CN103145713A - Doxofylline crystalline compound and lyophilized powder thereof - Google Patents
Doxofylline crystalline compound and lyophilized powder thereof Download PDFInfo
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Abstract
The invention relates to a doxofylline crystalline compound and lyophilized powder thereof. The doxofylline crystalline compound is measured by a powder X-ray diffraction measurement method; and an X-ray powder diffraction pattern represented by a diffraction angle of 2(theta)+/-0.2 degrees shows characteristic diffraction peaks at the positions of 10.21 degrees, 12.12 degrees, 14.39 degrees, 23.32 degrees, 24.43 degrees, 27.23 degrees, 28.60 degrees, 30.54 degrees, 32.28 degrees, 33.32 degrees, 34.38 degrees and 36.12 degrees. The re-dissolubility of the doxofylline crystalline compound provided by the invention is obviously improved, solid is not easily separated out after long-time placement, and the medication safety of a patient is greatly improved.
Description
Technical field
The present invention relates to field of medicaments, specifically, relate to a kind of doxofylline crystalline compounds and freeze-dried powder thereof.
Background technology
Respiratory diseases mortality accounts for the first place of all diseases, and is in respiratory disease, the most common with the chronic obstructive pulmonary diseases such as bronchial asthma and chronic bronchitis, pulmonary emphysema (COPD) again.In western countries, asthma is modal chronic disease.Asthma can cause respiratory tract muscle overstretched, and the people is had difficulty in breathing.Its M ﹠ M rises year by year.China COPD approximately causes dead and about this digital 5-10 times of 1,000,000 people's disability (doxofylline is a kind of medicine for the treatment of safely and effectively chronic obstructive pulmonary disease) every year according to statistics; National epidemiology survey demonstration in 2000, the morbidity of asthma is 0.25～4.63%, than increasing upper 10 year more than 1 times, its M ﹠ M is all in rising trend.Asthma is suffered from the whole nation approximately 200,000,000 people, and wherein 10%～15%, children.Show according to the investigation to Beijing,Shanghai and Guangzhou asthma patient and doctor, Guangzhou patient's seizure frequency is the highest.Have 69% child patient to show effect every year on average more than 7 times, than 7% height in Beijing and Shanghai nearly 10 times.
But doxofylline relaxing smooth muscle, has antiasthmatic effect, be used for the treatment of clinically the symptom of panting that bronchial asthma and chronic obstructive pulmonary disease etc. cause, compare with aminophylline with the conventional medicament theophylline, curative effect is high and toxicity is low, result for the treatment of is 10～15 times of aminophylline, and is rapid-action, has no habituation that this product causes and on the impact of central nervous system, gi tract and heart function etc.From being used for, this product at reducing heart rate, improve ventilation, reduce and all be better than theophylline aspect the air flue reaction.
Doxofylline and theophylline are similar, also can suppress the phosphodiesterase of maincenter and periphery, and cAMP is increased, and bring into play its bronchospasm effect, still, almost have no maincenter and cardiovascular untoward reaction.Studies have shown that, doxofylline lacks avidity to Adenosine Receptors, because the concentration of doxofylline and acceptor competition combination is considerably beyond the scope of its pharmacological action of bringing into normal play.In addition, the experiment of Franzone shows, doxofylline does not affect intracellular calcium store to storage and the release of calcium, also do not affect calcium ion and flows into cell, and with calcium antagonist competition acceptor, theophylline is just not different from it.Therefore, have no doxofylline and produce the typical cardiovascular and cerebrovascular untoward reaction of similar other methyl xanthine derivatives.
Summary of the invention
The first purpose of the present invention is to provide a kind of doxofylline crystalline compounds, makes it have better solubility property, with the curative effect of further raising preparation, thus validity and the security of assurance medicine.
In order to realize the foregoing invention purpose, the present invention takes following technical scheme:
A kind of doxofylline crystalline compounds, described doxofylline crystalline compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle represents at 10.21 °, 12.12 °, 14.39 °, 23.32 °, 24.43 °, 27.23 °, 28.60 °, 30.54 °, 32.28 °, 33.32 °, 34.38 ° and 36.12 °.
