.
Experimental Example 3 Thermogravimetric analysis (TGA)
The thermogravimetry for the agomelatine-hydroquinone co-crystals and agomelatine obtained in Example 1 was determined using a TGA Q-50 (TA instrument, USA) analyzer.
Approximately 10 mg of the powder of each sample was mounted in a platinum container and analyzed under the condition of a temperature increase rate of 10 ° C / min under a nitrogen atmosphere at a temperature range of 30 to 300 ° C.
The TGA results of the agomelatin-hydroquinone co-crystals of Example 1 are shown in FIG. 7, and the TGA results of agomelatine are shown in FIG.
As can be seen from the above TGA results, it was found that the agomelatin-hydroquinone co-crystals synthesized in Example 1 of the present invention had a mass reduction start temperature and velocity different from those of agomelatine, It was found that pure solid crystals with no residual solvent in the crystal structure were produced because mass loss was not observed at the temperature.
≪ Experimental Example 4 >
After stirring a suspension of the agomelatin-hydroquinone co-crystal powder obtained in Example 1 sufficiently in 10 ml of purified water at 25 ° C in a constant temperature water bath for 24 hours, the concentration of agomelatin in the solution was measured by UV-3600 (Shimadzu, Japan) spectrophotometer.
The water solubility of the agomelatin-hydroquinone co-crystals synthesized in Example 1 of the present invention was measured to be 0.33 mg / ml, which was <0.1 mg, which is known as the water solubility of conventional agomelatine (type II polymorph) / ml. < / RTI >
≪ Experimental Example 5 >
To compare and measure the intrinsic dissolution rate (IDR) of agomelatine and agomelatine-hydroquinone co-crystals, 50 mg of agomelatine and 72.63 mg of agomelatin-hydroquinone co-crystals of Example 1 were diluted to a constant surface area Type pellets and then subjected to a dissolution test.
The powder of each sample was placed in a 13 mm pellet die (specac, UK) and a 0.5-ton weight was applied for 2 minutes using a hydraulic compressor (specac, UK) to produce a constant pellet with a surface area of 1.33 cm 2 .
The prepared pellet was immobilized in a test solution (pH 1.2 HCl aqueous solution and pH 6.8 phosphate buffer solution) of 37 캜 and 37 캜, and then the pellet of agomelatine released from the pellet was stirred with a USP apparatus 2 (paddle method) .
3 ml of each solution was sampled from the test solution at 3, 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105 and 120 minutes. The concentration of agomelatine in the collected solution was measured by UV- (Shimadzu, Japan) spectrophotometer.
The dissolution test results of agomelatine and agomelatin-hydroquinone co-crystals in a pH 1.2 HCl aqueous solution and a pH 6.8 phosphate buffer solution are shown in FIG. 9, and the intrinsic dissolution rate was calculated from the above results, The ratio is shown in Table 3.
[Table 3]
As can be clearly seen from the above table, the agomelatine-hydroquinone co-crystals show a remarkably improved dissolution rate of 2.2 times in the acidic medium and 2.7 times in the neutral medium than agomelatine. Therefore, it can be seen that the co-crystallization of agomelatine-hydroquinone prepared in the example of the present invention exhibits an improved dissolution rate and thus exhibits remarkably excellent effects in terms of therapeutic effect.
≪ Experimental Example 6 >
The agomelatine-hydroquinone co-crystal powder obtained in Example 1 was allowed to stand at 70 DEG C for 30 days, and the sample was recovered and subjected to X-ray diffraction analysis. The results are shown in FIG.
As can be seen from the above test results, the recovered solid sample was consistent with the crystal form of the agomelatin-hydroquinone co-crystal obtained in Example 1, so that the pure crystalline phase was maintained.
Claims (17)
A co-crystal comprising one aromatic polyhydric alcohol selected from hydroquinone and resorcinol.
