CN104666283A - Preparation method of alcohol ethoxylate and product - Google Patents
Preparation method of alcohol ethoxylate and product Download PDFInfo
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- CN104666283A CN104666283A CN201410564470.0A CN201410564470A CN104666283A CN 104666283 A CN104666283 A CN 104666283A CN 201410564470 A CN201410564470 A CN 201410564470A CN 104666283 A CN104666283 A CN 104666283A
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Abstract
The invention relates to a preparation method of alcohol ethoxylate and a product. The preparation method of the alcohol ethoxylate comprises the following steps that 1) 1-dodecanol and a basic catalyst are combined to form a mixture, and the water content of the mixture of 1-dodecanol and the basic catalyst is controlled to be less than 0.1wt%, based on the total weight of 1-dodecanol and the basic catalyst; 2) oxirane is contacted with the mixture, and reacts with 1-dodecanol under the action of the basic catalyst to form a reaction product; and 3) the reaction product is subjected to fractional crystallization, so that alcohol ethoxylate is obtained.
Description
The application is Chinese invention application (denomination of invention: method and the product of preparing alcohol ethoxylate, the applying date: on June 10th, 2010; Application number: divisional application 201010196908.6).
Technical field
The present invention relates to the method preparing alcohol ethoxylate (alcohol ethoxylate, AE), according to alcohol ethoxylate, the pharmaceutical composition comprising this alcohol ethoxylate and their purposes that the inventive method obtains.
Background technology
Alcohol ethoxylate is the widely used medicament for a class sclerotherapy.Alcohol ethoxylate belongs to the many glycol ethers of alkyl, usually can be prepared by the reaction of alcohol and oxirane.This reaction produces the mixture of the ethoxylate with different oxygen ethylene (ethylene oxide, EO) unit number usually, and can not obtain pure alcohol ethoxylate.
But, prior art known prepare in the method for alcohol ethoxylate, usually make lauryl alcohol and reacting ethylene oxide, the method generally produces a large amount of by-products, and these by-product impurities are difficult to remove from product.In these products, the content of alcohol ethoxylate is generally about 95wt%, and some less desirable impurity content is higher.Thus, the purity of alcohol ethoxylate can not meet the requirement of pharmaceuticals industry increasingly stringent.
Therefore, still need to provide the method preparing highly purified alcohol ethoxylate, and for the purified alcohols ethoxylate pure as far as possible of its pharmaceutical applications.
Summary of the invention
The object of this invention is to provide method and the products obtained therefrom of the alcohol ethoxylate of the molecular weight distribution of preparation high-purity and uniqueness.The product obtained by the method has favourable character, makes it preferablyly apply for pharmacy.
The invention provides the method preparing alcohol ethoxylate, the method comprises the steps:
1) merge DODECANOL, 1-and base catalyst, the water content in the mixture of DODECANOL, 1-and base catalyst is controlled to and is less than 0.1wt%, based on the gross weight of DODECANOL, 1-and base catalyst;
2) make oxirane contact with this mixture, oxirane and DODECANOL, 1-are reacted under described base catalyst exists, thus obtains product; With
3) make described product carry out fractional crystallization, thus obtain described alcohol ethoxylate.
In one embodiment, fractional crystallization step comprises following operation: the first temperature a) being cooled to described product to be no more than about 15 DEG C, and then is heated to second temperature of about 20 DEG C to about 32 DEG C; And it is b) centrifugal from operation material a).
In another embodiment, described first temperature is about 0 DEG C to 15 DEG C, is preferably about 5 to about 15 DEG C, more preferably from about 5 to about 10 DEG C.In another embodiment, described second temperature is about 20 DEG C to 30 DEG C, is preferably about 25 to about 30 DEG C, more preferably from about 27 to about 29 DEG C.
In one embodiment, centrifugally to carry out at 5000 to 30000g.In another embodiment, centrifugal the 3rd temperature at about 20 DEG C to about 32 DEG C is carried out.
In one embodiment, water content controls to about 0.01wt% to about 0.03wt%, based on the gross weight of DODECANOL, 1-and base catalyst.
In one embodiment, control water content to comprise: the mixture of DODECANOL, 1-and base catalyst is kept at least 3 hours with the pressure being less than 10 millibars the temperature of about 70 DEG C to about 130 DEG C.
In one embodiment, base catalyst is selected from potassium hydroxide, sodium hydroxide, Feldalat NM and their combination.Preferably, base catalyst is potassium hydroxide.
In one embodiment, the amount of potassium hydroxide is less than 0.5wt%, based on the gross weight of oxirane, DODECANOL, 1-and potassium hydroxide.Preferably, the amount of potassium hydroxide is 0.05wt% to about 0.1wt%, is preferably about 0.09wt%, based on the gross weight of oxirane, DODECANOL, 1-and potassium hydroxide.
In one embodiment, reaction temperature is about 130 DEG C to about 180 DEG C, is preferably 155 DEG C to about 170 DEG C.
In one embodiment, base catalyst is potassium hydroxide, and its amount is about 0.09wt%, based on the gross weight of oxirane, DODECANOL, 1-and potassium hydroxide; Water content is 0.01wt% to about 0.02wt%, based on the gross weight of DODECANOL, 1-and potassium hydroxide; Reaction temperature is about 155 DEG C to about 170 DEG C; Reaction pressure is 1 to 4 bar (100kPa to 400kPa).
