Type-G crystal form of fenolamine, preparation method, composition and use thereof

Abstract

The present invention discloses a type-G crystal form of fenolamine, a preparation method thereof, and a composition and use thereof. In particular, disclosed is a type-G crystal form of the fenolamine compound (chemical name: trans-2-(2,5-dimethoxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)-N-(4-hydroxyphenylethyl)acrylamide, a preparation method thereof, and a composition and use thereof. Specifically, the present invention discloses the presence of a solid of a type-G fenolamine crystal form in solid state; a method for preparing the solid of type-G crystal form; and use of the solid of the type-G fenolamine crystal form as a pharmaceutical active ingredient in the manufacture of a medicament for prevention and treatment of Parkinson's disease (PD), improvement of learning and memory disorder, and treatment of memory loss and Alzheimer's disease (AD). ##STR00001##

Claims

1. A solid of a type-G fenolamine crystal form, wherein the solid of the type-G crystal form is a fenolamine hydrate and, by using powder X-ray diffraction analysis under CuKα radiation experimental conditions, has diffraction peaks at positions with 2-Theta values or d values and diffraction peaks with relative intensity peak height values or peak area values as shown below: TABLE-US-00004 2-Theta d (Å) Height % Area % Peak ±0.2° ±0.2 Å ±10% ±10% 1 7.3 12.2 20 29 2 7.8 11.4 15 18 3 9.2 9.6 10 11 4 10.7 8.2 21 23 5 11.3 7.8 34 58 6 11.6 7.6 29 48 7 12.6 7.0 7 8 8 13.1 6.7 47 64 9 13.6 6.5 13 18 10 15.0 5.9 10 11 11 15.6 5.7 5 4 12 17.6 5.0 33 45 13 18.3 4.8 70 72 14 19.6 4.5 37 57 15 19.9 4.5 41 76 16 20.4 4.3 78 84 17 20.8 4.3 21 30 18 22.1 4.0 16 15 19 22.7 3.9 4 2 20 23.4 3.8 100 100 21 23.9 3.7 12 14 22 24.7 3.6 51 45 23 25.5 3.5 69 82 24 26.5 3.4 6 6 25 27.2 3.3 9 10 26 27.9 3.2 7 6 27 28.6 3.1 12 13 28 29.1 3.1 12 19 29 30.5 2.9 8 9 30 31.5 2.8 5 5 31 32.9 2.7 6 14 32 33.9 2.6 3 4 33 34.3 2.6 3 5 34 34.9 2.6 1 1 35 35.6 2.5 4 6 36 37.3 2.4 3 3 37 38.1 2.4 6 8 38 40.1 2.2 4 8 39 41.5 2.2 2 2 40 42.3 2.1 6 5

2. The solid of a type-G fenolamine crystal form according to claim 1, wherein the solid of the type-G crystal form contains a hydrated water component, and it shows one weight loss peak in the range of 40 to 150° C. with a weight loss of 3.0% to 5.0% by using thermogravimetric analysis and has a water content of 3.0% to 5.0% by using Karl Fischer moisture analysis.

3. The solid of a type-G fenolamine crystal form according to claim 1, wherein by using differential scanning calorimetry analysis, one endothermic peak is present at a temperature of 96° C.±3° C. in a DSC spectrum in a range of 30 to 150° C. and at a heating rate of 3° C. per minute.

4. The solid of a type-G fenolamine crystal form according to claim 1, wherein by using attenuated total reflection Fourier infrared spectroscopy analysis, IR characteristic peaks are present at 3375, 2937, 2836, 1643, 1591, 1580, 1525, 1509, 1498, 1466, 1453, 1425, 1412, 1370, 1261, 1220, 1181, 1166, 1121, 1071, 1042, 1033, 1019, 944, 923, 895, 851, 817, 788, 774, 755, 732, 711, and 693 cm.sup.−1, wherein the allowable deviation of the IR characteristic peaks is ±2 cm.sup.−1.

5. The solid of a type-G fenolamine crystal form according to claim 1, wherein the solid of the type-G fenolamine crystal form is prepared by suspending a fenolamine solid material in water and stirring for 1 to 24 hours at an ambient temperature of 4° C. to 80° C. and an ambient humidity of 10% to 80% under normal pressure, and drying by suction filtration under reduced pressure for 1 to 24 hours.

6. A pharmaceutical composition comprising from 0.1 to 95 wt. % of a solid of mixed fenolamine crystal forms comprising the solid of a type-G fenolamine crystal form according to claim 1.

7. A pharmaceutical composition comprising an effective amount of the solid of type-G fenolamine crystal form according to claim 1, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7 comprising an amount of a solid of mixed fenolamine crystal forms comprising the solid of a type-G fenolamine crystal form according to claim 1 in the range of 10 to 500 mg.

9. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is in a dosage form of a tablet, a capsule, a pill, a powder for injection, a sustained release preparation, or a controlled release preparation, and is in a solid dosage form.

10. A pharmaceutical composition comprising from 0.1 to 95 wt. % of a solid of a mixed fenolamine crystal forms comprising the solid of a type-G fenolamine crystal form according to claim 2.

11. A pharmaceutical composition comprising from 0.1 to 95 wt. % of a solid of a mixed fenolamine crystal forms comprising the solid of a type-G fenolamine crystal form according to claim 3.

12. A pharmaceutical composition comprising from 0.1 to 95 wt. % of a solid of a mixed fenolamine crystal forms comprising the solid of a type-G fenolamine crystal form according to claim 5.

13. A pharmaceutical composition comprising an effective amount of the solid of mixed fenolamine crystal forms according to claim 6 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13 comprising an amount of a solid of mixed fenolamine crystal forms comprising the solid of a type-G fenolamine crystal form according to claim 1 in the range of 10 to 500 mg.

15. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is in a dosage form of a tablet, a capsule, a pill, a powder for injection, a sustained release preparation, or a controlled release preparation, and is in a solid dosage form.

16. A method of treating Parkinson's disease, improving learning and memory disorders, and treating memory loss and Alzheimer's disease comprising administering to a patient or animal in need thereof an effective amount of the solid of a fenolamine crystal form according to claim 1.

17. A method of treating Parkinson's disease, improving learning and memory disorders, and treating memory loss and Alzheimer's disease comprising administering to a patient or animal in need thereof the pharmaceutical composition according to claim 6 comprising an effective amount of the solid of mixed fenolamine crystal forms.

18. A method of treating Parkinson's disease, improving learning and memory disorders, and treating memory loss and Alzheimer's disease comprising administering to a patient or animal in need thereof an effective amount of the pharmaceutical composition according to claim 7.

19. A pharmaceutical composition comprising from 0.1 to 95 wt. % of a solid of a mixed fenolamine crystal forms comprising the solid of a type-G fenolamine crystal form according to claim 4.

20. A method of treating Parkinson's disease, improving learning and memory disorders, and treating memory loss and Alzheimer's disease comprising administering to a patient or animal in need thereof the pharmaceutical composition according to claim 19 comprising an effective amount of the solid of mixed fenolamine crystal forms.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a powder X-ray diffraction pattern of a type-G fenolamine crystal form sample;

(2) FIG. 2 is a TG diagram of a type-G fenolamine crystal form sample;

(3) FIG. 3 is a DSC profile of a type-G fenolamine crystal form sample;

(4) FIG. 4 is an infrared absorption spectrum of a type-G fenolamine crystal form sample.

DETAILED DESCRIPTION OF THE INVENTION

(5) The technical solutions of the present invention are described in details below with reference to the accompanying drawings and examples. However, the scope of protection of the present invention includes these embodiments but is not limited thereto.

Example 1

(6) Preparation Method 1 of Type-G Fenolamine Crystal Form Sample:

(7) 0.5 g of a solid sample of fenolamine recrystallized from ethanol as solvent was added to 50 mL of distilled water, placed under conditions of a constant temperature of 40° C. and an ambient humidity of 30%, stirred at a constant rate for 6 hours, filtered, and dried under reduced pressure for 2 hours to obtain a solid sample. Powder X-ray diffraction analysis (FIG. 1) shows that the obtained sample is a solid of a type-G crystal form, and the thermogravimetric diagram, DSC profile, and infrared spectrum are shown in FIG. 2 to FIG. 4.

(8) Preparation Method 2 of Type-G Fenolamine Crystal Form Sample:

(9) 0.5 g of a solid sample of fenolamine recrystallized from acetone as solvent was added to 100 mL of distilled water, placed under conditions of a constant temperature of 50° C. and an ambient humidity of 50%, stirred at a constant rate for 3 hours, filtered, and dried under reduced pressure for 4 hours to obtain a solid sample. Powder X-ray diffraction analysis gives a pattern consistent to that of FIG. 1, and the thermogravimetric diagram, DSC profile, and infrared spectrum are consistent with those shown in FIG. 2 to FIG. 4, indicating that the obtained sample is a solid of a type-G crystal form.

