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

Abstract

The present invention discloses a type-B crystal form of fenolamine, a preparation method thereof, and a composition and use thereof, more particularly a type-B 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-B fenolamine crystal form in solid state; a method for preparing the solid of type-B crystal form; and use of the solid of the type-B 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 the type-B fenolamine crystal form, wherein the solid of the type-B fenolamine crystal form is a subtype having a ratio of fenolamine molecule to crystallized ethanol molecule of 1:0.2, and by using powder X-ray diffraction analysis under the CuK radiation experimental conditions, has diffraction peaks at positions with 2-Theta values)(), which include: 10.60.2, 16.00.2, 21.40.2, 21.70.2, 24.40.2 and 25.60.2.

2. The solid of the type-B fenolamine crystal form according to claim 1, wherein by using differential scanning calorimetry analysis, one endothermic peak at 123 C.3 C. and one at 130 C.3 C. are present respectively in the DSC pattern thereof in a range of 30 to 150 C. and at a heating rate of 3 C. per minute.

3. The solid of the type-B fenolamine crystal form according to claim 1, wherein by using attenuated total reflection Fourier infrared spectroscopy analysis, IR characteristic peaks are present at 3392, 3174, 3014, 2937, 2834, 2060, 1864, 1649, 1591, 1514, 1497, 1464, 1428, 1414, 1359, 1287, 1267, 1223, 1171, 1126, 1108, 1046, 952, 933, 907, 896, 857, 819, 773, 735, 710, 688, 643, 629, 562, 541, 514, 493, 452 cm-1, and wherein the allowable deviation of the IR characteristic peaks is 2 cm.sup.1.

4. A preparation method for the solid of the type-B fenolamine crystal form according to claim 1, wherein the solid of the type-B fenolamine crystal form is prepared by dissolving a fenolamine material completely with ethanol as sole solvent or a mixed solvent containing ethanol at a temperature of 15 C. to 80 C., followed by recrystallization at ambient temperature of 4 C. to 80 C. and ambient humidity of 10% to 75% under normal pressure or vacuum conditions.

5. The preparation method according to claim 4, wherein the mixed solvent containing ethanol has an ethanol content by mass of more than or equal to 40%.

6. A solid of mixed fenolamine crystal forms, wherein the solid of the type-B fenolamine crystal form according to claim 1 is comprised in an amount of 1% to 99.9%.

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

8. The pharmaceutical composition according to claim 7, wherein daily dose of fenolamine is in the range of 10 to 3000 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, an injection, a sustained release preparation, or a controlled release preparation, and is in a solid dosage form.

10. The preparation method according to claim 5, wherein the mixed solvent containing ethanol is a mixed solvent of ethanol and at least one solvent selected from methanol, isopropanol, n-propanol, n-butanol, chloroform, dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, pyridine, dioxane, glacial acetic acid, formic acid, ethyl ether, toluene, benzene, n-hexane, cyclohexane, DMF, petroleum ether, and water.

11. The solid of mixed fenolamine crystal forms according to claim 6, wherein the type-B fenolamine crystal form is comprised in an amount of 10% to 99.99%.

12. The solid of mixed fenolamine crystal forms according to claim 6, wherein the type-B fenolamine crystal form is comprised in an amount of 50% to 99.9%.

13. The solid of mixed fenolamine crystal forms according to claim 6, wherein the type-B fenolamine crystal form is comprised in an amount of 90% to 99.9%.

14. A pharmaceutical composition, wherein the composition comprises an effective amount of the solid of mixed fenolamine crystal forms according to claim 6 and a pharmaceutically acceptable carrier.

15. A method for treatment of Parkinson's disease, wherein the method comprises administering the solid of the type-B fenolamine crystal form according to claim 1.

16. A method for treatment of Parkinson's disease, wherein the method comprises administering the solid of mixed fenolamine crystal forms according to claim 6.

17. A method for treatment of Parkinson's disease, wherein the method comprises administering the pharmaceutical composition according to claim 7.

