CN108558655B - 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance, preparation method and pharmaceutical composition thereof - Google Patents
2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance, preparation method and pharmaceutical composition thereof Download PDFInfo
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Abstract
The invention discloses a 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph, wherein the XRPD pattern of the polymorph has diffraction peaks at 5.5 +/-0.2, 7.9 +/-0.2, 15.9 +/-0.2, 19.3 +/-0.2, 20.3 +/-0.2, 22.2 +/-0.2, 22.6 +/-0.2, 23.1 +/-0.2, 25.1 +/-0.2, 26.5 +/-0.2, 27.9 +/-0.2, 30.2 +/-0.2, 33.6 +/-0.2 and 36.0 +/-0.2. In addition, a preparation method and a pharmaceutical composition of the polymorphic substance are also disclosed. The 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph has good stability, and the XRPD pattern of the polymorph shows that the crystal form is not changed in long-term and accelerated tests, so that the polymorph is favorable for long-term storage; moreover, the preparation method of the polymorphic substance provided by the invention is simple to operate, does not need harsh operation equipment and process, is green in solvent, small in dosage and low in production cost, and is more suitable for industrial production.
Description
The application is a divisional application filed in 10 months and 31 days 2014, wherein the application is the application number 201410607321.8 and the invention name is '2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance, a preparation method thereof and a pharmaceutical composition'.
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph, and a preparation method and a pharmaceutical composition thereof.
Background
Fenofibric acid, chemically known as 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid, of the formula (1) below:
the medicine is a new medicine for treating hyperlipidemia, and the clinical treatment criteria of patients with hyperlipidemia recommend that fenofibric acid medicines and statins are combined to further improve the blood lipid. The combined treatment significantly improves the levels of High Density Lipoprotein (HDL) and triglyceride compared to the statin alone, and significantly improves the levels of high density lipoprotein (LDL) compared to the product alone. All combinations and statins have clinical effects of lowering high density lipoprotein (LDL).
US20050148594a1 discloses several pharmaceutically acceptable salts of fenofibric acid, especially choline fenofibric acid, as a sustained release drug which reduces the amount of drug used; US20090187040a1 discloses two fenofibric acid polymorphs and a preparation scheme thereof, wherein the XRPD characteristic diffraction peak of form a has a 2 theta value of 15.4 and the XRPD characteristic diffraction peak of form B has 2 theta values of 7.7, 7.9, 17.4, 24.5.
In recent years, polymorphism of drug molecules is attracting more and more attention of scientists, and since different polymorphic forms have great differences in stability, dissociation degree, bioavailability and the like, it is necessary to perform polymorphic research on drug molecules as much as possible to ensure that the best crystal form is obtained, so as to obtain higher stability, dissociation degree, bioavailability and the like, and thus generate higher bioactivity. Therefore, research and control of crystal forms become important content in the process of drug development. The actual blood level of the drug can be advantageously influenced by selecting polymorphic forms with different solubilities and intrinsic dissolution rates.
The fenofibric acid has good market prospect, but the currently reported fenofibric acid crystal forms are few in types, and further research on the polymorphism is very necessary for searching for a stable medicinal crystal form.
Disclosure of Invention
The present inventors have surprisingly found a stable and novel polymorph of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid.
The invention aims to provide a novel 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance.
The second object of the present invention is to provide a process for the preparation of the above novel 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph.
It is a third object of the present invention to provide a pharmaceutical composition comprising the above-mentioned novel 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph.
Specifically, the invention provides a novel 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance, which has diffraction peaks at 5.5 +/-0.2, 7.9 +/-0.2, 15.9 +/-0.2, 22.2 +/-0.2, 22.6 +/-0.2, 23.1 +/-0.2, 27.9 +/-0.2 and 30.2 +/-0.2 of 2 theta values in an XRPD pattern.
In a preferred embodiment provided herein, the present invention provides a novel polymorph of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid having an XRPD pattern with diffraction peaks at 2. theta. values of 5.5. + -. 0.2, 7.9. + -. 0.2, 15.9. + -. 0.2, 19.3. + -. 0.2, 20.3. + -. 0.2, 22.2. + -. 0.2, 22.6. + -. 0.2, 23.1. + -. 0.2, 25.1. + -. 0.2, 26.5. + -. 0.2, 27.9. + -. 0.2, 30.2. + -. 0.2, 33.6. + -. 0.2, 36.0. + -. 0.2.