(10) Preparation Method 3 of Type-G Fenolamine Crystal Form Sample:

(11) 0.5 g of a solid sample of fenolamine recrystallized from isopropanol as solvent was added to 40 mL of distilled water, placed under conditions of a constant temperature of 60° C. and an ambient humidity of 40%, stirred at a constant rate for 8 hours, filtered, and dried under reduced pressure for 8 hours to obtain a solid sample. Powder X-ray diffraction analysis gives a pattern consistent to that of FIG. 1, and the thermogravimetric diagram, DSC profile, and infrared spectrum are consistent with those shown in FIG. 2 to FIG. 4, indicating that the obtained sample is a solid of a type-G crystal form.

(12) Preparation Method 4 of Type-G Fenolamine Crystal Form Sample:

(13) 0.5 g of a solid sample of fenolamine recrystallized from chloroform as solvent was added to 80 mL of distilled water, placed under conditions of a constant temperature of 60° C. and an ambient humidity of 40%, stirred at a constant rate for 5 hours, filtered, and dried under reduced pressure for 12 hours to obtain a solid sample. Powder X-ray diffraction analysis gives a pattern consistent to that of FIG. 1, and the thermogravimetric diagram, DSC profile, and infrared spectrum are consistent with those shown in FIG. 2 to FIG. 4, indicating that the obtained sample is a solid of a type-G crystal form.

(14) Preparation Method 5 of Type-G Fenolamine Crystal Form Sample:

(15) 0.5 g of a solid sample of fenolamine recrystallized from ethyl acetate as solvent was added to 100 mL of distilled water, placed under conditions of a constant temperature of 50° C. and an ambient humidity of 40%, stirred at a constant rate for 2 hours, filtered, and dried under reduced pressure for 6 hours to obtain a solid sample. Powder X-ray diffraction analysis gives a pattern consistent to that of FIG. 1, and the thermogravimetric diagram, DSC profile, and infrared spectrum are consistent with those shown in FIG. 2 to FIG. 4, indicating that the obtained sample is a solid of a type-G crystal form.

(16) Preparation Method 6 of Type-G Fenolamine Crystal Form Sample:

(17) 0.5 g of a solid sample of amorphous fenolamine was added to 150 mL of distilled water, placed under conditions of a constant temperature of 50° C. and an ambient humidity of 40%, stirred at a constant rate for 10 hours, filtered, and dried under reduced pressure for 24 hours to obtain a solid sample. Powder X-ray diffraction analysis gives a pattern consistent to that of FIG. 1, and the thermogravimetric diagram, DSC profile, and infrared spectrum are consistent with those shown in FIG. 2 to FIG. 4, indicating that the obtained sample is a solid of a type-G crystal form.

Example 2

(18) Stability of Solid of Type-G Fenolamine Crystal Form:

(19) Type-G fenolamine crystal form samples were placed in open clean watch glasses, and kept under conditions of a high temperature of 60° C., a high temperature of 40° C., and 25° C., a relative humidity of 90%±5%, and illumination at 4500 lx±500 lx for 10 days, and samples were taken on Days 0, 5, and 10. Powder X-ray diffraction (with a resultant pattern consistent to that in FIG. 1) and gas chromatography means were used for analysis. The results show that the type-G fenolamine crystal form is stable under conditions of high temperature, high humidity and light illumination, indicating that the solid of the type-G crystal form has good stability. All of the products from Example 1 were subjected to this test and achieved the same effect.

Example 3

(20) Preparation Method 1 of Combinational Drug Preparation (Tablet):

(21) A preparation method of a combinational drug tablet is characterized in that a pure product of type-G fenolamine crystal form or a solid of mixed crystal forms containing any ratio of the type-G crystal form used as a pharmaceutical raw material for a combinational drug, together with several excipients as adjuvant ingredients for preparing a combinational drug tablet, are used and formulated in a certain ratio into a tablet sample containing 50 to 500 mg drug per tablet. Table 2 shows the proportions in the tablet formulation:

(22) TABLE-US-00002 TABLE 2 Formulations for preparing fenolamine combinational drug tablets Amount in Formulation Names of raw materials and Formulation Formulation Formulation Formulation Formulation Formulation Formulation excipients 1 2 3 4 5 6 7 Fenolamine (mg) 50.0 75.0 100.0 150.0 250.0 300.0 500.0 Lactose (mg) q.s. q.s. q.s. q.s. q.s. q.s. q.s. Starch (mg) q.s. q.s. q.s. q.s. q.s. q.s. q.s. Low substituted hydroxypropyl q.s. q.s. q.s. q.s. q.s. q.s. q.s. cellulose (mg) Microcrystalline cellulose (mg) q.s. q.s. q.s. q.s. q.s. q.s. q.s. Talc powder (mg) q.s. q.s. q.s. q.s. q.s. q.s. q.s. Magnesium stearate (mg) q.s. q.s. q.s. q.s. q.s. q.s. q.s. 1% sodium hydroxymethyl- q.s. q.s. q.s. q.s. q.s. q.s. q.s. cellulose (mg)