18. A method for treatment of Parkinson's disease, wherein the method comprises administering the solid of mixed fenolamine crystal forms according to claim 12.

19. The solid of a type-B fenolamine crystal form according to claim 1, wherein the type-B crystal form shows a symmetry of a monoclinic crystal system upon single crystal X-ray diffraction analysis, with a Cc space group and unit cell parameters of: a=31.18 , b=8.92 , c=22.50 , ==90, 3=128.4, and an intracellular molecule number Z=8, and includes crystallized ethanol molecules in unit cells in addition to fenolamine molecules.

20. A solid of type-B fenolamine crystal forms comprising the type-B crystal form according to claim 1 and at least one other subtype of a type-B fenolamine crystal form, wherein the ratio of fenolamine molecule to crystallized ethanol molecule in the type-B fenolamine crystal forms is within the range of 1:0.5 to 1:0.1.

21. The solid of the type-B fenolamine crystal forms according to claim 20, wherein the at least one other subtype is a subtype, which has a ratio of fenolamine molecule to crystallized ethanol molecule of 1:0.5.

22. The solid of the type-B fenolamine crystal form according to claim 1, wherein by using differential scanning calorimetry analysis, a weight loss peak is present in the range of 100 to 150 C. with a weight loss of 1.5% to 5.0%.

23. The solid of a type-B fenolamine crystal form according to claim 1, wherein by using powder X-ray diffraction analysis under the CuK radiation experimental conditions, the solid of the type-B fenolamine crystal form subtype has diffraction peaks at positions with 2-Theta values)() or d values () and diffraction peaks with relative intensity peak height values (Height %) or peak area values (Area %) as shown below: TABLE-US-00007 Peak 2-Theta 0.2 d() 0.2 Height % 10% Area % 10% 1 7.3 12.1 34 28 2 8.0 11.0 12 8 3 10.1 8.7 14 17 4 10.6 8.4 79 62 5 11.5 7.7 48 38 6 12.7 7.0 6 6 7 12.9 6.8 6 6 8 13.5 6.5 11 6 9 14.5 6.1 9 9 10 16.0 5.5 100 100 11 16.7 5.3 16 10 12 17.4 5.1 21 32 13 17.6 5.0 25 40 14 17.8 5.0 25 44 15 18.4 4.8 24 19 16 18.8 4.7 16 15 17 19.6 4.5 46 36 18 20.2 4.4 27 24 19 20.7 4.3 3 1 20 21.4 4.2 50 46 21 21.7 4.1 26 48 22 22.3 4.0 6 2 23 23.0 3.9 13 11 24 24.4 3.7 81 95 25 24.8 3.6 27 23 26 25.6 3.5 51 60 27 26.1 3.4 33 32 28 26.9 3.3 9 7 29 27.6 3.2 3 3 30 27.8 3.2 3 3 31 28.4 3.1 4 6 32 29.5 3.0 4 3 33 30.0 3.0 4 5 34 31.8 2.8 4 9 35 32.3 2.8 10 12 36 33.4 2.7 1 1 37 34.1 2.6 3 1 38 34.9 2.6 5 8 39 36.6 2.5 4 8 40 38.2 2.4 4 8 41 38.5 2.3 5 7 42 39.7 2.3 3 4 43 41.2 2.2 1 2 44 42.1 2.1 3 3 45 43.1 2.1 2 1 46 46.9 1.9 2 2 47 49.9 1.8 1 1

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a graph of the molecular arrangement in a type-B fenolamine crystal form sample;

(2) FIG. 2 is a theoretical powder X-ray diffraction spectrum of a type-B fenolamine crystal form sample (fenolamine:ethanol=2:1);

(3) FIG. 3 is a theoretical powder X-ray diffraction spectrum of a type-B fenolamine crystal form sample (fenolamine:ethanol=4:1);

(4) FIG. 4 is a theoretical powder X-ray diffraction spectrum of a type-B fenolamine crystal form sample (fenolamine:ethanol=2:0);

(5) FIG. 5 is a powder X-ray diffraction spectrum of a type-B fenolamine crystal form sample;

(6) FIG. 6 is a powder X-ray diffraction spectrum of a type-B fenolamine crystal form sample;

(7) FIG. 7 is a DSC pattern of a type-B fenolamine crystal form sample;

(8) FIG. 8 is a TG diagram of type-B fenolamine crystal form sample;

(9) FIG. 9 is an infrared absorption spectrum of a type-B fenolamine crystal form sample;

(10) FIG. 10 is a graph of the dissolution curves of the type-B fenolamine crystal form in six different solvent systems.