In one embodiment, method of the present invention also comprises other purification step.Preferably, this other purification step carries out after fractional crystallization step.
In one embodiment, described other purification step comprises: with gas bleed from the material of fractional crystallization step more than 30 minutes, then keep more than 5 hours in the temperature of 50 DEG C to 100 DEG C and the pressure that is less than 20 millibars.
Present invention also offers the alcohol ethoxylate of the purification prepared by the inventive method, it comprises:
There is the compound of following structural formula (I),
Wherein n is the integer of 1 ~ 23, and meansigma methods is 7.8 to 9.8;
The mean molecule quantity of the alcohol ethoxylate of wherein said purification is about 530 to about 620;
The alcohol ethoxylate of described purification has monomodal molecular weight distribution in the molecular weight ranges of 180 to 1160;
Molecular weight is the total amount of formula (I) compound of about 620 to about 760 is about 27.5wt% to 31wt%, based on the gross weight of alcohol ethoxylate Chinese style (I) compound of described purification; And
The total amount that molecular weight is greater than formula (I) compound of about 980 is less than 3wt%, based on the gross weight of alcohol ethoxylate Chinese style (I) compound of described purification; Desirably, the alcohol ethoxylate of this purification is prepared by method of the present invention.
In one embodiment, in the alcohol ethoxylate of purification of the present invention, molecular weight is that formula (I) compound of about 610 to about 640 accounts for about 8.0wt% to about 9.0wt%, molecular weight is that formula (I) compound of about 660 to about 690 accounts for about 7.5wt% to about 8.5wt%, and/or molecular weight is that formula (I) compound of about 700 to about 730 accounts for about 6.5wt% to about 7.5wt%, separately based on the gross weight of formula (I) compound.
In one embodiment, the total amount of formula (I) compound is greater than 96wt%, preferably higher than 98wt%, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, the alcohol ethoxylate of purification also comprises the impurity composition that total amount is less than 2wt%, based on the gross weight of the alcohol ethoxylate of described purification.
In one embodiment, impurity composition comprises and is selected from ethylene glycol, diethylene glycol, Polyethylene Glycol, formaldehyde and has formula C
10h
21(CH
2cH
2o)
mthe composition of the compound of OH, wherein m is 0 or positive integer.
In another embodiment, the impurity composition amount of comprising is less than the ethylene glycol of 50ppm, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, the impurity composition amount of comprising is less than the diethylene glycol of 100ppm, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, the impurity composition amount of comprising is less than the Polyethylene Glycol of 1wt%, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, the impurity composition amount of comprising is less than the formaldehyde of 5ppm, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, what the impurity composition amount of comprising was less than 1wt% has formula C
10h
21(CH
2cH
2o)
mthe compound of OH, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, the alcohol ethoxylate of purification of the present invention has the following character of at least one: refractive index is about 1.4 to about 1.5; Saponification number is about 0.05% to about 0.5%, particularly 0.05% to about 0.3%; Peroxide value is about 0.01% to about 0.3%; PH value is about 6.5 to about 7.1; Cloud point in water is about 80 to 90 DEG C; Water content is less than 1wt%; Hydroxyl value is about 90 to 100.
In another embodiment, the alcohol ethoxylate of described purification has following character:
Acid number is less than 0.2; Saponification number is less than 0.5%; Peroxide value is less than 0.5%; And water content is less than 1wt%.
Present invention also offers a kind of pharmaceutical composition, it comprises the alcohol ethoxylate of purification of the present invention.
In one embodiment, this pharmaceutical composition also comprises pharmaceutically useful diluent and/or excipient.
The invention provides alcohol ethoxylate or the application of pharmaceutical composition in the cirsoid medicine of preparation treatment of purification of the present invention.
The invention provides alcohol ethoxylate or the application of pharmaceutical composition in the uterus of preparation treatment jenny (comprising people) and/or the medicine of diseases of fallopian tubes of purification of the present invention.
The alcohol ethoxylate that the invention provides purification of the present invention is as the purposes of nonionic emulsifier and/or cosurfactant.
The invention provides the purposes of alcohol ethoxylate as the additive of people's care product of purification of the present invention.In one embodiment, people's care product comprises hair conditioner product, such as shampoo, hair-care agent, facial cream and body frost.
Accompanying drawing explanation
Fig. 1 shows the flow chart of the inventive method.Term " IPC " expression " technology controlling and process " used in the application, it represents the controlled condition of the inventive method.Term " IPC1 " expression " controls water content to the level (especially about 0.01wt% to 0.03wt%) lower than 0.1wt%, the gross weight based on DODECANOL, 1-and base catalyst ".Term " IPC2 " represents technology controlling and process 2, and wherein pH value is 6.5 ~ 7.5, cloud point is 78 DEG C ~ 86 DEG C and DODECANOL, 1-content is less than 1.50wt%.Term " IPC3 " represents technology controlling and process 3, as mentioned below.
Fig. 2 shows the percentage composition curve in the product that embodiment 1-3 obtains with formula (I) compound of different oxygen ethylene unit number n.
Fig. 3 shows the molecular weight distribution curve of the product prepared according to embodiment 1, and it is measured by HPLC.
Fig. 4 shows the relation curve of the concentration of alcohol ethoxylate in blood plasma of purification and the time after drug administration.In the diagram, AETH 1% (R) represents the solution of the alcohol ethoxylate of the purification from embodiment 1 of 1wt%, and it is for the varicose of (R) reticular veins (reticular varicose veins); AETH 0.5% (S) represents the solution of the alcohol ethoxylate of the purification from embodiment 1 of 0.5wt%, and it is for the thread varicosis of (S) Aranea (spider varicose veins).