The prepared doxofylline crystalline compounds of the present invention is different from the published various doxofylline crystal of prior art.
Above-mentioned doxofylline crystalline compounds adopts following method to be prepared from:
(1) getting the doxofylline crude product, fully to be dissolved in volume ratio be in the mixing solutions of water/propyl carbinol/acetonitrile of 4: 3: 1.5, be heated to reflux, stir the molten doxofylline solution that obtains clearly, wherein the mixed liquor volume of water/propyl carbinol/acetonitrile is 4.5～5.5 times of doxofylline crude product weight;
(2) dripping volume ratio under return stirring in the doxofylline solution is the ether/methanol solution of 4: 1, and wherein ether/methanol solution volume is 0.7～0.9 times of doxofylline crude product weight;
(3) stopped heating stirs borehole cooling to 5～10 ℃ at rotating speed 30～50rmp, and wherein cooling rate is 5～8 ℃/5min, and standing crystallization filters, and filter cake washs with ether, and vacuum-drying gets the doxofylline crystalline compounds.
According to doxofylline crystalline compounds of the present invention, the mixed liquor volume of water/propyl carbinol/acetonitrile is 5 times of doxofylline crude product weight; Ether/methanol solution volume is 0.7～0.9 times of doxofylline crude product weight.
According to doxofylline crystalline compounds of the present invention, the described dropping of step (2) can be this area dropping of understanding usually, and the preferred rate of addition of the present invention drips off for being controlled at 8～10min.
According to doxofylline crystalline compounds of the present invention, stir borehole cooling to 8 ℃ at rotating speed 40rmp in step (3).
According to doxofylline crystalline compounds of the present invention, in step (3), cooling rate is 6.5 ℃/5min.
According to doxofylline crystalline compounds of the present invention, standing crystallization 18～24h in step (3).
Any described doxofylline crystalline compounds according to the present invention after step (1) obtains doxofylline solution, also uses the activated carbon processing of decolouring.
In addition, the present invention also provides the doxofylline that contains above-mentioned doxofylline crystalline compounds freeze-dried powder.
Described lyophilized powder is prepared from by following weight part composition: 80～120 parts of any described doxofylline crystalline compounds of the present invention, 100～115 parts of Citric Acids, 180～220 parts, N.F,USP MANNITOL, 4000 parts of waters for injection; Wherein be preferably 100 parts of the described doxofylline crystalline compounds of claim 1-7 any one, 108 parts of Citric Acids, 200 parts, N.F,USP MANNITOL, 4000 parts of waters for injection.
According to doxofylline freeze-dried powder of the present invention, described doxofylline lyophilized powder is prepared according to the method that comprises the steps:
(1) accurately take N.F,USP MANNITOL, Citric Acid, the doxofylline water for injection dissolving of cumulative volume 4/5, and regulate pH value to 2.0～3.0, water for injection adds to full dose;
(2) adding weight is the gac of doxofylline weight 0.1%, stirs decarburization; Again through 0.22 μ m millipore filtration essence filter;
(3) lid is rolled in packing, half tamponade, lyophilize, after the assay was approved packing.
According to doxofylline freeze-dried powder of the present invention, step (3) lyophilize is:
The pre-freeze temperature :-45 ℃, the time: 5 hours, vacuum tightness: 10Pa;
Distillation phase temperature :-45 ℃～-5 ℃, vacuum tightness: 13.33Pa, heat-up rate: 3～4 ℃/h;
The dry epoch temperature :-5 ℃～40 ℃, vacuum tightness: 13.33Pa, heat-up rate: 3～4 ℃/h;
Treat that temperature rises to 40 ℃, be incubated 5-6 hour, make the complete freeze-drying of sample.
The present invention is by a large amount of experiments, find to adopt the doxofylline crystallization of the inventive method preparation, be dissolved in water and lyophilize after its crystal habit there is no change, and this crystallization solubility property in water is better, after being mixed with solution, steady dissolution is better, the long-time placement is difficult for separating out solid, more guaranteed drug safety, makes doxofylline more using under rugged environment.
Description of drawings
Fig. 1 is doxofylline X diffractogram of the present invention.