DETAILED DESCRIPTION OF THE INVENTION

(11) 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 but is not limited thereto.

Example 1

(12) Preparation Method 1 of Type-B Fenolamine Crystal Form Sample:

(13) 1.46 kg of fenolamine was dissolved in 7.3 L of anhydrous ethanol by heating and stirring, then hot press-filtered into a crystallization kettle in a refining-drying-packing workshop, and allowed to stand at 20 C. overnight. The product was collected after filtration and dried under vacuum at 85 C. until there was no scent of ethanol (for about 48 hours, in this case the product was fenolamine with crystallized ethanol). The obtained product was finely ground, sieved through an 80 mesh sieve, and dried under 10 mmHg vacuum at 100 C. for about 96 hours (the materials were turned over every 12 hours). The ethanol content was measured and when it was 1.7 to 2.4%, the product was qualified and 1.276 kg of the product was obtained. The product has an ethanol content of 2.0% as determined by gas chromatography, which is a subtype of the type-B fenolamine crystal form containing crystallized ethanol; the powder X-ray diffraction spectrum, differential scanning calorimetric pattern, thermogravimetric diagram and infrared spectrum were shown in FIG. 5 and FIGS. 7-9.

(14) Preparation Method 2 of Type-B Fenolamine Crystal Form Sample:

(15) A fenolamine sample was completely dissolved in anhydrous ethanol as solvent at 40 C. and then allowed to stand at a temperature of 4 to 40 C. for 1 to 5 days so as to obtain a colorless transparent crystal of fenolamine. Single crystal X-ray diffraction analysis shows the sample has a symmetry of a monoclinic crystal system, with a Cc space group and cell parameters of: a=31.18 , b=8.92 , c=22.50 , ==90, =128.4, and an intracellular molecule number Z=8, and includes crystallized ethanol molecules in unit cells in addition to fenolamine molecules with a ratio of fenolamine to ethanol molecule of 2:1 (FIG. 1). Powder X-ray diffraction analysis was carried out, with the powder X-ray diffraction pattern shown in FIG. 6.

(16) Preparation Method 3 of Type-B Fenolamine Crystal Form Sample:

(17) By using a mixed solvent containing ethanol, such as a mixed solvent system having an ethanol content of 40%, 75%, or 95%, a fenolamine sample was completely dissolved at 15 to 80 C., and then allowed to stand at a temperature of 10-20 C. for 7 days so as to obtain a colorless and transparent crystal of fenolamine. Powder X-ray diffraction analysis was carried out, with an X-ray powder diffraction pattern consistent with that of FIG. 6.

(18) By using a mixed solvent containing ethanol, such as a mixed solvent system with ethanol:methanol (2:1), a fenolamine sample was completely dissolved at 50 C., and then allowed to stand at a temperature of 20 C. for 7 days so as to obtain a colorless and transparent crystal of fenolamine. Powder X-ray diffraction analysis was carried out, with an X-ray powder diffraction pattern consistent with that of FIG. 6.

(19) By using a mixed solvent containing ethanol, such as a mixed solvent system with ethanol:chloroform (1:1), a fenolamine sample was completely dissolved at 30 C., and then allowed to stand at a temperature of 10 C. for 10 days so as to obtain a colorless and transparent crystal of fenolamine. Powder X-ray diffraction analysis was carried out, with an X-ray powder diffraction pattern consistent with that of FIG. 6.

