CN110054599A - A kind of Trimetazidine oxalates and its preparation method and application - Google Patents
A kind of Trimetazidine oxalates and its preparation method and application Download PDFInfo
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Abstract
The present invention provides a kind of Trimetazidine oxalates, molecular formula C18H26N2O11, by Trimetazidine, 1:2 reacts to obtain the Trimetazidine oxalates in molar ratio with oxalic acid.The angle of repose of the Trimetazidine oxalates is less than Trimetazidine Hydrochloride, and its surface topography improves the mobility and hygroscopicity of drug compared to the prism-shaped crystal of Trimetazidine Hydrochloride bulk pharmaceutical chemicals for sheet；It is 4.66MPa that Trimetazidine oxalates tensile strength in 150MPa, which reaches maximum value, simultaneously, is significantly higher than the tensile strength of Trimetazidine Hydrochloride under same pressure, improves drug pelleting property.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of Trimetazidine oxalates and its preparation method and application.
Background technique
Energetic supersession in cardiac muscle cell of the Trimetazidine Hydrochloride by ensureing hypoxic-ischemic, prevents intracellular ATP levels
Decline, ensures the function of ionic pump while maintaining intracellular environment, improves and receives-potassium pump normal transport with cross-film.Animal is real
Display is tested, Trimetazidine Hydrochloride helps to maintain the energetic supersession in the cardiac muscle cell of hypoxic-ischemic, moreover it is possible to reduce solid flesh stalk
Dead range, and any direct blood flow kinetic effect will not be generated.The check experiment of Patients With Angina Pectoris is shown, in human body
It is interior to increase coronary flow reserve, treat the myocardial ischemia induced by delayed motion, and can limit rapid blood pressure fluctuate and
Do not cause heart rate significant changes, is substantially reduced angina pectoris attacking frequency.Trimetazidine Hydrochloride is with good safety and reliably
Curative effect, just more and more widely be applied to clinic.
However, the angle of repose of Trimetazidine Hydrochloride bulk pharmaceutical chemicals is big, density is small, have hygroscopicity, mobility and compressibility compared with
Difference.
Patent CN1166408C discloses a kind of preparation method of substrate tablet containing Trimetazidine Hydrochloride, by accounting for piece
The hydroxypropyl methyl cellulose of agent total weight 25~50% reaches the target of control medicament slow release.The patent uses hydroxypropyl methyl
Cellulose is as slow-release material, since the mobility and compressibility of hydroxypropyl methyl cellulose are poor, when preparing tablet, to setting
Standby is more demanding, and the slice weight fluctuation range that final mobility of particle difference will lead to product is larger, influences product quality；It simultaneously can
Pressure property is poor, it is necessary to qualified tablet can be just produced at a higher pressure, and producing under biggish pressure can increase for a long time
The loss of tablet press machine and punch die increases production cost, is unfavorable for commercially producing for this product.
Patent CN102319225B discloses a kind of trimetazidine hydrochloride sustained-release tablets and preparation method thereof, poly- by addition
Ethylene oxide reaches the target of Drug controlled release as sustained-release matrix material.But polyoxyethylene hygroscopicity is stronger, is used alone
Polyoxyethylene is as sustained-release matrix material, due to framework material moisture absorption, can equally mobility of particle be caused to be deteriorated, cause finished product sheet
The uniformity of dosage units of agent is unqualified；In addition, polyoxyethylated hygroscopicity can make the bad stability of sustained release tablets, during storage
Impurity rapid development, and excessive impurity will cause the increase of drug side-effect, be unfavorable for providing safer drug for patient.
Therefore, in the present invention by the way that its salt form is made in Trimetazidine and oxalic acid, improve Trimetazidine Hydrochloride fusing point,
A variety of physicochemical properties such as solubility, apparent form and its mobility, hygroscopicity and flakiness.
Summary of the invention
The purpose of the present invention is overcoming the mobility of existing Trimetazidine Hydrochloride, flakiness poor and having hygroscopicity,
The problem of tablet influences finished tablet quality is made.
For this purpose, the present invention provides a kind of Trimetazidine oxalates, molecular formula C18H26N2O11, Trimetazidine grass
By Trimetazidine, 1:2 reacts to obtain hydrochlorate in molar ratio with oxalic acid.