[Chemical Formula 1]
[Table 1]
[Table 2]
Preparing a solution by dissolving one aromatic polyhydric alcohol selected from hydroquinone and resorcinol in a straight or branched chain C1-C5 alcohol, ester or ether;
And removing the organic solvent from the solution. ≪ Desc / Clms Page number 24 >
Hydroquinone, and resorcinol. ≪ RTI ID = 0.0 > 11. < / RTI >
Introducing the agomelatine, the aromatic polyhydric alcohol and the metal ball into a milling port; And
And rotating the milling pot at the roller.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020140033531A KR101404836B1 (en) | 2014-03-21 | 2014-03-21 | Co-crystals of agomelatine and preparation methods therof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020140033531A KR101404836B1 (en) | 2014-03-21 | 2014-03-21 | Co-crystals of agomelatine and preparation methods therof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR101404836B1 true KR101404836B1 (en) | 2014-06-09 |
Family
ID=51132167
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020140033531A KR101404836B1 (en) | 2014-03-21 | 2014-03-21 | Co-crystals of agomelatine and preparation methods therof |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR101404836B1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101470794B1 (en) * | 2014-06-30 | 2014-12-08 | 순천향대학교 산학협력단 | Method of preparing agomelatine cocrystal and composition including the same |
| KR101790411B1 (en) * | 2015-09-25 | 2017-10-26 | 순천향대학교 산학협력단 | Method of preparing micron powder of agomelatine cocrystal with narrow particle size distribution |
| KR101821855B1 (en) * | 2015-06-29 | 2018-01-24 | 순천향대학교 산학협력단 | Co-crystals of Febuxostat and methods of preparing therof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7927613B2 (en) | 2002-02-15 | 2011-04-19 | University Of South Florida | Pharmaceutical co-crystal compositions |
| WO2012146371A1 (en) | 2011-04-28 | 2012-11-01 | Zentiva, K.S. | Pharmaceutically acceptable cocrystals of n-[2-(7-methoxy-1-naphtyl)ethyl]acetamide and methods of their preparation |
| JP2013014584A (en) | 2011-06-09 | 2013-01-24 | Lab Servier | New co-crystal of agomelatine, method for preparing the same and pharmaceutical composition containing the same |
| EP2551257A1 (en) | 2011-07-28 | 2013-01-30 | Laboratorios Del. Dr. Esteve, S.A. | Co-crystals of agomelatine with co-crystal-formers |
-
2014
- 2014-03-21 KR KR1020140033531A patent/KR101404836B1/en not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7927613B2 (en) | 2002-02-15 | 2011-04-19 | University Of South Florida | Pharmaceutical co-crystal compositions |
| WO2012146371A1 (en) | 2011-04-28 | 2012-11-01 | Zentiva, K.S. | Pharmaceutically acceptable cocrystals of n-[2-(7-methoxy-1-naphtyl)ethyl]acetamide and methods of their preparation |
| JP2013014584A (en) | 2011-06-09 | 2013-01-24 | Lab Servier | New co-crystal of agomelatine, method for preparing the same and pharmaceutical composition containing the same |
| EP2551257A1 (en) | 2011-07-28 | 2013-01-30 | Laboratorios Del. Dr. Esteve, S.A. | Co-crystals of agomelatine with co-crystal-formers |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101470794B1 (en) * | 2014-06-30 | 2014-12-08 | 순천향대학교 산학협력단 | Method of preparing agomelatine cocrystal and composition including the same |
| WO2016003161A1 (en) * | 2014-06-30 | 2016-01-07 | 순천향대학교 산학협력단 | Method for preparing agomelatine cocrystals and composition containing same |
| US9795574B2 (en) | 2014-06-30 | 2017-10-24 | Soonchunhyang University Industry Academy Cooperation Foundation | Method for preparing agomelatine cocrystals and composition containing same |
| KR101821855B1 (en) * | 2015-06-29 | 2018-01-24 | 순천향대학교 산학협력단 | Co-crystals of Febuxostat and methods of preparing therof |
| KR101790411B1 (en) * | 2015-09-25 | 2017-10-26 | 순천향대학교 산학협력단 | Method of preparing micron powder of agomelatine cocrystal with narrow particle size distribution |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2022088504A (en) | L-ornithine phenyl acetate and methods of making the same | |
| JP2012519715A (en) | Novel crystalline form VI of Agomelatine, production method and application thereof | |
| WO2021136477A1 (en) | Cocrystal of dihydrochloride of compound i and preparation method therefor and use thereof | |
| KR101404836B1 (en) | Co-crystals of agomelatine and preparation methods therof | |
| DK2690087T3 (en) | NEW CRYSTAL FORM VII OF AGOMELATIN, METHOD OF PREPARING AND USING THEREOF AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME | |
| JP2014516921A (en) | Mixed crystal agomelatin (type VIII), preparation method and use thereof, and pharmaceutical composition containing the same | |
| CN113105389A (en) | Aripiprazole pharmaceutical co-crystal and preparation method thereof | |
| JP2019504046A (en) | Crystalline form of thienopyrimidine compounds | |
| NO329346B1 (en) | Pharmaceutical salts of reboxetine | |
| US20030114536A1 (en) | Venlafaxine hydrochloride monohydrate and methods for the preparation thereof | |
| KR101470794B1 (en) | Method of preparing agomelatine cocrystal and composition including the same | |
| Yu et al. | Salt or/and cocrystal? The case of the antidepressant drug venlafaxine | |
| JP4711961B2 (en) | 2-Methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane tartrate | |
| KR101821855B1 (en) | Co-crystals of Febuxostat and methods of preparing therof | |
| US9981912B2 (en) | Cocrystal of lorcaserin, preparation methods, pharmaceutical compositions and uses thereof | |
| CN114105888B (en) | Eutectic crystal of propylthiouracil and nutrient micromolecule with antioxidant activity and preparation method thereof | |
| WO2022009815A1 (en) | Succinate of octahydrothienoquinoline compound, and crystals thereof | |
| KR101790411B1 (en) | Method of preparing micron powder of agomelatine cocrystal with narrow particle size distribution | |
| TW202128604A (en) | An efficient crystallization process for preparing ultrapure treprostinil and crystal prepared therefrom | |
| EP3999035A1 (en) | Solid formulation of a 1,2,4-oxadiazole derivative | |
| WO2020041683A2 (en) | Acid addition salts of apomorphine, pharmaceutical compositions containing the same, and methods of using the same | |
| WO2018162393A1 (en) | Vinpocetine co-crystals and preparation process thereof | |
| NZ615707B2 (en) | New crystalline form vii of agomelatine, preparation method and use thereof and pharmaceutical composition containing same | |
| NZ615714B2 (en) | Mixed crystalline form-VIII of agomelatine, its method of preparation, application and pharmaceutical use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| A302 | Request for accelerated examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| LAPS | Lapse due to unpaid annual fee |