Detailed description of the invention
The method preparing alcohol ethoxylate of the present invention
The invention provides the method preparing alcohol ethoxylate, the method comprises the steps:
1) merge DODECANOL, 1-and base catalyst, the water content in the mixture of DODECANOL, 1-and base catalyst is controlled to and is less than 0.1wt%, based on the gross weight of DODECANOL, 1-and base catalyst;
2) make oxirane contact with this mixture, oxirane and DODECANOL, 1-are reacted under described base catalyst exists, thus obtains product; With
3) make described product carry out fractional crystallization, thus obtain described alcohol ethoxylate.
Below describe condition and the step of the inventive method in detail.
1. react
Method of the present invention first DODECANOL, 1-and base catalyst is merged, and controls water content in mixture to the level expected, and then add oxirane and react, thus generation alcohol ethoxylate.
According to the present invention, importantly, before oxirane and DODECANOL, 1-react, control the water content in the mixture of DODECANOL, 1-and base catalyst, because if the water content in this mixture is higher, the impurity of some such as Polyethylene Glycol can be produced.The water in this mixture should be removed as much as possible before mixture oxirane being joined DODECANOL, 1-and base catalyst.
Against expectation, inventor finds when the water content in mixture controls to the level lower than 0.1wt% (gross weight based on DODECANOL, 1-and base catalyst), greatly can reduce the amount of Polyethylene Glycol that reaction produces and other impurity, such as, in product, the amount of PEG, ethylene glycol and diethylene glycol is less than 0.5wt%, thus can significantly improve the purity of product.In other words, can be obtained by method of the present invention there is the product higher relative to those product purities prepared by conventional method.Thus, the water content in mixture should be low as far as possible.
But, the water content controlled in mixture is uneconomic to too low level.In a preferred embodiment of the invention, before starting to react in mixture oxirane being joined DODECANOL, 1-and base catalyst, water content in mixture controls to the level of about 0.01wt% ~ 0.03wt%, based on the gross weight of DODECANOL, 1-and base catalyst.In above-mentioned scope, water content controls to the level lower than 0.02wt%.
In order to reduce this water content, the reaction reagent that water content is as far as possible low should be used.In addition, before input reactive component, can be dry by reaction vessel, with as much as possible except anhydrating.
When water content before adding oxirane in mixture does not reach aspiration level, control the step of water content and comprise: the mixture of DODECANOL, 1-and base catalyst is kept at least 3 hours in the temperature (preferably 100 DEG C) of about 70 DEG C to about 130 DEG C and the pressure that is less than 10 millibars.Then, get blend sample, measure water content.If water content does not reach desired level, namely lower than 0.1wt%, repeat the step of this control water content until meet the demands.
Measuring water content in mixture can use methods known in the art to carry out, such as seasoning (such as, atmosphere pressure desiccation, boulton process and infrared drying method), the way of distillation, Ka Er-Fischer's method etc.In the present invention, Ka Er-Fischer's method usually can be used to measure this water content.
After water content in the mixture of DODECANOL, 1-and base catalyst is controlled to the level of expectation, oxirane is joined in this mixture.Then, oxirane can react with DODECANOL, 1-under base catalyst exists.
This reaction is carried out usually under an inert atmosphere.Thus, before the reaction starts, the noble gas of such as nitrogen, helium etc. is injected in reactor.
Oxirane follows S with the reaction of DODECANOL, 1-in the presence of acidic
n1-mechanism, and reaction starts at the temperature more much lower than reaction when using base catalyst.But the shortcoming of acidic catalyst produces a lot of by-product.Therefore, industrial significance is not had.Thus, in this application, preferred base catalyst.
Oxirane follows S with the reaction of DODECANOL, 1-under base catalyst exists
n2-mechanism.Usually, base catalyst known in the art may be used for the present invention.In one embodiment of the invention, base catalyst can be selected from potassium hydroxide, sodium hydroxide, Feldalat NM and their combination.
As mentioned above, the base catalyst of solid form is preferably used, to control the water content in the mixture of DODECANOL, 1-and base catalyst.
In the base catalyst of these such as potassium hydroxide, sodium hydroxide, Feldalat NMs, Feldalat NM can produce the impurity of a small amount of Polyethylene Glycol that such as methylates.
In the base catalysts such as these such as potassium hydroxide, sodium hydroxide, Feldalat NMs, the chemical property of potassium hydroxide and sodium hydroxide is closely similar.But potassium hydroxide demonstrates higher basicity, thus the nucleophilicity of its alcoholates is better.In addition, potassium ion is more soluble than sodium ion in Polyethylene Glycol, and thus the alcoholates of potassium more dissociates.Therefore, in the preferred embodiment of the present invention, the preferred potassium hydroxide of base catalyst.In one embodiment, the potassium hydroxide of solid form is used.
In one embodiment of the invention, the amount of base catalyst is enough to reaction is carried out with acceptable speed.If the amount of base catalyst is too large, reaction is very fast, but product can turn yellow, and this is less desirable.If the consumption of base catalyst is too little, reaction rate can be lower, and this is not cost-effective.