(20) By using a mixed solvent containing ethanol, such as a mixed solvent system with ethanol:acetonitrile (3:1), a fenolamine sample was completely dissolved at 60 C., and then allowed to stand at a temperature of 40 C. for 5 days so as to obtain a colorless and transparent crystal of fenolamine. Powder X-ray diffraction analysis was carried out, with an X-ray powder diffraction pattern consistent with that of FIG. 6.

(21) By using a mixed solvent containing ethanol, such as a mixed solvent system with ethanol: acetone (1:1), a fenolamine sample was completely dissolved at 20 C., and then allowed to stand at a temperature of 4 C. for 12 days so as to obtain a colorless and transparent crystal of fenolamine. Powder X-ray diffraction analysis was carried out, with an X-ray powder diffraction pattern consistent with that of FIG. 6.

(22) By using a mixed solvent containing ethanol, such as a mixed solvent system with ethanol: cyclohexane (1:1), a fenolamine sample was completely dissolved at 20 C., and then allowed to stand at a temperature of 4 C. for 12 days so as to obtain a colorless and transparent crystal of fenolamine. Powder X-ray diffraction analysis was carried out, with an X-ray powder diffraction pattern consistent with that of FIG. 6.

(23) The mixed solvent containing ethanol refers to a mixed solvent prepared by mixing ethanol with one or more of a single solvent system such as methanol, isopropanol, n-propanol, n-butanol, chloroform, dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, pyridine, dioxane, glacial acetic acid, formic acid, ethyl ether, toluene, benzene, n-hexane, cyclohexane, DMF, petroleum ether, or water in arbitrary proportion, preferably with an ethanol volume ratio of greater than 40%.

(24) Preparation Method 4 of Type-B Fenolamine Crystal Form Sample:

(25) Materials of the type-B fenolamine crystal form subtypes having different ethanol contents were obtained by drying the type-B fenolamine crystal form subtype having an ethanol content of 5.3% under different drying conditions. The results are shown in Table 2:

(26) TABLE-US-00003 TABLE 2 Average Serial content in No. Sample No. ethanol (%) 1 Type-B fenolamine crystal form crude drug 5.30 2 Type-B fenolamine crystal form crude drug dried 4.55 under reduced pressure at 60 c. for 24 hours 3 Type-B fenolamine crystal form crude drug dried 3.92 under the reduced pressure at 80 c. for 24 hours 4 Type-B fenolamine crystal form crude drug dried 3.57 under the reduced pressure at 100 c. for 12 hours 5 Type-B fenolamine crystal form crude drug dried 3.76 under the reduced pressure at 100 c. for 24 hours 6 Type-B fenolamine crystal form crude drug dried 3.71 under the reduced pressure at 105 c. for 4 hours 7 Type-B fenolamine crystal form crude drug dried 3.66 under the reduced pressure at 105 c. for 12 hours 8 Type-B fenolamine crystal form crude drug dried 3.45 under the reduced pressure at 105 c. for 24 hours

Example 2

(27) Advantageous Feature in Drug Safety of Type-B Fenolamine Crystal Form Solid

(28) The solid of type-B fenolamine crystal form contains ethanol as crystallized solvent, which has little effect on human health, and therefore the type-B fenolamine crystal form solid has the advantageous feature in drug safety.

Example 3

(29) Advantageous Feature in Solubility of Type-B Fenolamine Crystal Form Solid in Six Solvent Systems

(30) The solubility was evaluated by using a type-B fenolamine crystal form sample (fenolamine:ethanol=1:0.2) having a crystallized ethanol content of 2.0%.

(31) The solvent systems were selected by: (1) referring to solvent systems used in the dissolution determination method in the Appendix of the Pharmacopoeia; (2) referring to the digestive solution pH in various organs of an organism; (3) improving the solubility of water-insoluble drugs. Based the above three references, solvent systems with six pH values were set up: a 0.1 N hydrochloric acid solution with pH 1.2; an acetate buffer solution with pH 4.5; a phosphate buffer solution with pH 6.5; an water solution with pH 6.7; a 0.2% SDS solution with pH 7.0; a 0.5% SDS solution with pH 7.3.