Fig. 2 is doxofylline (trial target 1) the X diffractogram after freeze-drying of the present invention.
Embodiment
Below with embodiment, technical scheme of the present invention is explained in more detail, but it is not to be limitation of the present invention.
The preparation of embodiment 1 doxofylline crystalline compounds
(1) getting commercially available doxofylline crude product 10g, fully to be dissolved in the 45ml volume ratio be in the mixing solutions of water/propyl carbinol/acetonitrile of 4: 3: 1.5, to be heated to reflux, and stirs the molten doxofylline solution that obtains clearly;
(2) dripping the 9ml volume ratio under return stirring in the doxofylline solution is the ether/methanol solution of 4: 1, and 8～10min drips off;
(3) stopped heating stirs borehole cooling to 10 ℃ at rotating speed 50rmp, and wherein cooling rate is 8 ℃/5min, standing 18h crystallization, filter, filter cake washs with the 5ml ether, and vacuum-drying gets the doxofylline crystalline compounds, yield 88.5%, HPLC99.54%, mp178～181 ℃.
Described doxofylline crystalline compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle represents at 10.21 °, 12.12 °, 14.39 °, 23.32 °, 24.43 °, 27.23 °, 28.60 °, 30.54 °, 32.28 °, 33.32 °, 34.38 ° and 36.12 °.
The preparation of embodiment 2 doxofylline crystalline compounds
(1) getting commercially available doxofylline crude product 10g, fully to be dissolved in the 55ml volume ratio be in the mixing solutions of water/propyl carbinol/acetonitrile of 4: 3: 1.5, to be heated to reflux, and stirs the molten doxofylline solution that obtains clearly;
(2) dripping the 7ml volume ratio under return stirring in the doxofylline solution is the ether/methanol solution of 4: 1, and it drips off in 8～10min;
(3) stopped heating stirs borehole cooling to 5 ℃ at rotating speed 30rmp, and wherein cooling rate is 5 ℃/5min, standing 24h crystallization, filter, filter cake washs with the 5ml ether, and vacuum-drying gets the doxofylline crystalline compounds, yield 88.7%, HPLC99.50%, mp178～181 ℃.
Described doxofylline crystalline compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle represents at 10.21 °, 12.13 °, 14.38 °, 23.31 °, 24.43 °, 27.23 °, 28.61 °, 30.56 °, 32.28 °, 33.33 °, 34.38 ° and 36.12 °.
The preparation of embodiment 3 doxofylline crystalline compounds
(1) getting commercially available doxofylline crude product 10g, fully to be dissolved in the 50ml volume ratio be in the mixing solutions of water/propyl carbinol/acetonitrile of 4: 3: 1.5, to be heated to reflux, and stirs the molten doxofylline solution that obtains clearly; Add the 2g activated carbon, backflow 0.5h filters, and collects filtrate;
(2) dripping the 8ml volume ratio under return stirring in the filtrate of step (1) is the ether/methanol solution of 4: 1, and it drips off in 8～10min;
(3) stopped heating stirs borehole cooling to 8 ℃ at rotating speed 40rmp, and wherein cooling rate is 6.5 ℃/5min, standing 20h crystallization, filter, filter cake washs with the 5ml ether, and vacuum-drying gets the doxofylline crystalline compounds, yield 88.3%, HPLC99.79%, mp179～181 ℃.
Described doxofylline crystalline compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle represents at 10.22 °, 12.13 °, 14.38 °, 23.34 °, 24.43 °, 27.23 °, 28.61 °, 30.54 °, 32.27 °, 33.31 °, 34.37 ° and 36.12 °.
Embodiment 4 doxofylline freeze-dried powders
1. write out a prescription
2. preparation technology
2.1 cillin bottle cleans and sterilization
2.2 rubber plug cleaning and sterilization
2.3 dosing process
Accurately take recipe quantity N.F,USP MANNITOL, Citric Acid, doxofylline suitable quantity of water heating for dissolving.
Then mentioned solution is added to 4/5 of cumulative volume with water for injection, and regulate the pH value to 2.0-3.0, water for injection adds to full dose.