Be in the situation of potassium hydroxide at base catalyst, its amount is less than 0.5wt%, based on the gross weight of oxirane, DODECANOL, 1-and potassium hydroxide.In another embodiment of the present invention, the amount of potassium hydroxide is about 0.05wt% extremely about 0.1wt%, preferably about 0.09wt%, based on the gross weight of oxirane, DODECANOL, 1-and potassium hydroxide.Or the amount of potassium hydroxide is chosen as the 0.1-1.0wt% of the amount relative to DODECANOL, 1-usually.
In one embodiment of the invention, the mol ratio of oxirane and DODECANOL, 1-is 7.8:1 ~ 9.8:1.
The reaction of oxirane and DODECANOL, 1-is heat release (Δ h=-94kJ/ moles of ethylene oxide).Reaction can be carried out at higher temperature, such as about 130-180 DEG C, preferably about 155 DEG C-170 DEG C.When temperature is lower than 150 DEG C, react too slow.When too high reaction temperature, product can turn yellow.Polyoxyethylene chain distribution is not by the impact of temperature.
Pressure does not also affect for polyoxyethylene chain distribution.The reaction of oxirane and DODECANOL, 1-can be carried out at middle pressure, such as 1-3 bar (100kPa ~ 300kPa).The pressure that should be avoided in higher than 3 bar keeps long-time (a few hours), because may produce the auto polymerization of oxirane.
In a preferred embodiment, can select following parameter: base catalyst is potassium hydroxide, its amount is about 0.09wt%, based on the gross weight of oxirane, DODECANOL, 1-and potassium hydroxide; Water content is 0.01wt% to about 0.02wt%, based on the gross weight of DODECANOL, 1-and potassium hydroxide; The mol ratio of oxirane and DODECANOL, 1-is about 8.8:1; Reaction temperature is about 155 DEG C to about 170 DEG C; Reaction pressure is 1 to 4 bar (100kPa to 400kPa).
In one embodiment, after the mixture that whole oxirane joins DODECANOL, 1-and base catalyst, reaction can be made to carry out about 10 minutes to 50 hours again, such as about 30 minutes to 24 hours.
Can reaction terminating be made by adding acid such as acetic acid, thus obtain product.After a period of time is carried out in reaction, sampling, measures pH value, cloud point and DODECANOL, 1-content.When pH value be 6.5 ~ 7.5, cloud point be 78 DEG C ~ 86 DEG C and DODECANOL, 1-content is less than 1.50wt% time, can think and react completely.Now, acetic acid can be added and carry out cessation reaction.
2. purification reaction product
Usually, product comprises desired product alcohol ethoxylate, and some impurity are unreacted DODECANOL, 1-such as, and the by-product of reaction is as Polyethylene Glycol, formaldehyde, acetaldehyde, Isosorbide-5-Nitrae-dioxane, ethylene glycol, diethylene glycol etc.
In order to obtain the end product alcohol ethoxylate of purity of the present invention higher and unique molecular amount distribution, method of the present invention comprises fractional crystallization step.This fractional crystallization step mainly can remove Polyethylene Glycol (PEG) etc. from product.As mentioned above, PEG is the by-product of ethoxylation, is formed by the reaction of oxirane and residual water.This fractional crystallization step is the committed step of the inventive method.This step greatly can improve the purity of product alcohol ethoxylate, reduces the content that such as prior art is difficult to the impurity of the PEG removed etc.
In this fractional crystallization step, first make product freezing, be then annealed to such temperature: higher than the fusing point of alcohol ethoxylate, and lower than the fusing point of PEG.Thus, namely PEG can be removed from product by methods such as precipitations.In one embodiment, this annealing temperature is 15 to 50 DEG C, preferably 20 to 32 DEG C.
Have multiple method can remove the PEG of precipitation, such as, filter, centrifugal etc.In one embodiment, high speed frozen centrifugation can use as the fast method of a kind of PEG for removing precipitation from product.Favor speed is the high speed frozen centrifugation of 2000 to 40000rpm (5000 ~ 30000g).
In one embodiment, fractional crystallization step comprises following operation:
A) described product is cooled to be no more than first temperature of about 15 DEG C, is then heated to second temperature of about 20 DEG C to about 32 DEG C; With
B) centrifugal from operation material a).
Operation a) in, the first temperature can not be too high, otherwise the yield of the method can reduce.In one embodiment, the first temperature can be about 0 DEG C to 15 DEG C, such as about 5 to 15 DEG C, about 5 to 12 DEG C, about 5 to 10 DEG C.Material can be about 10 minutes to 30 hours in the time that the first temperature keeps, such as 0.5 hour, 1 hour, 2 hours, 5 hours, 10 hours, 15 hours, 24 hours etc.
Operation a) in, the second temperature can not be too high or too low, otherwise the efficiency of the method can be affected.In another embodiment, the second temperature can be about 20 DEG C to 30 DEG C, such as about 25 to 30 DEG C, about 27 to 29 DEG C.Material can be about 10 minutes to 30 hours in the time that the second temperature keeps, such as 0.5 hour, 1 hour, 2 hours, 5 hours, 10 hours, 15 hours, 24 hours etc.When being heated to the second temperature, should be noted that and prevent product section overheated and exceed final temperature.
Then, to carrying out centrifugal from operation material a).In one embodiment, centrifugally to carry out at high speeds, such as, carry out at 2000 to 40000rpm (centrifugal force corresponding to 5000 to 30000g).In another embodiment, in order to not make the effect of centrifugal produced heat affecting fractional crystallization, centrifugal the 3rd temperature 20 to 32 DEG C, preferably 20 to 30 DEG C is carried out.