(23) q.s.: appropriate amount

(24) The process of formulating a pure product of type-G fenolamine crystal form or a solid of mixed crystal forms containing any ratio of the type-G crystal form as a pharmaceutical raw material into a tablet preparation includes: uniformly mixing several excipients and the pharmaceutical raw material, adding an appropriate amount of a 1% sodium carboxymethylcellulose solution to prepare a soft material, sieving and granulating, drying the wet granules, sieving the granules, adding magnesium stearate and talc powder before mixing evenly, and pressing to obtain the tablets.

(25) Preparation Method 2 of Combinational Drug Preparation (Capsule):

(26) A preparation method of a combinational drug capsule is characterized in that a pure product of type-G fenolamine crystal form or a solid of mixed crystal forms containing any ratio of the type-G crystal form used as a pharmaceutical raw material for a combinational drug, together with several excipients as adjuvant ingredients for preparing a combinational drug capsule, are used and formulated in a certain ratio into a capsule sample containing 50 to 500 mg drug per tablet. Table 3 shows the proportions in the capsule formulation:

(27) TABLE-US-00003 TABLE 3 Formulations of raw materials and excipients for preparing fenolamine combinational drug capsules Amount in Formulation Names of raw materials and Formulation Formulation Formulation Formulation Formulation Formulation Formulation excipients 1 2 3 4 5 6 7 Fenolamine (mg) 50.0 75.0 100.0 150.0 250.0 300.0 500.0 Lactose (mg) q.s. q.s. q.s. q.s. q.s. q.s. q.s. Starch (mg) q.s. q.s. q.s. q.s. q.s. q.s. q.s. Microcrystalline cellulose (mg) q.s. q.s. q.s. q.s. q.s. q.s. q.s. Magnesium stearate (mg) q.s. q.s. q.s. q.s. q.s. q.s. q.s. 1% sodium hydroxymethyl- q.s. q.s. q.s. q.s. q.s. q.s. q.s. cellulose (mg)

(28) q.s.: appropriate amount

(29) The process of formulating a pure product of type-G fenolamine crystal form or a solid of mixed crystal forms containing any ratio of the type-G crystal form as a pharmaceutical raw material into a tablet preparation includes: uniformly mixing several excipients and the pharmaceutical raw material, adding an appropriate amount of a 1% sodium carboxymethylcellulose solution and granulating to prepare wet granules, drying and sieving the granules, adding magnesium stearate before uniformly mixing, and incorporating into a capsule. Alternatively, without the granulating step, the type-G fenolamine crystal form raw material is directly mixed with several excipients uniformly, and sieved and incorporated directly into a capsule.

Example 4

(30) Dosage 1 for Administration of a Crystalline Fenolamine Combinational Drug (Tablet):

(31) A pharmaceutical composition is developed and prepared by using a crystalline fenolamine sample as a pharmaceutically active ingredient, characterized in that the type-G fenolamine crystal form is used as a pharmaceutically active ingredient with a daily dose of 10 to 3000 mg, and can be prepared to be given in 1 to 6 common tablets each containing 10, 100, 200, 300, or 500 mg of the active ingredient once or twice per day, respectively.

(32) Dosage 2 for Administration of a Crystalline Fenolamine Combinational Drug (Capsule):

(33) A pharmaceutical composition is developed and prepared by using a crystalline fenolamine sample as a pharmaceutically active ingredient, characterized in that the type-G fenolamine crystal form is used as a pharmaceutically active ingredient with a daily dose of 10 to 3000 mg, and can be prepared to be given in 1 to 6 capsules each containing 10, 100, 200, 300, or 500 mg of the active ingredient once or twice per day, respectively.

(34) It is noteworthy that there are many factors influencing the given dosage of the active ingredient in the crystalline fenolamine pharmaceutical composition of the present invention, for example, different daily doses resulted from different preventative or therapeutic uses; different daily doses resulted from differences in the nature of the disease and the severity of the disease; different daily doses resulted from differences in gender, age, and body surface area of the patient, the route of administration, the number of administrations, and the purpose of treatment. In addition, the absorption and blood concentration of the crystalline sample may also vary, resulting in a suitable daily dosage in the range of 0.01 to 300 mg/kg body weight, preferably 1 to 50 mg/kg body weight, for using the crystalline fenolamine component according to the present invention. According to the actual needs in the prevention and treatment of various conditions in use, different overall dosage regimens may be established which can be accomplished by giving the active ingredient of the type-G fenolamine crystal form once or several times.