(32) Measurement was carried out according to the solubility determination method (Guidelines for Dissolution Test Technique of General Oral Solid Preparations (Draft), October 2012, the Drug Review Center). With the percentage of the samples dissolved by mass calculated from the absorbance data, solubility curves were respectively drawn with time as abscissa and dissolved contents as ordinate and shown in FIG. 10. The data are shown in Table 3 below:

(33) TABLE-US-00004 TABLE 3 Dissolution data of type-B fenolamine crystal form in various solvent systems (%) Time (min) Solvent Systems 5 15 30 60 120 180 240 300 360 420 0.1N hydrochloric 0.00 0.00 2.35 5.75 11.42 14.07 18.54 20.04 23.69 25.07 acid Acetate buffer 0.00 0.00 0.49 2.57 7.54 11.34 15.82 19.51 20.15 20.71 Phosphate buffer 49.51 49.81 49.89 49.96 51.08 51.72 51.87 53.32 53.40 53.47 0.2% SDS 21.57 32.50 42.43 59.66 91.98 92.35 95.75 95.82 95.90 95.93 0.5% SDS 35.04 55.30 73.32 86.90 97.35 97.69 98.40 98.47 98.51 100.00 Water 0.00 0.34 2.01 5.26 11.42 20.22 21.94 26.04 28.96 32.13

Example 4

(34) Stability of Type-B Fenolamine Crystal Form Solid

(35) Type-B fenolamine crystal form samples (having a crystallized ethanol content of 2.58%) 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 lx500 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-B fenolamine crystal form is stable under conditions of high temperature, high humidity and light illumination, with transformation to subtypes having lower ethanol contents and a crystallized ethanol content of about 2.1% for 10 days at high temperature.

Example 5

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

(37) A preparation method of a combinational drug tablet is characterized in that a pure product of type-B fenolamine crystal form or a solid of mixed crystal forms containing any ratio of the type-B 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 10 to 500 mg drug per tablet. Table 4 shows the proportions in the tablet formulation:

(38) TABLE-US-00005 TABLE 4 Formulations for preparing fenolamine combinational drug tablets Amount in Formulation Names of raw materials Formulation Formulation Formulation Formulation Formulation Formulation Formulation and excipients 1 2 3 4 5 6 7 Fenolamine (mg) 10.0 50.0 100.0 200.0 250.0 300.0 500.0 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 q.s q.s q.s q.s q.s q.s q.s hydroxymethylcellulose (mg)

(39) The process of formulating a pure product of type-B fenolamine crystal form or a solid of mixed crystal forms containing any ratio of the type-B 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 hydroxymethylcellulose 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.

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

(41) A preparation method of a combinational drug capsule is characterized in that a pure product of type-B fenolamine crystal form or a solid of mixed crystal forms containing any ratio of the type-B 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 10 to 500 mg drug per capsule. Table 5 shows the proportions in the capsule formulation:

(42) TABLE-US-00006 TABLE 5 Formulations of raw materials and excipients for preparing fenolamine combinational drug capsule preparations Amount in Formulation Names of raw materials Formulation Formulation Formulation Formulation Formulation Formulation Formulation and excipients 1 2 3 4 5 6 7 Fenolamine (mg) 10.0 50.0 100.0 200.0 250.0 300.0 500.0 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 q.s q.s q.s q.s q.s q.s q.s hydroxymethylcellulose (mg)

(43) The process of formulating a pure product of type-B fenolamine crystal form or a solid of mixed crystal forms containing any ratio of the type-B 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-B fenolamine crystal form raw material is directly mixed with several excipients uniformly, and sieved and incorporated directly into a capsule.

Example 6

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

(45) A pharmaceutical composition is developed and prepared by using a crystalline fenolamine sample as a pharmaceutically active ingredient, characterized in that the type-B 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.

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

(47) A pharmaceutical composition is developed and prepared by using a crystalline fenolamine sample as a pharmaceutically active ingredient, characterized in that the type-B 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.

(48) 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-B fenolamine crystal form once or several times.