2.5 decarburization, essence filter
Add 0.1% gac, stir decarburization; Again through 0.22 μ m millipore filtration essence filter.
2.6 packing, tamponade technological process
Loading amount requires: theoretical loading amount 4.0ml.
Check half tamponade degree: the situation such as check whether the plug of leakage is arranged, tamponade, pressure are askew, take out with aseptic nipper, with manual half tamponade of aseptic technique.
2.7 lyophilize: put into Freeze Drying Equipment by 100 grades of passages after pressing the half intermediates sabot of filling in, carry out lyophilize,
Processing parameter
Pre-freeze temperature :-45 ℃ of times: 5 hours
Condensing temperature :-45 ℃ of vacuum tightness: 10Pa
Distillation phase temperature :-45 ℃～-5 ℃ vacuum tightnesss: 13.33Pa heat-up rate: 3～4 ℃/h
Dry epoch temperature :-5 ℃～40 ℃ vacuum tightnesss: 13.33Pa heat-up rate: 3～4 ℃/h
Treat that temperature rises to 40 ℃, insulation was observed 5-6 hour, made the complete freeze-drying of sample.
Tamponade is carried out under the condition of vacuum slightly, to guarantee the integrity of sealing, control its tamponade degree.
2.8 roll lid, after the assay was approved packing
Embodiment 5 doxofylline freeze-dried powders
1. write out a prescription
2. preparation technology
2.1 cillin bottle cleans and sterilization
2.2 rubber plug cleaning and sterilization
2.3 dosing process
Accurately take recipe quantity N.F,USP MANNITOL, Citric Acid, doxofylline suitable quantity of water heating for dissolving.
Then mentioned solution is added to 4/5 of cumulative volume with water for injection, and regulate the pH value to 2.0-3.0, water for injection adds to full dose.
2.5 decarburization, essence filter
Add 0.1% gac, stir decarburization; Again through 0.22 μ m millipore filtration essence filter.
2.6 packing, tamponade technological process
Loading amount requires: theoretical loading amount 4.0ml.
Check half tamponade degree: the situation such as check whether the plug of leakage is arranged, tamponade, pressure are askew, take out with aseptic nipper, with manual half tamponade of aseptic technique.
2.7 lyophilize: put into Freeze Drying Equipment by 100 grades of passages after pressing the half intermediates sabot of filling in, carry out lyophilize,
Processing parameter
Pre-freeze temperature :-45 ℃ of times: 5 hours
Condensing temperature :-45 ℃ of vacuum tightness: 10Pa
Distillation phase temperature :-45 ℃～-5 ℃ vacuum tightnesss: 13.33Pa heat-up rate: 3～4 ℃/h
Dry epoch temperature :-5 ℃～40 ℃ vacuum tightnesss: 13.33Pa heat-up rate: 3～4 ℃/h
Treat that temperature rises to 40 ℃, insulation was observed 5-6 hour, made the complete freeze-drying of sample.
Tamponade is carried out under the condition of vacuum slightly, to guarantee the integrity of sealing, control its tamponade degree.
2.8 roll lid, after the assay was approved packing.
Embodiment 6 doxofylline freeze-dried powders
1. write out a prescription
2. preparation technology
2.1 cillin bottle cleans and sterilization
2.2 rubber plug cleaning and sterilization
2.3 dosing process
Accurately take recipe quantity N.F,USP MANNITOL, Citric Acid, doxofylline suitable quantity of water heating for dissolving.
Then mentioned solution is added to 4/5 of cumulative volume with water for injection, and regulate the pH value to 2.0-3.0, water for injection adds to full dose.
2.5 decarburization, essence filter
Add 0.1% gac, stir decarburization; Again through 0.22 μ m millipore filtration essence filter.
2.6 packing, tamponade technological process
Loading amount requires: theoretical loading amount 4.0ml.
Check half tamponade degree: the situation such as check whether the plug of leakage is arranged, tamponade, pressure are askew, take out with aseptic nipper, with manual half tamponade of aseptic technique.