Further, the molecular formula of the crystal of above-mentioned Trimetazidine oxalates is C18H26N2O11, and the X-ray of its crystal
Diffracting spectrum has diffraction maximum at 2 θ=7.84 °, 11.60 °, 11.95 °, 16.54 °, 17.49 °, 19.41 °, 27.82 °, wherein 2
θ value error range is ± 0.2 °.
Further, in the crystal structure of above-mentioned Trimetazidine oxalates, 1 Trimetazidine molecule and 2 oxalic acid molecules
It is connected by 3 N-H...O hydrogen bonds, the bond distance of three hydrogen bonds is respectively With hydrogen bond phase
The Δ D of C in two C-O of oxalic acid molecule evenC-ORespectively With
The present invention also provides the preparation methods of above-mentioned Trimetazidine oxalates, include the following steps:
1) Trimetazidine Hydrochloride bulk pharmaceutical chemicals are weighed, are dissolved in water, and alkaline solution is added dropwise, solution ph is adjusted and is greater than 10；
Then organic extractant extraction is added, collection organic solvent layer extract liquor rotates at 37 DEG C obtains oily liquids；
2) oily liquids for obtaining step 1) organic solvent dissolves simultaneously constant volume, obtains Trimetazidine solution；
3) two oxalic acid hydrates are weighed, with organic solvent dissolution and constant volume, obtain two oxalic acid hydrate solution；
4) 1:2 is mixed in molar ratio for the two oxalic acid hydrate solution that the Trimetazidine solution and step 3) for taking step 2) to obtain obtain
It closes, stands filtering, filtrate is dried in vacuo in 40 DEG C of baking ovens to get Trimetazidine oxalate powder.
Further, in the preparation method of above-mentioned Trimetazidine oxalates, when preparing the crystal of Trimetazidine oxalates,
Further include step 5) crystallisation by cooling, the Trimetazidine oxalate powder that step 4) obtains is dissolved in water or organic solvent or both
In the mixed solvent, heating makes Trimetazidine oxalate powder be completely dissolved into clear solution, then cools down by 1~2 DEG C/h rate,
A period of time is stood to get the crystal of Trimetazidine oxalates.
Further, it in the preparation method of Trimetazidine oxalates, when preparing the crystal of Trimetazidine oxalates, also wraps
The crystallization of step 5) volatility process is included, the Trimetazidine oxalate powder that step 4) obtains is dissolved in the mixed of water or organic solvent or both
In bonding solvent, Trimetazidine oxalate powder is made to be completely dissolved into clear solution, then is placed at room temperature for volatilization a period of time or subtracts
The crystal that pressure is evaporated to get Trimetazidine oxalates.
Further, sodium hydroxide solution, ammonium hydroxide or ethanol amine that the alkaline solution is 10%, the organic extractant
For toluene, ether, ethyl acetate or chloroform, the organic solvent be isopropanol, methanol, acetonitrile, ethyl alcohol, in ethyl acetate at least
It is a kind of.
In addition, the present invention also provides the tablet containing above-mentioned Trimetazidine oxalates, composition includes Trimetazidine
Oxalates, lubricant, filler and disintegrating agent, the filler are microcrystalline cellulose, lactose, starch, mannitol, calcium monohydrogen phosphate
At least one of dihydrate, filler account for the 0~80% of total weight of tablet；The lubricant be magnesium stearate, talcum powder,
At least one of colloidal silicon dioxide, superfine silica gel powder, lubricant account for the 0.5~2% of total weight of tablet；The disintegrating agent is to hand over
Join at least one of sodium carboxymethylcellulose, crospovidone, cross-linked carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, collapses
Solution agent accounts for the 0.5~8% of total weight of tablet.
The preparation method of above-mentioned tablet adds recipe quantity firstly, Trimetazidine oxalates is uniformly mixed with filler
Disintegrating agent mix, then be added recipe quantity lubricant mix, sieving, finally by direct powder compression be made Trimetazidine grass
Hydrochlorate tablet.
It is described the present invention also provides application of the above-mentioned Trimetazidine oxalates in preparation treatment cardiovascular disease medicine
Cardiovascular disease includes coronary heart disease, coronary artery disease, angina pectoris, heart failure.