After centrifugal, target product alcohol ethoxylate is present in supernatant.By the mode of toppling over, supernatant can be separated.
In order to improve the purity etc. of alcohol ethoxylate further, method of the present invention also comprises other purification step.Term used in this application " other purification step " does not comprise fractional crystallization step as above.
This other purification step can carry out before or after fractional crystallization step.In one embodiment, this other purification step carries out after fractional crystallization step.
In one embodiment, this other purification step comprises: with gas bleed (rinsing) from the material of fractional crystallization step more than 30 minutes, then keep more than 5 hours in the temperature of 50 DEG C to 100 DEG C and the pressure that is less than 20 millibars.
Particularly, this other purification step can be carried out as follows: with nitrogen wash from the material of fractional crystallization step more than 30 minutes, be then heated to 80 ± 10 DEG C and at the pressure evacuation lower than 20 millibars more than 5 hours.
Inventor surprisingly finds, the alcohol ethoxylate of the purification obtained according to the inventive method not only has higher purity, but also has unique molecular weight distribution, will describe the alcohol ethoxylate of this purification in detail below.
The alcohol ethoxylate of purification
Present invention also offers the alcohol ethoxylate of purification, it comprises:
There is the compound of following structural formula (I),
Wherein n is the integer of 1 ~ 23, and meansigma methods is 7.8 to 9.8;
The mean molecule quantity of the alcohol ethoxylate of wherein said purification is about 530 to about 620;
The alcohol ethoxylate of described purification has monomodal molecular weight distribution in the molecular weight ranges of 180 to 1160;
Molecular weight is the total amount of formula (I) compound of about 620 to about 760 is about 27.5wt% to 31wt%, based on the gross weight of alcohol ethoxylate Chinese style (I) compound of described purification; And
The total amount that molecular weight is greater than formula (I) compound of about 980 is less than 3wt%, based on the gross weight of alcohol ethoxylate Chinese style (I) compound of described purification.
The molecular formula of this formula (I) compound is C
12h
25(OCH
2cH
2)
noH.
In one embodiment, in the alcohol ethoxylate of purification of the present invention, molecular weight is that formula (I) compound of about 610 to about 640 accounts for about 8.0wt% to about 9.0wt%, molecular weight is that formula (I) compound of about 660 to about 690 accounts for about 7.5wt% to about 8.5wt%, and/or molecular weight is that formula (I) compound of about 700 to about 730 accounts for about 6.5wt% to about 7.5wt%, separately based on the gross weight of formula (I) compound.
Term used in this application " alcohol ethoxylate of purification " refers to directly according to the material that the inventive method obtains, and it is not containing other material any of having a mind to add.The alcohol ethoxylate of purification of the present invention can be used as the raw material of various application.Or the alcohol ethoxylate of this purification can use with other desired combinations of substances.
The alcohol ethoxylate of this purification can be prepared by method of the present invention.The alcohol ethoxylate of the purification obtained according to the inventive method has unique molecular weight distribution and higher purity.
The molecular weight distribution of polymer can have molecular weight distribution that is unimodal, bimodal or multimodal usually.These terms refer to that these terms refer to that y-axle is the number of local maximum in the curve of occurrence number (frequency) in x-molecular shaft amount direction (namely molecular weight increases progressively direction).Thus, monomodal molecular weight distribution has a local maximum.Term used in this application " peak molecular weight " is defined as the molecular weight the most usually occurred in molecular weight distribution.In statistics term, peak molecular weight is the mode (mode) of molecular weight distribution.
The alcohol ethoxylate of purification of the present invention has unique molecular weight distribution.In one embodiment, the alcohol ethoxylate of this purification has monomodal molecular weight distribution in the molecular weight ranges of 180 to 1160; Molecular weight is the total amount of formula (I) compound of about 620 to about 760 is about 27.5wt% to 31wt%, based on the gross weight of alcohol ethoxylate Chinese style (I) compound of described purification; And the total amount that molecular weight is greater than formula (I) compound of about 980 is less than 3wt%, based on the gross weight of alcohol ethoxylate Chinese style (I) compound of described purification.In another embodiment, the peak molecular weight of the alcohol ethoxylate of purification of the present invention is about 550 ~ 600.
The alcohol ethoxylate of purification of the present invention also has higher purity.In other words, in the alcohol ethoxylate of purification of the present invention, the total amount of formula (I) compound is higher than the product of prior art.In one embodiment, the total amount of formula (I) compound is greater than 96wt%, preferably higher than 98wt%, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, the alcohol ethoxylate of purification also comprises the impurity composition that total amount is less than 2wt%, based on the gross weight of the alcohol ethoxylate of described purification.
Term used in this application " impurity composition " refers to the material not belonging to formula (I) compound.In one embodiment, impurity composition comprises and is selected from ethylene glycol, diethylene glycol, Polyethylene Glycol, formaldehyde and has formula C
10h
21(CH
2cH
2o)
mthe composition of the compound of OH, wherein m is 0 or positive integer.
In another embodiment, the impurity composition amount of comprising is less than the ethylene glycol of 50ppm, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, the impurity composition amount of comprising is less than the diethylene glycol of 100ppm, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, the impurity composition amount of comprising is less than the Polyethylene Glycol of 1wt%, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, the impurity composition amount of comprising is less than the formaldehyde of 5ppm, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, what the impurity composition amount of comprising was less than 1wt% has formula C
10h
21(CH
2cH
2o)
mthe compound of OH, based on the gross weight of the alcohol ethoxylate of described purification.