2.7 lyophilize: put into Freeze Drying Equipment by 100 grades of passages after pressing the half intermediates sabot of filling in, carry out lyophilize,
Processing parameter
Pre-freeze temperature :-45 ℃ of times: 5 hours
Condensing temperature :-45 ℃ of vacuum tightness: 10Pa
Distillation phase temperature :-45 ℃～-5 ℃ vacuum tightnesss: 13.33Pa heat-up rate: 3～4 ℃/h
Dry epoch temperature :-5 ℃～40 ℃ vacuum tightnesss: 13.33Pa heat-up rate: 3～4 ℃/h
Treat that temperature rises to 40 ℃, insulation was observed 5-6 hour, made the complete freeze-drying of sample.
Tamponade is carried out under the condition of vacuum slightly, to guarantee the integrity of sealing, control its tamponade degree.
2.8 roll lid, after the assay was approved packing
Embodiment 7 doxofylline freeze-dried powders
1. write out a prescription
2. preparation technology
2.1 cillin bottle cleans and sterilization
2.2 rubber plug cleaning and sterilization
2.3 dosing process
Accurately take recipe quantity N.F,USP MANNITOL, Citric Acid, doxofylline suitable quantity of water heating for dissolving.
Then mentioned solution is added to 4/5 of cumulative volume with water for injection, and regulate the pH value to 2.0-3.0, water for injection adds to full dose.
2.5 decarburization, essence filter
Add 0.1% gac, stir decarburization; Again through 0.22 μ m millipore filtration essence filter.
2.6 packing, tamponade technological process
Loading amount requires: theoretical loading amount 4.0ml.
Check half tamponade degree: the situation such as check whether the plug of leakage is arranged, tamponade, pressure are askew, take out with aseptic nipper, with manual half tamponade of aseptic technique.
2.7 lyophilize: put into Freeze Drying Equipment by 100 grades of passages after pressing the half intermediates sabot of filling in, carry out lyophilize,
Processing parameter
Pre-freeze temperature :-45 ℃ of times: 5 hours
Condensing temperature :-45 ℃ of vacuum tightness: 10Pa
Distillation phase temperature :-45 ℃～-5 ℃ vacuum tightnesss: 13.33Pa heat-up rate: 3～4 ℃/h
Dry epoch temperature :-5 ℃～40 ℃ vacuum tightnesss: 13.33Pa heat-up rate: 3～4 ℃/h
Treat that temperature rises to 40 ℃, insulation was observed 5-6 hour, made the complete freeze-drying of sample.
Tamponade is carried out under the condition of vacuum slightly, to guarantee the integrity of sealing, control its tamponade degree.
2.8 roll lid, after the assay was approved packing
The impact of test example 1 freeze-dry process on crystal habit
Get embodiment 1 product 10g, be dissolved in 266.7ml water for injection, divide according to 4ml to be filled in ampoule, half tamponade, lyophilize:
Pre-freeze temperature :-45 ℃ of times: 5 hours
Condensing temperature :-45 ℃ of vacuum tightness: 10Pa
Distillation phase temperature :-45 ℃～-5 ℃ vacuum tightnesss: 13.33Pa heat-up rate: 3～4 ℃/h
Dry epoch temperature :-5 ℃～40 ℃ vacuum tightnesss: 13.33Pa heat-up rate: 3～4 ℃/h
Treat that temperature rises to 40 ℃, insulation was observed 5-6 hour, made the complete freeze-drying of sample.
10 parts of random sampling are done respectively the X-RAY diffraction and are obtained as shown in Figure 2 the XRD figure spectrum, and this collection of illustrative plates is No. 1 sample wherein, and other samples are substantially in full accord, no longer repeat to list.Fig. 2 and Fig. 1 have the same characteristic features peak, prove that it is identical crystalline powder.
Test example 2
Trial target 1-3 product and reference substance 1～4 are got in lyophilized powder solubility property check of the present invention, detect its solubility property in water for injection under differing temps.
Its method is, with reference to the 2010 editions II appendix IX B of section clarity test procedures of Chinese Pharmacopoeia.Use the SC series clarity detector of Shanghai Huanghai Sea medicine inspection Instr Ltd..
Illumination range: 1000-4000LX; Time limit scope: 1-99S Set arbitrarily; Power: the 30W(single face); Fluorescent tube: the 20W(Special fluorescent lamp).