The oversubscription alite of drug together crystalline substance be by bulk pharmaceutical chemicals and other physiologically acceptable acid, alkali, non-ionic compound,
Crystal is formed by the effect of the non-covalent bonds such as hydrogen bond, Van der Waals force, pi-pi accumulation effect, halogen key, and the salt and eutectic of drug can be with
Change a variety of physicochemical properties such as fusing point, solubility, the apparent form of drug, it is also possible to change the mobility and flakiness of drug
Deng, therefore there is very high application value in drug research.And the pKa of Trimetazidine Hydrochloride is 4.84 in the present invention, oxalic acid
PKa is 1.4, and the Δ pKa of the two is 3.44, at very big a possibility that salt.
Compared with prior art, beneficial effects of the present invention:
(1) this Trimetazidine oxalates provided by the invention passes through Trimetazidine with oxalic acid with the molar ratio 1:2 system of reacting
, angle of repose is less than Trimetazidine Hydrochloride, and its surface topography is sheet, compared to the prism of Trimetazidine Hydrochloride bulk pharmaceutical chemicals
Shape crystal greatly increases the specific surface area of drug, improves the mobility of drug.
(2) this Trimetazidine oxalates tensile strength in 150MPa provided by the invention reaches maximum value and is
4.66MPa, higher than the tensile strength of Trimetazidine Hydrochloride under same pressure, so as to improve drug pelleting property.
(3) this Trimetazidine oxalates provided by the invention is under same relative humidity, compared with Trimetazidine Hydrochloride,
Hydroscopicity significantly reduces, and so as to improve the hygroscopicity of drug, improves the stability of drug.
Detailed description of the invention
Fig. 1 is the process flow chart that Trimetazidine oxalates is prepared in the present invention；
Fig. 2 be Trimetazidine oxalates and Trimetazidine Hydrochloride in the present invention, two oxalic acid hydrates, Trimetazidine Hydrochloride and
The infared spectrum of two oxalic acid hydrate physical mixtures；
Fig. 3 is Trimetazidine oxalates and Trimetazidine Hydrochloride of the present invention, two oxalic acid hydrates, Trimetazidine Hydrochloride and two
The XRD diagram of oxalic acid hydrate physical mixture；
Fig. 4 is the DSC figure of Trimetazidine oxalates and Trimetazidine Hydrochloride of the present invention, two oxalic acid hydrates；
Fig. 5 is that the SEM of Trimetazidine oxalates and Trimetazidine Hydrochloride schemes in the present invention；
Fig. 6 be in the present invention tensile strength of Trimetazidine oxalates and Trimetazidine Hydrochloride with pressure change schematic diagram；
Fig. 7 is the hygroscopicity measurement result figure of Trimetazidine oxalates and Trimetazidine Hydrochloride in the present invention；
Fig. 8 is the crystal structure schematic diagram of Trimetazidine oxalates in the present invention；
Fig. 9 is the crystal hydrogen bond figure of Trimetazidine oxalates in the present invention；
Figure 10 is accumulation graph of the crystal along a axis direction of Trimetazidine oxalates in the present invention；
Figure 11 is accumulation graph of the crystal along b axis direction of Trimetazidine oxalates in the present invention.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts all other
Embodiment shall fall within the protection scope of the present invention.
Present embodiments provide a kind of Trimetazidine oxalates, molecular formula C18H26N2O11, the Trimetazidine oxalates
By Trimetazidine, 1:2 reacts to obtain in molar ratio with oxalic acid.Specific preparation flow is as shown in Figure 1.
The Trimetazidine Hydrochloride bulk pharmaceutical chemicals of about 5g are weighed in small beaker, 5mL ultrapure water is added to make to dissolve.It is slowly added dropwise 10%
Sodium hydroxide solution, adjust pH to 11 or so.Isometric toluene is added to extract three times, collection toluene layer rotates at 37 DEG C to be obtained
The oily liquids of about 3.083g.Oily liquids is dissolved with isopropanol, and is settled in the volumetric flask of 50mL, 61.66mg/ is obtained
The Trimetazidine solution of mL.Weigh two oxalic acid hydrates of 1.4593g, in the volumetric flask for dissolving and being settled to 50mL with isopropanol,
Obtain the two oxalic acid hydrate solution of 29.186mg/mL.