In another embodiment, the alcohol ethoxylate of purification of the present invention has the following character of at least one: refractive index is about 1.4 to about 1.5; Saponification number is about 0.05% to about 0.5%, particularly 0.05% to about 0.3%; Peroxide value is about 0.01% to about 0.3%; PH value is about 6.5 to about 7.1; Cloud point in water is about 80 to 90 DEG C; Water content is less than 1wt%; Hydroxyl value is about 90 to 100.
In another embodiment, the alcohol ethoxylate of described purification has following character: acid number is less than 0.2; Saponification number is less than 0.5%; Peroxide value is less than 0.5%; And water content is less than 1wt%.
Inventor surprisingly finds, of the present invention have the distribution of unique molecular amount and the alcohol ethoxylate of highly purified purification when being used for the treatment of varicosis, and safety and effectiveness have unexpected advantage.As previously mentioned, in the methods of the invention, in the mixture of DODECANOL, 1-and base catalyst, water content is lower, and the impurity level that reaction is produced is just lower; And the fractional crystallization step adopted can remove some impurity and improve purity.The more important thing is, this fractional crystallization step can also change the distribution of molecular weight of product, make the total amount of formula (I) compound of high molecular (being such as greater than about 980) lower, and the total amount with formula (I) compound of intermediate molecular weight (such as molecular weight is about 620 to about 760, is 10 ~ 13 corresponding to EO unit number n) can improve.Inventor also infers, may be that its total amount improves because EO unit number n is that the hydrophilic of formula (I) compound of 10 ~ 13 is moderate, makes the alcohol ethoxylate of purification of the present invention can more easily with effectively by patient is utilized.Thus, the alcohol ethoxylate of purification of the present invention is safer and effective in treatment varicosis.
Pharmaceutical composition
The present invention goes back the pharmaceutical composition of providing package containing the alcohol ethoxylate of purification of the present invention.
In one embodiment, this pharmaceutical composition also comprises pharmaceutically useful diluent and/or excipient etc.
Well known to a person skilled in the art that those pharmaceutically useful diluent and/or excipient may be used for the present invention.In one embodiment, lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, Talcum, mannose, ethanol etc. can be used as diluent and/or excipient.
Purposes of the present invention
Formula (I) compound may be used for the sclerotherapy of the hemorrhage emergency treatment hemostasis of esophageal variceal vein under scope and cirso-.Thus, the present invention relates to alcohol ethoxylate or the application of pharmaceutical composition in the cirsoid medicine of preparation treatment of purification of the present invention.
Formula (I) compound may be used for uterus and the treatment of oviducal Non-surgical.Thus, the invention still further relates to alcohol ethoxylate or the application of pharmaceutical composition in the uterus of preparation treatment jenny (comprising people) and/or the medicine of diseases of fallopian tubes of purification of the present invention.
The alcohol ethoxylate that the invention still further relates to purification of the present invention is as the purposes of nonionic emulsifier and/or cosurfactant.
The invention still further relates to the purposes of alcohol ethoxylate as the additive of people's care product of purification of the present invention.In one embodiment, people's care product comprises hair conditioner product, such as shampoo, hair-care agent, facial cream and body frost.
method of testing
From Ph.Eur (namely the method for testing that the present invention uses is, European Pharmacopoeia, European Pharmacopeia) and USP/NF is (namely, American Pharmacopeia-NF, United Stated Pharmacopeia-National Formalary) standard method, be described below:
1. refractive index
According to Ph.Eur.2.2.6, measure the refractive index of fining molten sample at 30 DEG C.
2.pH value
According to Ph.Eur.2.2.3, measure the pH value of 10% (w/w) solution 25 ± 2 DEG C of constant-current titrations.
3. water content
According to Ph.Eur.2.5.12, method A, adopts Ka Er-Karl Fischer titration to measure the water content of 5g sample.
4. acid number (acid value)
According to Ph.Eur.2.5.1, measure acid number.
5. hydroxyl value (N) and mean molecule quantity (M)
According to Ph.Eur.2.5.3, method A, uses 5.0mL acetylation mixture R1 (acetylation mixture R1) to 2g sample determination hydroxyl value (N).Acetylation mixture R1 is prepared as follows: be dissolved in anhydrous pyridine by 25.0ml acetic anhydride R, be diluted to 100.0ml by same solvent.By hydroxyl value (N), calculate mean molecule quantity (M) and averaged oxygen ethylene unit number (AEN) according to following formula:
M＝56110/N AEN＝(M-186.34)/44.05
6. saponification number
According to Ph.Eur.2.5.6,10g sample is used to measure saponification number.
7. peroxide value
According to Ph.Eur.2.5.5 method A, measure peroxide value.
8. cloud point
Cloud point is the feature of any ehtoxylated polymer, relevant with oxygen ethylene unit number.Measure cloud point to can be used for controlling the degree of polymerization.
Method:
10% (w/w) sample solution of about 5mL is placed in testing tube (diameter 16mm).This pipe is placed in water-bath (1000mL beaker), is slowly heated to about 75 DEG C.Then, heating is continued with the speed of 1 DEG C/min.Thermocouple thermometer is inserted into the position of the bottom about 5mm from this pipe.This temperature is read when sample solution bleaches and be muddy.