In a more preferred embodiment provided herein, the present invention provides a novel polymorph of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid having an XRPD pattern substantially as shown in figure 1.
In an embodiment provided herein, the present invention provides a novel polymorph of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid having a DSC endothermic transition at about 183.7 ℃.
In a preferred embodiment provided herein, the present invention provides a novel polymorph of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid having a DSC profile substantially as shown in figure 2.
In an embodiment provided herein, the present invention provides a novel polymorph of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid in an anhydrous crystalline form.
In the embodiments provided herein, the present invention provides a novel 2- [4- (4-chlorobenzoyl) phenoxy]-2-methylpropanoic acid polymorph with infrared absorption spectrum of 3400-2500 cm-1、3076cm-1、2991cm-1、2900cm-1、1707cm-1、1647cm-1、1597cm-1，1500cm-1,1468cm-1、1398cm-1、1382cm-1，1365cm-1、1303cm-1、1285cm-1、1236cm-1，930cm-1、1148cm-1、858cm-1There is an absorption peak.
In one embodiment, the present invention provides a novel polymorphic form of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid having an infrared absorption spectrum substantially as shown in figure 3.
In another aspect, the present invention provides a process for preparing the above 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph, comprising the steps of:
a) mixing 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid and solvent under stirring, and heating until the solid is completely dissolved;
b) cooling and crystallizing;
c) filtering, recovering the precipitate, and drying to obtain the 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph.
In an embodiment of the present invention, the present invention provides a preparation method of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph, wherein the solvent used is one or more of methanol, ethanol, isopropanol, tertiary amyl alcohol and water, and preferably the solvent is isopropanol and/or water.
In the embodiment of the invention, the preparation method of the 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph provided by the invention comprises the step of cooling to-10 ℃, preferably-5-0 ℃ in the cooling crystallization process.
In an embodiment of the present invention, the present invention provides a process for the preparation of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorphs, wherein the temperature of heating in step a) is 20 ℃ to 100 ℃, preferably 50 ℃ to 80 ℃.
In an embodiment of the present invention, the present invention provides a process for preparing 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph, wherein the ratio of solvent to 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph is 2mL/g to 10 mL/g.
In an embodiment of the present invention, the present invention provides a process for preparing 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph, wherein the temperature of drying is 30-80 ℃, preferably 40-60 ℃.
The stability of the 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance is considered, and accelerated (temperature is 40 +/-2 ℃, humidity is 75% +/-5%, time is 6 months) and long-term (temperature is 25 +/-2 ℃, humidity is 60% +/-10%, time is 12 months) stability tests are carried out. The experimental results show that: the 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance prepared by the invention has good stability, and the XRPD pattern of the polymorphic substance in long-term and accelerated tests shows that the polymorphic substance is not changed (figure 4 and figure 5), thereby being beneficial to long-term storage.
On the other hand, the preparation method of the 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph provided by the invention is simple to operate, does not need harsh operation equipment and process, is green in solvent, small in dosage and low in production cost, and is more suitable for industrial production.
For the same crystal form of the same compound, the XRPD patterns are similar as a whole, and the characteristic peak positions thereof are subject to error due to differences in instruments and measurement conditions, so that when determining the diffraction angles 2 θ of the XRPD patterns in the description and claims of the present invention, the obtained values are understood to be within ± 1.0 degrees of the values, preferably within ± 0.2 degrees of the values; melting point in a DSC thermogram, the resulting value is understood to be within. + -. 3.0 ℃ of the value, preferably within. + -. 1 ℃ of the value.
In a third aspect, the present invention provides a pharmaceutical composition comprising a pharmacologically effective amount of the above polymorphic form of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid and a pharmacologically acceptable carrier therefor.
In an embodiment of the present invention, the present invention provides a pharmaceutical composition comprising a pharmacologically effective amount of a polymorph of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid, wherein the pharmacologically acceptable carrier may be selected from a combination of one or more of a filler, a disintegrant, a binder, a glidant, and/or a lubricant.