It takes Trimetazidine solution 10mL to be slowly added dropwise and mix with two oxalic acid hydrate solution 20mL and (is equivalent to Trimetazidine: two
Oxalic acid hydrate=1:2), stand 3h after filter, filtrate is dried in vacuo in 40 DEG C of baking ovens obtain 922mg white Sibutramine Hydrochloride he
KIH 9201 salt powder.
In the ampoule of 10mL, the water that 2mL is dissolved in by Trimetazidine oxalate powder about 50mg obtained above is weighed
In, 80 DEG C are heated to, Trimetazidine oxalate powder is made to be completely dissolved into clear solution, is cooled down by 1~2 DEG C/h rate, it is quiet
It sets, the acicular Trimetazidine oxalic acid salt crystal suitable for single crystal X-ray diffraction experiment is grown after a period of time.
Certainly above-mentioned when preparing the crystal of Trimetazidine oxalates, it can also be crystallized and diffusion method knot by volatility process
It is brilliant.Wherein, volatility process crystallization is that Trimetazidine oxalate powder obtained above is dissolved in water or organic solvent, is heated to 80
DEG C, so that Trimetazidine oxalate powder is completely dissolved into clear solution, then be placed at room temperature for volatilization a period of time or be evaporated under reduced pressure,
Up to the crystal of Trimetazidine oxalates.Diffusion method crystallization is that Trimetazidine oxalate powder obtained above is dissolved in higher boiling
Good solvent in, then the Trimetazidine oxalate solution of dissolution is placed in the container equipped with low-boiling poor solvent, it is close
Envelope, and the ratio of good solvent and poor solvent is 1:2~1:4, in sealed solvent, low boiling point poor solvent is volatized into height
In boiling point good solvent, the solubility of solid is reduced, so that nucleus be precipitated, obtains the crystal of Trimetazidine oxalates.
Below to Trimetazidine Hydrochloride (TMZ), two oxalic acid hydrates (OAD), the object of Trimetazidine Hydrochloride and two oxalic acid hydrates
Manage a variety of physical properties of Trimetazidine oxalates (Salt) powder made from mixture (PM) and the present embodiment, and flowing
Property and can tabletting performance studied.
1, infrared scan (FTIR) is analyzed
To Trimetazidine Hydrochloride, two oxalic acid hydrates, the physical mixture of Trimetazidine Hydrochloride and two oxalic acid hydrates, Yi Jiben
The powder of Trimetazidine oxalates made from embodiment carries out infrared scan analysis, and result is as shown in Figure 2.
As shown in Figure 2, Trimetazidine Hydrochloride (TMZ) is in 3494cm-1There is-N-H stretching vibration at place, in 1603cm-1、
1503cm-1、1456cm-1There is-C=C vibration at place.Two oxalic acid hydrates (OAD) are in 3489cm-1There is the peak-OH of a Qiang Erkuan at place,
In 1700cm-1There is the peak-C=O in left and right.The spectrogram of the physical mixture (PM) of Trimetazidine Hydrochloride and two oxalic acid hydrates is hydrochloric acid
The simple superposition of Trimetazidine and oxalic acid spectrogram.In the Trimetazidine oxalates (Salt) of the present embodiment, 3494cm-1Place's ownership
In-N-H peak red shift to 3453cm-1, 1700cm-1The peak that place belongs to-C=O is blue shifted to 1720cm-1, show Trimetazidine with
Oxalic acid forms N-H after combining with 1:2 ... O hydrogen bond.
2, X-ray diffraction scanning (PXRD) analysis
By the Trimetazidine oxalic acid of Trimetazidine Hydrochloride, two oxalic acid hydrates, the physical mixture of the two and the present embodiment
The powder of salt, is equably laid in sample cell, and for copper target as x-ray source, operating voltage is set as 40kV, operating current 40mA,
The scanning step of powder sample is 0.02 °, and 0.1 second every step residence time, scanning speed is 10 °/min, and scanning angle range is
5 ° -50 °, the X ray diffracting spectrum for obtaining sample is as shown in Figure 3.