Get respectively each 10 parts of each test sample, every part of 0.5g adds respectively 15 times of waters for injection, uses KJ-202 type vibrator with 1000 beats/mins of vibrations, and timing detects clarity take instrument and reaches No. 0.5 turbidity standard as molten clear.Get the molten clear time average of each test sample, result is as shown in table 1:
Table 1, product solubility property detect (s)
| ? | 30 |
20℃ | 15 |
10℃ | 5 |
0℃ |
| Trial target 1 | 2.4 | 3.1 | 4.5 | 8.7 | 15.7 | 28.8 |
| Trial target 2 | 2.5 | 3.1 | 4.7 | 8.5 | 15.8 | 28.5 |
| Trial target 3 | 2.3 | 3.0 | 4.5 | 8.4 | 15.5 | 28.2 |
| Reference substance 1 | 5.1 | 8.2 | 15.5 | 40.7 | 62.4 | 100.4 |
| Reference substance 2 | 8.7 | 10.1 | 19.8 | 45.1 | 68.9 | Insoluble |
| Reference substance 3 | 7.5 | 8.8 | 18.8 | 45.7 | 64.2 | Insoluble |
| Reference substance 4 | 9.2 | 11.4 | 18.5 | 44.6 | 67.5 | Insoluble |
| Reference substance 5 | 9.6 | 10.9 | 17.9 | 45.2 | 69.1 | Insoluble |
Table 2, product steady dissolution detection (25 ℃)
| ? | 1h | 2h | 10h | 24h | 48h |
| Trial target 1 | 0.5 number | 0.5 number | 0.5 number | 0.5 number | 0.5 number |
| Trial target 2 | 0.5 number | 0.5 number | 0.5 number | 0.5 number | 0.5 number |
| Trial target 3 | 0.5 number | 0.5 number | 0.5 number | 0.5 number | 0.5 number |
| Reference substance 1 | 0.5 number | 0.5 number | No. 1 | The naked eyes visible particle | The naked eyes visible particle |
| Reference substance 2 | 0.5 number | 0.5 number | No. 1 | No. 4 | The naked eyes visible particle |
| Reference substance 3 | 0.5 number | No. 1 | No. 1 | The naked eyes visible particle | The naked eyes visible particle |
| Reference substance 4 | 0.5 number | 0.5 number | No. 1 | The naked eyes visible particle | The naked eyes visible particle |
| Reference substance 5 | 0.5 number | 0.5 number | No. 1 | The naked eyes visible particle | The naked eyes visible particle |
Table 3, product steady dissolution detection (10 ℃)
| ? | 1h | 2h | 10h | 24h | 48h |
| Trial target 1 | 0.5 number | 0.5 number | No. 1 | No. 1 | No. 4 |
| Trial target 2 | 0.5 number | 0.5 number | No. 1 | No. 2 | No. 4 |
| Trial target 3 | 0.5 number | 0.5 number | No. 1 | No. 2 | No. 4 |
| Reference substance 1 | No. 1 | No. 4 | The naked eyes visible particle | The naked eyes visible particle | The naked eyes visible particle |
| Reference substance 2 | No. 1 | No. 3 | The naked eyes visible particle | The naked eyes visible particle | The naked eyes visible particle |
| Reference substance 3 | No. 1 | No. 4 | The naked eyes visible particle | The naked eyes visible particle | The naked eyes visible particle |
| Reference substance 4 | No. 1 | No. 3 | The naked eyes visible particle | The naked eyes visible particle | The naked eyes visible particle |
| Reference substance 5 | No. 2 | No. 4 | The naked eyes visible particle | The naked eyes visible particle | The naked eyes visible particle |
Can find out from table 2, table 3, product of the present invention dissolving rear stability is good, and long-time placement still can reach the turbidity standard level No. 0.5, namely can only reach No. 1 turbidity standard in 10 hours and place at most under 25 ℃ of reference substances.