In an embodiment of the present invention, there is provided a pharmaceutical composition comprising a pharmacologically effective amount of a polymorph of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid, wherein the filler is selected from any one or a mixture of two or more of lactose, maltodextrin, mannitol, microcrystalline cellulose, pregelatinized starch and sucrose esters; the disintegrant is selected from one or more of crospovidone, croscarmellose sodium, sodium starch glycolate, microcrystalline cellulose and pregelatinized starch; the adhesive comprises any one or a mixture of more than two of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone and copovidone; the glidant is any one or a mixture of more than two of colloidal silicon dioxide, talcum powder, magnesium stearate and mannitol; the lubricant is one or a mixture of more than two of magnesium stearate, calcium stearate, glyceryl monostearate, hydrogenated castor oil, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, zinc stearate, talcum powder, microcrystalline cellulose and sucrose ester.
In an embodiment of the present invention, the pharmaceutical composition comprising a pharmacologically effective amount of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph provided by the present invention, preferably, the filler is microcrystalline cellulose, the disintegrant is crospovidone, the binder is copovidone, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate.
In an embodiment of the present invention, the present invention provides a pharmaceutical composition comprising a pharmacologically effective amount of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph, wherein the pharmaceutical composition comprises 35.0mg of the above 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph, 57.2mg of microcrystalline cellulose, 2.7mg of crospovidone, 2.4mg of copovidone, 1.2mg of colloidal silicon dioxide, 0.7mg of magnesium stearate; or comprises 105.0mg of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic form, 171.6mg of microcrystalline cellulose, 8.1mg of crospovidone, 7.2mg of copovidone, 3.6mg of colloidal silicon dioxide and 2.1mg of magnesium stearate.
In an embodiment of the present invention, the present invention provides a pharmaceutical composition comprising a pharmacologically effective amount of a polymorph of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid, wherein the pharmaceutical composition is prepared by direct compression of a powder.
In a fourth aspect, the invention provides the application of the 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance in a medicine for treating hyperlipidemia.
Experiments prove that after the 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance is used as a main medicine material to prepare tablets, detailed dissolution and stability comparison researches are carried out on the polymorphic substance and the original medicine, and experiments prove that the medicine prepared by the crystalline form of the invention has consistent dissolution and stability behaviors with the medicine of the original company, and is in line with the medicine.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of a 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph of the present invention.
FIG. 2 is a DSC analysis chart of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorphic substance of the present invention.
FIG. 3 is a Fourier infrared spectrum of a polymorphic form of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid according to the present invention.
FIG. 4 is an X-ray powder diffraction pattern for an accelerated test of 6 months for a 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph of the present invention.
FIG. 5 is a long term 12 month X-ray powder diffraction pattern of a 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorph of the present invention.
Detailed Description
The present invention is further explained below with reference to specific examples, but these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
In the present invention, the method and conditions for correlation detection are as follows:
1. infrared absorption Spectrum (IR)
The instrument comprises the following steps: bruker TENSOR 27 type infrared spectrometer
And (3) correcting the instrument: the wave number of the instrument is corrected by the infrared spectrum absorption peak of the polystyrene film (refer to the appendix IV C of the 2010 version of Chinese pharmacopoeia of the second part)
The method comprises the following steps: KBr pellet process
2. Differential thermal analysis (DSC)
The instrument comprises the following steps: NETZSCH DSC 204 type differential thermal analyzer
Temperature range: 40-220 deg.C
The heating rate is as follows: 10 ℃/min
3. Powder X-ray diffraction (PXRD)
1. Test unit: chinese pharmaceutical university analysis and test center
The instrument comprises the following steps: bruker D8Advance X-ray diffractometer
And (3) testing conditions are as follows: 40kv 40mA slit: 1.0/1.0/Ni/0.1 step size: 0.02 ° target type: cu
Range:3.00-40.00Deg scan Rate：10.00Deg/min
Definitions and abbreviations
The following abbreviations used hereinbefore and throughout the description of the invention thereof shall be understood to have the following meanings, unless otherwise indicated:
XRPD X-ray powder diffraction
DSC differential scanning calorimetry
mL of
mg of
L liter
Kg kilogram
EXAMPLE 12 preparation of a polymorph of- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid
Adding 3.2g of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid into a 50mL three-neck flask, adding 32mL of isopropanol, heating to 65 ℃, dissolving and stirring for half an hour, adding 0.03g of medicinal activated carbon, continuously stirring for half an hour, performing suction filtration while hot, cooling the filtrate to 10 ℃, separating out a solid, performing suction filtration again, and performing forced air drying on the obtained white solid powder at 55 ℃ for 3 hours to obtain 2.8g of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph, wherein the yield is 87.5%. Its X-ray powder diffraction pattern is shown in FIG. 1, DSC spectrum is shown in FIG. 2, and infrared spectrum is shown in FIG. 3.