From the figure 3, it may be seen that Trimetazidine Hydrochloride 6.79 °, 11.32 °, 16.20 °, 16.99 °, 18.83 °, 23.3 °,
Have high-intensitive diffraction maximum at 28.67 °, two oxalic acid hydrates 14.79 °, 18.68 °, 25.84 °, 28.95 °, 31.07 °,
There is high-intensitive diffraction maximum at 36.88 °, 39.43 °, the XRD spectrum of physical mixture is the simple superposition of the two.The present embodiment
The powder of Trimetazidine oxalates show diffraction maximum similar with Trimetazidine Hydrochloride at 23.3 °, 27.1 °, but
It is observed at 7.84 °, 11.60 °, 11.95 °, 16.54 °, 17.49 °, 19.41 °, 27.82 ° and new is different from Trimetazidine Hydrochloride
With unique peak of two oxalic acid hydrates, illustrates that Trimetazidine Hydrochloride is reacted with two oxalic acid hydrates with 1:2 and form new solid form.
3, elemental analysis
It is carried out using powder of the Vario micro cube type elemental analyser to the Trimetazidine oxalates of the present embodiment
C, the measurement of H, N content, after drug powder is vacuum dried, precision weighs about 5mg or so and is wrapped in Xi Zhouzhong, is placed on 950-
In 1150 DEG C of quartz combustion tube, moment burns under the action of quantitative oxygen.Instrument uses the operation mode of CHNS, analysis time
For 10min, sulfanilamide (SN) is used to be corrected as standard substance to instrument, the carrier gas used is He, gas pressure 1200-
1250mbar, gas flow rate 200mL/min, sample injector are 80 hole location of standard type.By the result and theoretical calculation of practical measurement
Result carry out analysis comparison, the results are shown in Table 1.
Table 1: Trimetazidine oxalates elemental analysis result
As shown in Table 1, the content calculated value of C, H, N in the Trimetazidine oxalates of the present embodiment and measuring
Value is coincide substantially, and the fine difference between numerical value may be due to caused by sample purity.It is tested in conjunction with single crystal X-ray diffraction
As a result, explanation theoretically predict the result is that correct.
4, dsc analysis
Using the Trimetazidine grass of differential scanning calorimeter measurement Trimetazidine Hydrochloride, two oxalic acid hydrates and the present embodiment
Hydrochlorate powder, result are as shown in Figure 4.
As shown in Figure 4, the endothermic peak of Trimetazidine Hydrochloride bulk pharmaceutical chemicals is in 241.9 DEG C of positions, the endothermic peak of two oxalic acid hydrates
102.4 DEG C of positions, and the endothermic peak of the Trimetazidine oxalate powder of the present embodiment, 221.2 DEG C of positions, endothermic peak is not
It is same as Trimetazidine Hydrochloride and two oxalic acid hydrates, illustrates that the present embodiment generates new substance.
5, sem analysis
Using the Trimetazidine oxalic acid salt fines of scanning electron microscope (SEM) measurement Trimetazidine Hydrochloride and the present embodiment
End, result are as shown in Figure 5.
As seen from Figure 5, Trimetazidine Hydrochloride bulk pharmaceutical chemicals are prism-shaped crystal, and the Trimetazidine oxalates of the present embodiment is
Sheet and big graininess, particulate powder will substantially improve the mobility of drug, this is consistent with the result of fluidity determining.
6, Study of Liquidity
Stopping for the Trimetazidine oxalate powder of Trimetazidine Hydrochloride and the present embodiment is measured using Repose angle gauge
Angle.Measurement result shows that the angle of repose of Trimetazidine Hydrochloride bulk pharmaceutical chemicals is 59.66 °, poor flow quality, Trimetazidine and oxalic acid
The angle of repose that the Trimetazidine oxalates to be formed is reacted with 1:2 is 38.39 °, is less than Trimetazidine Hydrochloride, illustrates Trimetazidine grass
Hydrochlorate can improve the mobility of drug, this is consistent with the result of SEM.
7, pelleting property is studied
Using DF-4B Manual tablet pressing machine to the powder of the Trimetazidine oxalates of Trimetazidine Hydrochloride bulk pharmaceutical chemicals and this implementation
End carries out the research of pelleting property.The piston diameter of the tabletting Oil cylinder is 70mm, mould diameter 10mm.Magnesium stearate is hanged
It floats in ethyl alcohol (5%, w/v), is both needed to be coated and dried with magnesium stearate uniform suspension before each use of mold, using formula
(1) actual pressure of tablet press machine is calculated:
Actual pressure=oil cylinder area/die area * pressure gauge reading --- formula (1)；
The reading for controlling pressure gauge, makes pressure 50,100,150,200,250,300,350MPa of tablet press machine, and control is every
The quality of tablet is 300mg, and the tablet pressed is placed for 24 hours at ambient temperature, then measures tablet using the instrument of tablet four
Hardness, using outside micrometer measurement tablet size, pass through formula (2) calculate tablet tensile strength, calculated result such as Fig. 6
It is shown.