Wherein, being prepared as of each reference substance:
Trial target 1: get embodiment 1 product and be prepared into lyophilized powder according to the freeze-dry process of embodiment 4;
Trial target 2: get embodiment 2 products and be prepared into lyophilized powder according to the freeze-dry process of embodiment 4;
Trial target 3: get embodiment 3 products and be prepared into lyophilized powder according to the freeze-dry process of embodiment 4;
Reference substance 1: get commercially available doxofylline 100g, add 1L water, stir and moltenly add 0.5 times of activated carbon backflow 1h after clear, be cooled to 80～90 ℃, filter, filtrate is stirred 2h under 15～25 ℃, be incubated standing 5h crystallization.The crystallization that obtains is prepared into lyophilized powder according to the freeze-dry process of embodiment 4;
Reference substance 2: get commercially available doxofylline 100g, with the dissolving of 700ml dehydrated alcohol reflux, moltenly naturally be cooled to room temperature after clear, standing crystallization, the crystallization that obtains is prepared into lyophilized powder according to the freeze-dry process of embodiment 4;
Reference substance 3: get commercially available doxofylline 100g, add the 2L volume ratio water of 1: 4/acetone mixing solutions, be heated to 60 ℃, stir 30min, filter, be cooled to 15 ℃, add anhydrous diethyl ether, be cooled to 0 ℃, insulated and stirred 12h, filter, the anhydrous diethyl ether washing, room temperature is placed 1h, vacuum-drying 3h.The crystallization that obtains is prepared into lyophilized powder according to the freeze-dry process of embodiment 4;
Reference substance 4: get commercially available doxofylline 100g, adding the 800ml volume ratio is the ethyl acetate/methanol solution of 1: 2, adds the 40g activated carbon, backflow 1h filters, and the filtrate room temperature is placed 24h, crystallization, the crystallization that obtains is prepared into lyophilized powder according to the freeze-dry process of embodiment 4;
Reference substance 5: get commercially available doxofylline 100g, adding the 500ml volume ratio is the methanol/chloroform solution of 5: 1, and backflow 1h filters, and the filtrate room temperature is placed 24h, crystallization, and the crystallization that obtains is prepared into lyophilized powder according to the freeze-dry process of embodiment 4.
It is that solvent carries out recrystallization to commercially available doxofylline that the present invention has also adopted the volume ratio ethyl acetate/ethanol of 1: 3, dioxane, Virahol, di-alcohol monomethyl ether, identical experiment has also been carried out in the crystallization that obtains, and obtain the experimental result of same trend, solubility property is similar with reference substance 1-5, but length is limit, and the present invention will not enumerate.
Claims (10)
1. doxofylline crystalline compounds, it is characterized in that, described doxofylline crystalline compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle represents at 10.21 °, 12.12 °, 14.39 °, 23.32 °, 24.43 °, 27.23 °, 28.60 °, 30.54 °, 32.28 °, 33.32 °, 34.38 ° and 36.12 °.
2. doxofylline crystalline compounds according to claim 1, is characterized in that, described doxofylline crystalline compounds adopts following method to be prepared from:
(1) getting the doxofylline crude product, fully to be dissolved in volume ratio be in the mixing solutions of water/propyl carbinol/acetonitrile of 4: 3: 1.5, be heated to reflux, stir the molten doxofylline solution that obtains clearly, wherein the mixed liquor volume of water/propyl carbinol/acetonitrile is 4.5～5.5 times of doxofylline crude product weight;
(2) dripping volume ratio under return stirring in the doxofylline solution is the ether/methanol solution of 4: 1, and wherein ether/methanol solution volume is 0.7～0.9 times of doxofylline crude product weight;
(3) stopped heating stirs borehole cooling to 5～10 ℃ at rotating speed 30～50rmp, and wherein cooling rate is 5～8 ℃/5min, and standing crystallization filters, and filter cake washs with ether, and vacuum-drying gets the doxofylline crystalline compounds.
3. doxofylline crystalline compounds according to claim 2, is characterized in that, the mixed liquor volume of water/propyl carbinol/acetonitrile is 5 times of doxofylline crude product weight; Ether/methanol solution volume is 0.7～0.9 times of doxofylline crude product weight.
4. doxofylline crystalline compounds according to claim 2, is characterized in that, stirs borehole cooling to 8 ℃ at rotating speed 40rmp in step (3).