9. content of formaldehyde
Use the content of formaldehyde in the alcohol ethoxylate of HPLC measurement purification.
Chromatographic condition
10. the content of ethylene glycol and diethylene glycol
Use capillary gas chromatography to measure the content of ethylene glycol in the alcohol ethoxylate of purification and diethylene glycol simultaneously, and evaluate by external standard method.
Chromatographic condition:
Temperature program(me):
| Speed (DEG C/min) | Temperature (DEG C) | Retention time (min) | |
| Start | - | 85 | 4 |
| 1 | 3 | 95 | 0 |
| 2 | 10 | 155 | 0 |
| 3 | 25 | 235 | 70 |
11. polyethyleneglycol contents
According to the USP/NF method of testing for polyoxyethylene (10) oleyl ether, carry out the measurement of Polyethylene Glycol, difference is that sample size is different.Process is summarized as follows.
Sodium chloride solution (29%): in 1000mL flask, 290g sodium chloride is dissolved in the water, adds water to volume line.
Process: the sample of 25g accurate weighing is transferred in the 250mL separator containing 50mL ethyl acetate.Add 50mL sodium chloride solution (29%).Acutely rock 2 minutes.Standing separation device 15 minutes.Lower floor's aqueous phase is drained in second 250mL separator.50mL sodium chloride solution (29%) is used to extract upper strata again.Aqueous phase is merged, adds 50mL ethyl acetate, acutely rock 2 minutes, as front standing separation.Lower floor's aqueous phase is drained in the 3rd 250mL separator.With 50mL chloroform extraction twice, rock 2 minutes at every turn.Nitrogen current is aided with, the chloroform extract evaporate to dryness that will merge in 250mL beaker in steam bath.With about 15mL chloroform dissolution residual substance, transfer in filter, in the beaker (this weight is designated as M1) that 100mL is weighed, collect filtrate.Rinse funnel several times with chloroform, the filtrate of evaporation merging as mentioned above and flushing, until do not have the abnormal smells from the patient of chloroform or ethyl acetate.Cool in exsiccator, and weigh (being designated as M2).
In the amount (m) of the Polyethylene Glycol of % in the alcohol ethoxylate of following calculating purification:
m(％)＝(M2-M1)x 100/W
Wherein:
W example weight, g
The weight of M1 100mL beaker, g
The weight of the dried screening+beaker of M2, g
Fatty alcohol (the C of the ethoxylation that 12. mensuration are relevant
10h
21(EO)
noH)
Use RI-detector to adopt reversed-phase HPLC, measure the fatty alcohol of relevant ethoxylation.
Chromatographic condition
The mensuration of 13. alcohol ethoxylates
Use RI-detector to adopt reversed-phase HPLC, measure alcohol ethoxylate.
Inner mark solution: the about 1000mg1-tetradecanol of accurate weighing is dissolved in 100.0mL isopropyl alcohol.
Sample solution: by the about 1000mg sample dissolution of accurate weighing in 5mL ethanol, be diluted with water to 100.0mL.With isopropyl alcohol, this sample solution of 2.0mL and 2.0mL inner mark solution are diluted to 10.0mL.
Chromatographic condition
Embodiment
The present invention is further illustrated by following non-limiting example.
The preparation of the alcohol ethoxylate of embodiment 1 purification of the present invention
Method of the present invention is described in detail with reference to Fig. 1.Fig. 1 shows the flow chart of the inventive method.
1. react
The reactor of clean dried is evacuated down to the pressure lower than 10 millibars, is then heated to about 135 DEG C.After 2 hours, by reactor cooled to about 40 DEG C, and be adjusted to normal pressure.
9.0kg DODECANOL, 1-and 25.0g potassium hydroxide are put in this reactor, at the temperature evacuation 3 hours of 100 ± 10 DEG C.In the process, the pressure in reactor is less than 10 millibars.Pass into nitrogen, and control the water content in reactor in technology controlling and process 1 (IPC1).Get the sample of mixture, adopt the water content of Ka Er-Fischer's method working sample.This water content will lower than 0.02wt%; Otherwise, need, by this mixture dry 2 hours again, again to control water content.Water content in reactor is controlled to lower than after 0.02wt%, by reactor evacuation.
Similarly, the container vacuum-pumping of oxirane will be used for.Then, 22.5 liters of oxirane are put in this container, make pressure be elevated to 7 bar with nitrogen.
For reaction, the pressure nitrogen in reactor is adjusted to 1 bar, and under agitation DODECANOL, 1-/potassium hydroxide mixture is heated at least 135 DEG C.After reaching this temperature, under agitation oxirane is joined in this reactor, and make the pressure in reactor be elevated to 1.8 bar.Join in reactor by oxirane continuously, charging rate makes pressure in reactor in the scope of 1 ~ 3 bar, and temperature is in the scope of 155 to 170 DEG C.Preferred temperature is 163 to 168 DEG C.If temperature is more than 170 DEG C, then need reactor cooled.
After whole oxirane has added, reaction is being spent the night under stirring.
2. neutralize
Now, the mixture in reactor is cooled to 40 ~ 60 DEG C, in minimum 1 hour, adds the acetic acid of 22.0g 98 ~ 100% under stirring, carry out the mixture in neutralization reactor.
After this, with nitrogen wash reactor 30 minutes, then 100 ± 10 DEG C of evacuation 3 hours.