Ts=2F/ π * D*L --- formula (2)；
Wherein, F is tablet hardness, N；D is tablet diameters, mm；L is tablet thickness, mm.
It will be appreciated from fig. 6 that the tensile strength of Trimetazidine Hydrochloride bulk pharmaceutical chemicals increases as pressure increases to 150MPa from 50MPa
Greatly, after pressure is more than 150MPa, tensile strength reduces, and illustrates that overcompression has occurred, tablet tensile strength in 150MPa is
1.21MPa illustrates that the compressibility of Trimetazidine Hydrochloride bulk pharmaceutical chemicals is bad less than 2.And the Trimetazidine oxalates of the present embodiment exists
It is 4.66MPa that tensile strength, which reaches maximum value, when 150MPa, hence it is evident that higher than the tensile strength of Trimetazidine Hydrochloride under same pressure, is said
Bright Trimetazidine can significantly improve its pelleting property after reacting with oxalic acid.
8, Study on Hygroscopicity
Using the suction of DVS Instrument measuring Trimetazidine Hydrochloride bulk pharmaceutical chemicals and the powder of the Trimetazidine oxalates of this implementation
Moist, the relative humidity for controlling instrument is 5% to 95%, and measurement result is as shown in Figure 7.
As shown in Figure 7, Trimetazidine Hydrochloride bulk pharmaceutical chemicals, critical relative moisture 80%, when relative humidity is 95%, sample
Product deliquesce, and become aqueous solution, and reaching maximum moisture absorption rate is 106.1%.The molecular formula of Trimetazidine oxalate powder is
C18H26N2O11(446.41g/mol), according to adsorption and de-adsorption curve it is found that the present embodiment Trimetazidine oxalates is opposite
In the range of humidity is 5% to 95%, it experienced slowly water suction and slowly the process of dehydration inhaled under 95% relative humidity
Wet rate, which reaches, is up to 2.14%, and drug increases weight between 2% to 15%, shows that the Trimetazidine oxalates of the present embodiment has and draws
It is moist.Bigger hesitation between the adsorption and de-adsorption curve of Trimetazidine oxalates, illustrates that its rate of water absorption is greater than
Rate of water loss.And under same relative humidity, compared with Trimetazidine Hydrochloride, the hydroscopicity of the present embodiment Trimetazidine oxalates
It decreases, especially in the case where relative humidity is 95% super-humid conditions, it is aqueous solution that Trimetazidine Hydrochloride moisture absorption, which deliquesces, and
The hydroscopicity of Trimetazidine oxalates shows Trimetazidine and oxalic acid at can significantly improve its moisture absorption after salt within 20%
Property, improve the stability of drug.
9, crystal structure is studied
Choosing size under the microscope is about 0.09 × 0.02 × 0.01mm3Trimetazidine oxalic acid salt crystal spread out in monocrystalline
Progress single crystal data collection on instrument is penetrated, incident wavelength is 1.54178nm (Cu K α radiation), at 293k, collects 14.376 °≤2
Diffraction data within the scope of θ≤72.454 ° collects 5108 point diffractions altogether, wherein independent point diffraction is 1361.Data use
Olex2 and ShelXS direct method analytic structure, and refine, the crystalline substance of Trimetazidine oxalates are carried out using SHELXL least square method
Body data are listed in Table 2 below.