5. doxofylline crystalline compounds according to claim 2, is characterized in that, in step (3), cooling rate is 6.5 ℃/5min.
6. doxofylline crystalline compounds according to claim 2, is characterized in that, standing crystallization 18～24h in step (3).
7. according to claim 2～6 described doxofylline crystalline compounds of any one, is characterized in that, after step (1) obtains doxofylline solution, also uses the activated carbon processing of decolouring.
8. doxofylline freeze-dried powder, it is characterized in that, described lyophilized powder is prepared from by following weight part composition: 80～120 parts of the described doxofylline crystalline compounds of claim 1-7 any one, 100～115 parts of Citric Acids, 180～220 parts, N.F,USP MANNITOL, 4000 parts of waters for injection; Wherein be preferably 100 parts of the described doxofylline crystalline compounds of claim 1-7 any one, 108 parts of Citric Acids, 200 parts, N.F,USP MANNITOL, 4000 parts of waters for injection.
9. doxofylline freeze-dried powder according to claim 8, is characterized in that, described doxofylline lyophilized powder is prepared according to the method that comprises the steps:
(1) accurately take N.F,USP MANNITOL, Citric Acid, the doxofylline water for injection dissolving of cumulative volume 4/5, and regulate pH value to 2.0～3.0, water for injection adds to full dose;
(2) adding weight is the gac of doxofylline weight 0.1%, stirs decarburization; Again through 0.22 μ m millipore filtration essence filter;
(3) lid is rolled in packing, half tamponade, lyophilize, after the assay was approved packing.
10. doxofylline freeze-dried powder according to claim 9, is characterized in that, step (3) lyophilize is:
The pre-freeze temperature :-45 ℃, the time: 5 hours, vacuum tightness: 10Pa;
Distillation phase temperature :-45 ℃～-5 ℃, vacuum tightness: 13.33Pa, heat-up rate: 3～4 ℃/h;
The dry epoch temperature :-5 ℃～40 ℃, vacuum tightness: 13.33Pa, heat-up rate: 3～4 ℃/h; Treat that temperature rises to 40 ℃, be incubated 5-6 hour, make the complete freeze-drying of sample.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103524503A (en) * | 2013-10-29 | 2014-01-22 | 天津梅花医药有限公司 | Doxofylline hemihydrate |
| CN103848831A (en) * | 2014-03-18 | 2014-06-11 | 山东罗欣药业股份有限公司 | Doxofylline compound and pharmaceutical composition thereof |
| CN105250227A (en) * | 2015-09-30 | 2016-01-20 | 合肥华方医药科技有限公司 | Citric acid caffeine freeze-dried powder and preparation method thereof |
| CN105287373A (en) * | 2015-12-01 | 2016-02-03 | 李正梅 | Anti-bronchial asthma doxofylline injection |
| CN111978324A (en) * | 2020-08-28 | 2020-11-24 | 开封康诺药业有限公司 | Crystal form of doxofylline and preparation method thereof |
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| CN102367254A (en) * | 2011-08-26 | 2012-03-07 | 贺金凤 | More stable doxofylline compound and pharmaceutical composite thereof |
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| CN103524503A (en) * | 2013-10-29 | 2014-01-22 | 天津梅花医药有限公司 | Doxofylline hemihydrate |
| CN103848831A (en) * | 2014-03-18 | 2014-06-11 | 山东罗欣药业股份有限公司 | Doxofylline compound and pharmaceutical composition thereof |
| CN103848831B (en) * | 2014-03-18 | 2015-03-11 | 山东罗欣药业集团股份有限公司 | Doxofylline compound and pharmaceutical composition thereof |
| CN105250227A (en) * | 2015-09-30 | 2016-01-20 | 合肥华方医药科技有限公司 | Citric acid caffeine freeze-dried powder and preparation method thereof |
| CN105287373A (en) * | 2015-12-01 | 2016-02-03 | 李正梅 | Anti-bronchial asthma doxofylline injection |
| CN111978324A (en) * | 2020-08-28 | 2020-11-24 | 开封康诺药业有限公司 | Crystal form of doxofylline and preparation method thereof |
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