EXAMPLE 22 preparation of a polymorph of- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid
Adding 3.2g of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid into a 50mL three-neck flask, adding 32mL of methanol, heating to 55 ℃, dissolving and stirring for 1 hour, continuously stirring for half an hour, performing suction filtration while hot, cooling the filtrate to 8 ℃, separating out a solid, performing suction filtration again, and performing forced air drying on the obtained white solid powder at 40 ℃ for 3 hours to obtain 2.9g of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph, wherein the yield is 90.6%. The X-ray powder diffraction pattern, DSC spectrogram and infrared spectrogram of the compound are the same as those in the example 1.
EXAMPLE 32 preparation of a polymorph of- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid
Adding 3.2g of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid into a 50mL three-neck flask, adding 32mL of ethanol, heating to 60 ℃, dissolving and stirring for 1 hour, adding 0.03g of medicinal activated carbon, continuously stirring for half an hour, performing suction filtration while the solution is hot, cooling the filtrate to 8 ℃, separating out a solid, performing suction filtration again, and performing forced air drying on the obtained white solid powder at 60 ℃ for 3 hours to obtain 2.8g of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph, wherein the yield is 87.5%. The X-ray powder diffraction pattern, DSC spectrogram and infrared spectrogram of the compound are the same as those in the example 1.
EXAMPLE 42 preparation of a polymorph of- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid
Adding 3.2g of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid into a 50mL three-neck flask, adding 31mL of ethanol and 1mL of distilled water, heating to 60 ℃, dissolving and stirring for 1 hour, adding 0.03g of medicinal activated carbon, continuously stirring for half an hour, carrying out suction filtration while hot, cooling the filtrate to 8 ℃, precipitating a solid, carrying out suction filtration again, carrying out forced air drying on the obtained white solid powder at 60 ℃ for 3 hours to obtain 3.1g of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph, wherein the yield is 93.7%. The X-ray powder diffraction pattern, DSC spectrogram and infrared spectrogram of the compound are the same as those in the example 1.
EXAMPLE 52 preparation of a polymorph of- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid
Adding 3.2g of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid into a 50mL three-neck flask, adding 35mL of tert-amyl alcohol, heating to 60 ℃, dissolving and stirring for 0.5 hour, adding 0.03g of medicinal activated carbon, continuously stirring for 1 hour, carrying out suction filtration while the solution is hot, cooling the filtrate to-10 ℃, precipitating a solid, carrying out suction filtration again, carrying out forced air drying on the obtained white solid powder at 55 ℃ for 3 hours to obtain 2.5g of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance, wherein the yield is 78.1%. The X-ray powder diffraction pattern, DSC spectrogram and infrared spectrogram of the compound are the same as those in the example 1.
EXAMPLE 62 preparation of a polymorph of- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid
Adding 3.2Kg of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid into a 100L three-neck flask, adding 31L of isopropanol and 0.8L of distilled water, heating to 65 ℃, dissolving and stirring for 1 hour, adding 0.03Kg of medicinal activated carbon, continuously stirring for 1 hour, carrying out suction filtration while hot, cooling the filtrate to 0 ℃, separating out a solid, carrying out suction filtration again, carrying out forced air drying on the obtained white solid powder at 60 ℃ for 3 hours to obtain 3.05Kg of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph, wherein the yield is 95.3%. The X-ray powder diffraction pattern, DSC spectrogram and infrared spectrogram of the compound are the same as those in the example 1.