The crystal of Trimetazidine oxalates simulates calculated XRD diagram after monocrystalline parses and matches with the XRD diagram of powder,
Illustrate that the substance being prepared is wanted substance, the Trimetazidine oxalates of the present embodiment is confirmed through single crystal method of X-ray diffractometry
For (C18H26N2O11)。
In addition, showing the crystal (C of Trimetazidine oxalates through single crystal X-ray analysis18H26N2O11) belong to monoclinic crystal
System, space group C2/c；In the asymmetric unit of crystal, contain 1 Trimetazidine molecule and 2 oxalic acid molecules.In structure cell
In have 8 Trimetazidine molecules, 16 oxalic acid molecules.It can be seen that 1 Trimetazidine molecule and 2 oxalic acid from Fig. 8 and Fig. 9
Molecule is connected by 3 N-H...O hydrogen bonds, and the bond distance of three hydrogen bonds is respectivelyWith
D in the connected oxalic acid molecule of hydrogen bondC-OBond distance's data are as shown in table 3, wherein C17In Δ DC-OForIt is less thanIllustrate that proton translocation has occurred in drug and oxalic acid molecule, generates Trimetazidine oxalates.The song of Figure 10 and Figure 11
For his KIH 9201 single-crystal of salt of beauty along a axis and the accumulation graph of b axis direction, specific hydrogen bond data are as shown in table 4.
Table 2: the crystallographic data of Trimetazidine oxalates
Table 3: the C-O bond distance's data for the oxalic acid molecule being connected with hydrogen bond
Table 4: the hydrogen bond data of Trimetazidine oxalic acid salt crystal
Using Trimetazidine oxalates provided in this embodiment can directly pressed powder Trimetazidine oxalic acid salt tablets are made,
Its composition includes Trimetazidine oxalates, lubricant, filler and disintegrating agent, and the filler is microcrystalline cellulose, cream
At least one of sugar, starch, mannitol, dicalcium phosphate dihydrate, filler account for the 0~80% of total weight of tablet；It is described
Lubricant is at least one of magnesium stearate, talcum powder, colloidal silicon dioxide, superfine silica gel powder, and lubricant accounts for total weight of tablet
0.5~2%；The disintegrating agent is croscarmellose sodium, crospovidone, cross-linked carboxymethyl starch sodium, low substitution hydroxyl
At least one of propyl cellulose, disintegrating agent account for the 0.5~8% of total weight of tablet.The tool of the Trimetazidine oxalic acid salt tablets
Production procedure is as follows: firstly, Trimetazidine oxalates is uniformly mixed with filler, the disintegrating agent for adding recipe quantity is mixed
Even, the lubricant that recipe quantity is then added mixes, is sieved, and Trimetazidine oxalic acid salt tablets finally are made in direct powder compression.
Using Trimetazidine oxalates provided by the above embodiment compared to Trimetazidine Hydrochloride have less hygroscopicity,
Better mobility and pelleting property, Trimetazidine Hydrochloride are protected by being reduced into Trimetazidine in vivo by Trimetazidine
Energetic supersession of the cell under anoxic and ischemia mitigates intracellular acidosis and prevents the poly- of sodium and calcium in cardiac muscle cell
Collection, keeps the stabilization of intracellular environment；As Ma Chunhong is right in " Trimetazidine treats 25 clinical observations of coronary disease and angina pectoris "
The effect of Trimetazidine treatment coronary disease and angina pectoris has carried out clinical observation, twists by comparing patient's heart of observation group and control group
Pain breaking-out situation, exercise tolerance improve the variation of situation and heart rate, blood pressure, find Trimetazidine to Treating Patients of Angina Pectoris
There is preferable clinical efficacy；For another example beam is apt in " protective effect of the Trimetazidine Hydrochloride to myocardial cell "
It has also been found that myocardial cell injury when Trimetazidine can mitigate acute ischemia, has the function of protecting Acute Ischemic Myocardium cell；Cause
This, Trimetazidine has significant curative effect in the cardiovascular diseases such as treatment coronary heart disease, coronary artery disease, angina pectoris, heart failure.
And Trimetazidine oxalates of the invention is also reduced into Trimetazidine in vivo, plays treatment in vivo by Trimetazidine and makees
With therefore, Trimetazidine oxalates of the invention also can be used for treating coronary heart disease, coronary artery disease, angina pectoris, heart failure etc.
Cardiovascular disease.
The foregoing examples are only illustrative of the present invention, does not constitute the limitation to protection scope of the present invention, all
It is within being all belonged to the scope of protection of the present invention with the same or similar design of the present invention.
Claims (10)
1. a kind of Trimetazidine oxalates, it is characterised in that: its molecular formula is C18H26N2O11, which passes through song
1:2 reacts to obtain his beautiful piperazine in molar ratio with oxalic acid.