EXAMPLE 72 preparation of a polymorph of- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid
Adding 1.60Kg of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid into a 100L three-neck flask, adding 16L of methanol and 0.2L of distilled water, heating to 50 ℃, dissolving and stirring for 1 hour, adding 0.01Kg of medicinal activated carbon, continuously stirring for 1 hour, carrying out suction filtration while hot, cooling the filtrate to-5 ℃, standing for 3 hours, carrying out suction filtration again, carrying out forced air drying on the obtained white solid powder at 60 ℃ for 3 hours to obtain 1.47Kg of 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorph, wherein the yield is 92.0%. The X-ray powder diffraction pattern, DSC spectrogram and infrared spectrogram of the compound are the same as those in the example 1.
EXAMPLE 8 dissolution contrast test of prepared samples
Tablets of different specifications were prepared using the formulations in table 1 below, using the products prepared in scale-up examples 6 and 7 as the main material, according to the powder direct compression process: bulk drug plus auxiliary material → sieving → mixing → adding lubricant → tabletting method.
TABLE 1
The tablets obtained as described above were subjected to a comparative study with the dissolution curve of FIBRICOR (Specification: 35mg, lot No. 6561702) produced by MUTUAL PHARMACEUTICAL COMPANY by the following method.
The test method comprises the following steps: according to the dissolution test method (appendix XC second method of second part of 2010 edition of Chinese pharmacopoeia), 900ml of dissolution medium is used, and the rotating speed is 75 rpm. Sampling 5ml at 5, 10, 15, 20, 30, 45, and 60min respectively, filtering with 0.45 μm filter membrane, and collecting the filtrate as sample solution. And dissolving a proper amount of fenofibric acid reference substance in a phosphate buffer solution with the pH value of 6.8 to prepare a solution containing about 0.035mg of fenofibric acid in each 1ml of the solution as a reference substance solution. According to high performance liquid chromatography (appendix V D of the second part of the 2010 version of Chinese pharmacopoeia), octadecylsilane chemically bonded silica is used as a filler, a water phase (5ml of phosphoric acid diluted to 1000ml with water) -methanol (20:80) is used as a mobile phase, the detection wavelength is 290nm, the flow rate is 1ml/min, and the column temperature is 25 ℃. Precisely measuring 10 μ l of each of the reference solution and the sample solution, respectively injecting into a liquid chromatograph, and recording chromatogram. And calculating the dissolution rate by the peak area according to an external standard method and drawing a cumulative dissolution curve.
Dissolution medium: 0.1M hydrochloric acid solution, pH 4.5 acetate buffer, pH 5.5 phosphate buffer and pH6.8 phosphate buffer.
The similarity between the self-made sample and the original dissolution curve is compared by adopting an F2 similarity factor method, the result shows that the dissolution curves of the self-made sample and the original dissolution curve are consistent, and the comparison of the dissolution curves of the 35mg specification is shown in a table 2.
TABLE 2
1In 0.1M hydrochloric acid solution, the self-made sample and the original research reagent are basically not dissolved out; in a phosphate buffer solution with the pH value of 6.8, the dissolution of the self-made sample and the original research reagent is more than or equal to 85 percent within 15min, F2 does not need to be calculated, and the dissolution curves are consistent; in the remaining media F2 > 50, the dissolution behavior was consistent.
The similarity between the dissolution curves of the self-made sample and the original preparation is compared by adopting an F2 similarity factor method, the result shows that the dissolution curves of the self-made sample and the original preparation are consistent, and the comparison of the dissolution curves of 105mg specifications is shown in a table 3.
TABLE 3
1In 0.1M hydrochloric acid solution, the self-grinding tablet and the original grinding tablet are not dissolved out basically; in the phosphate buffer solution with the pH value of 6.8, the dissolution of the self-grinding tablet and the original grinding tablet is more than or equal to 85 percent within 15min, F2 does not need to be calculated, the dissolution curves are consistent, and the dissolution behaviors are consistent when F2 is more than 50 in other media.
Example 9 comparative study of stability of prepared samples
The stability of the home-made sample (prepared in example 8, size: 35mg) was compared with the original formulation (size: 35mg, lot # 6561702) in high temperature, high humidity, light conditions for 10 days of bare die placement and accelerated change of key mass attributes for 6 months with tape packaging, and the results of the stability comparison are shown in Table 4 below. The result shows that the stability of the self-made sample is consistent with that of the original preparation.
TABLE 4
Remarking: "/" indicates no test study data.