2. Trimetazidine oxalates as described in claim 1, it is characterised in that: the molecular formula of its crystal is C18H26N2O11, and
The X-ray diffracting spectrum of its crystal is at 2 θ=7.84 °, 11.60 °, 11.95 °, 16.54 °, 17.49 °, 19.41 °, 27.82 °
There is diffraction maximum, wherein 2 θ value error ranges are ± 0.2 °.
3. Trimetazidine oxalates as claimed in claim 2, it is characterised in that: in its crystal structure, 1 Trimetazidine molecule
It is connect with 2 oxalic acid molecules by 3 N-H...O hydrogen bonds, the bond distance of three hydrogen bonds is respectivelyThe Δ D of C in two C-O of the oxalic acid molecule being connected with hydrogen bondC-ORespectivelyWith
4. the preparation method of Trimetazidine oxalates as described in claim 1, characterized by the following steps:
1) Trimetazidine Hydrochloride bulk pharmaceutical chemicals are weighed, are dissolved in water, and alkaline solution is added dropwise, solution ph is adjusted and is greater than 10；Then
Organic extractant extraction is added, collection organic solvent layer extract liquor rotates at 37 DEG C obtains oily liquids；
2) oily liquids for obtaining step 1) organic solvent dissolves simultaneously constant volume, obtains Trimetazidine solution；
3) two oxalic acid hydrates are weighed, with organic solvent dissolution and constant volume, obtain two oxalic acid hydrate solution；
4) 1:2 is mixed the two oxalic acid hydrate solution that the Trimetazidine solution for taking step 2) to obtain is obtained with step 3) in molar ratio,
Filtering is stood, filtrate is dried in vacuo in 40 DEG C of baking ovens to get Trimetazidine oxalate powder.
5. the preparation method of Trimetazidine oxalates as claimed in claim 4, it is characterised in that: preparing Trimetazidine oxalic acid
Further include step 5) crystallisation by cooling when the crystal of salt, the Trimetazidine oxalate powder that step 4) obtains is dissolved in water or organic
The in the mixed solvent of solvent or both, heating makes Trimetazidine oxalate powder be completely dissolved into clear solution, then presses 1~2
DEG C/cooling of h rate, a period of time is stood to get the crystal of Trimetazidine oxalates.
6. the preparation method of Trimetazidine oxalates as claimed in claim 4, it is characterised in that: preparing Trimetazidine oxalic acid
When the crystal of salt, further includes the crystallization of step 5) volatility process, the Trimetazidine oxalate powder that step 4) obtains is dissolved in water or is had
The in the mixed solvent of solvent or both makes Trimetazidine oxalate powder be completely dissolved into clear solution, then is placed at room temperature for
The crystal for volatilizing for a period of time or being evaporated under reduced pressure to get Trimetazidine oxalates.
7. the preparation method of the Trimetazidine oxalates as described in claim 4 or 5 or 6, it is characterised in that: the alkaline solution
For 10% sodium hydroxide solution, ammonium hydroxide or ethanol amine, the organic extractant is toluene, ether, ethyl acetate or chloroform, institute
Stating organic solvent is at least one of isopropanol, methanol, acetonitrile, ethyl alcohol, ethyl acetate.
8. the tablet containing Trimetazidine oxalates as claimed in any one of claims 1 to 3, it is characterised in that: its composition
Including Trimetazidine oxalates, lubricant, filler and disintegrating agent, the filler is microcrystalline cellulose, lactose, starch, sweet
Reveal at least one of alcohol, dicalcium phosphate dihydrate, filler accounts for the 0~80% of total weight of tablet；The lubricant is hard
At least one of fatty acid magnesium, talcum powder, colloidal silicon dioxide, superfine silica gel powder, lubricant account for the 0.5~2% of total weight of tablet；
The disintegrating agent is croscarmellose sodium, in crospovidone, cross-linked carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose
At least one, disintegrating agent accounts for the 0.5~8% of total weight of tablet.
9. the preparation method of tablet as claimed in claim 8, it is characterised in that: firstly, by Trimetazidine oxalates and filling
Agent is uniformly mixed, and the disintegrating agent for adding recipe quantity mixes, and the lubricant that recipe quantity is then added mixes, is sieved, finally by powder
Trimetazidine oxalic acid salt tablets are made in last direct tablet compressing.
10. Trimetazidine oxalates as claimed in any one of claims 1 to 3 answering in preparation treatment cardiovascular disease medicine
With.
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