The data of example 8 and example 9 show that the dissolution rate and stability of the new crystal form prepared by the invention are consistent with those of the original research after being prepared into a medicine, and the new crystal form meets the relevant quality requirements of the medicine.
Claims (5)
1. A process for preparing 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropionic acid polymorphs comprising the steps of:
a) mixing 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid and solvent under stirring, and heating until the solid is completely dissolved;
b) cooling and crystallizing;
c) filtering, recovering the precipitate, and drying to obtain a 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polycrystalline type;
wherein the solvent is methanol and water, ethanol and water, or isopropanol and water; the ratio of methanol to water is 16L: 0.2L; the ratio of ethanol to water is 31L: 1L; the ratio of isopropanol to water is 31L: 0.8L;
the polymorphic substance has diffraction peaks at 2 theta values of 5.5 +/-0.2, 7.9 +/-0.2, 15.9 +/-0.2, 19.3 +/-0.2, 20.3 +/-0.2, 22.2 +/-0.2, 22.6 +/-0.2, 23.1 +/-0.2, 25.1 +/-0.2, 26.5 +/-0.2, 27.9 +/-0.2, 30.2 +/-0.2, 33.6 +/-0.2 and 36.0 +/-0.2 in an XRPD pattern.
2. The preparation method according to claim 1, wherein in the step b), the temperature is reduced to-10 to 10 ℃.
3. The preparation process according to claim 1 or 2, wherein the polymorph has XRPD pattern diffraction peaks as shown in figure 1.
4. The preparation process according to claim 1 or 2, wherein the DSC profile of the polymorph has an endothermic transition at about 183.7 ℃.
5. The preparation process according to claim 1 or 2, wherein the polymorph is in an anhydrous crystalline form.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810167207.6A CN108558655B (en) | 2014-10-31 | 2014-10-31 | 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance, preparation method and pharmaceutical composition thereof |
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| CN201410607321.8A CN104447292A (en) | 2014-10-31 | 2014-10-31 | 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionic acid polymorph as well as preparation method and pharmaceutical composition thereof |
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| CN107550875A (en) * | 2017-08-21 | 2018-01-09 | 赵剑锋 | A kind of Fenofibric Acid piece of stabilization and preparation method thereof |
| CN110041191A (en) * | 2019-04-30 | 2019-07-23 | 湖南九典宏阳制药有限公司 | A kind of purification process of pelubiprofen |
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| US6027747A (en) * | 1997-11-11 | 2000-02-22 | Terracol; Didier | Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions |
| CN102304103A (en) * | 2011-06-03 | 2012-01-04 | 郑州泰基鸿诺药物科技有限公司 | Fenofibrate acid salt, preparation method, pharmaceutical composition and application |
| CN102659609A (en) * | 2012-05-17 | 2012-09-12 | 安润医药科技（苏州）有限公司 | Fenofibric acid salt, and preparation method, application and medicinal composition thereof |
| CN103965038A (en) * | 2013-01-24 | 2014-08-06 | 肖广常 | Refining method for high-purity clofibric acid blood-lipid regulating drug--fenofibric acid |
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| US7259186B2 (en) * | 2002-12-17 | 2007-08-21 | Abbott Laboratories | Salts of fenofibric acid and pharmaceutical formulations thereof |
| US20090187040A1 (en) * | 2008-01-18 | 2009-07-23 | Tong Sun | Fenofibric acid polymorphs; methods of making; and methods of use thereof |
| CN103922925B (en) * | 2014-05-09 | 2015-12-30 | 成都医路康医学技术服务有限公司 | A kind of production technique of Fenofibric Acid |
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| US6027747A (en) * | 1997-11-11 | 2000-02-22 | Terracol; Didier | Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions |
| CN102304103A (en) * | 2011-06-03 | 2012-01-04 | 郑州泰基鸿诺药物科技有限公司 | Fenofibrate acid salt, preparation method, pharmaceutical composition and application |
| CN102659609A (en) * | 2012-05-17 | 2012-09-12 | 安润医药科技（苏州）有限公司 | Fenofibric acid salt, and preparation method, application and medicinal composition thereof |
| CN103965038A (en) * | 2013-01-24 | 2014-08-06 | 肖广常 | Refining method for high-purity clofibric acid blood-lipid regulating drug--fenofibric acid |
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