From reactor, technology controlling and process 2 (IPC2) is carried out in sampling.Table 1 is listed in the requirement of IPC2.After this, product is poured in rustless steel container, and weigh.
3. fractional crystallization step
After weighing, product is cooled to the temperature of 8 DEG C (wherein minimum cool time: 24 hours); And then be heated to the temperature (minimum heating-up time: 24 hours) of 28 ± 1.0 DEG C.Note needing to prevent product section overheated.
Then, product is poured in concentrator bowl.By product in centrifuges (purchased from Eppendorf, Heraeus uso.) between 9000rpm, the temperature of 20 to 30 DEG C centrifugal 20 minutes.After centrifugal, supernatant is poured in clean rustless steel container.Solid grain is retained in concentrator bowl.
Repeat this process, complete until all materials are centrifugal.
4. other purification step
Merging supernatant from centrifugation step is transferred in purification devices, at 40 ± 10 DEG C with nitrogen wash 40 ± 10 minutes, then 80 ± 10 DEG C temperature and be less than the temperature evacuation more than 5 hours of 20 millibars.Technology controlling and process 3 (IPC3) is carried out in sampling.The requirement of IPC3 is as following table 1.
Table 1
The alcohol ethoxylate of product-purification that embodiment 1 obtains is analyzed.The results are shown in table 2.
Embodiment 2-4
Repeat the step of embodiment 1.The alcohol ethoxylate of product-purification that embodiment 2-4 obtains is analyzed.The results are shown in table 2.
Table 2
CE1 is comparative example, is the standard commercial purchased from Europe.
As shown in table 2, inventor surprisingly finds, compared with CE1, in the alcohol ethoxylate of embodiment 1-4 purification, the content of some impurity significantly reduces.Such as, compared with CE1, in the alcohol ethoxylate of embodiment 1-4 purification, the content of Polyethylene Glycol is reduced to 0.2% from 1.26%.Similarly, the content of formaldehyde, ethylene glycol and diethylene glycol also significantly reduces.This shows, the alcohol ethoxylate of the purification obtained according to the inventive method has significantly low impurity content.In other words, the alcohol ethoxylate of purification of the present invention has significantly high purity.
Obtaining the above results is because such fact: in premix, water content is lower.Further, in preparation method process of the present invention, the step of water content in the mixture of DODECANOL, 1-and potassium hydroxide and fractional crystallization and centrifugal step have been carried out reducing.
Cloud point directly corresponds to the chain length distribution of alcohol ethoxylate.
The cloud point of the product prepared by art methods is generally 65-70 DEG C.As can be seen from Table 2, the cloud point of the alcohol ethoxylate of embodiment 1-4 purification is about 83-84 DEG C or 80-84 DEG C, is significantly higher than prior art products.This result shows, the ratio in the alcohol ethoxylate of embodiment 1-4 purification with formula (I) compound long compared with long-chain is higher than prior art products.
Fig. 2 and 3 can confirm this result further.
Fig. 2 shows the weight percentage curve in the product that embodiment 1-3 obtains with formula (I) compound of different oxygen ethylene unit number n.In Fig. 2, vertical coordinate accounts for the percetage by weight of formula (I) total amount of compound for formula (I) compound with different oxygen ethylene unit (EO) number n.This percetage by weight can use technology HPLC known in the art to measure.
Fig. 3 shows the molecular weight distribution curve of the product prepared according to embodiment 1.It is measured by HPLC.
As can be seen from Figures 2 and 3, the alcohol ethoxylate of purification of the present invention has unique molecular weight distribution.The alcohol ethoxylate of the purification of embodiment 1 has monomodal molecular weight distribution in the molecular weight ranges of 180 to 1160; Molecular weight is the total amount of formula (I) compound of about 620 to about 760 is about 28.5wt%, based on the gross weight of formula (I) compound; The total amount that molecular weight is greater than formula (I) compound of about 980 is less than 3wt%, based on the gross weight of formula (I) compound.The peak molecular weight of the alcohol ethoxylate of the purification of embodiment 1 is about 583.Further, molecular weight be about 610 to 640 formula (I) compound account for about 8.4%, molecular weight be about 660 to 690 formula (I) compound account for about 7.7%, molecular weight be about 700 to 730 formula (I) compound account for about 6.8%, based on the gross weight of formula (I) compound.
The result of table 2 and Fig. 2 and 3 further illustrates, and method of the present invention can provide that impurity content is low, cloud point is high and have the product of specified molecular weight distribution etc.These character make the alcohol ethoxylate of purification of the present invention advantageously to apply.This point can be confirmed in the examples below further.
The application of the alcohol ethoxylate of embodiment 5 purification of the present invention
the safety of the alcohol ethoxylate of part I purification of the present invention and effect
Carry out this research to illustrate in the patient of reticular veins (reticular vein) and Aranea thread veins (spider vein), the alcohol ethoxylate of purification of the present invention relative to
effect of (sodium tetradecyl sulfate) and placebo (0.9%NaCl solution) and toleration.In this research, to total, 338 patients treat, wherein 53 patients receive placebo, and 180 patients accept the alcohol ethoxylate of embodiment 1, and 105 patients accept
In this research, the alcohol ethoxylate of embodiment 1,
and the dosage of placebo is respectively: the alcohol ethoxylate of 0.5% and 1% embodiment 1,1%
and 0.9%NaCl.
Display is analyzed in rough estimates, and in the evaluation improved according to the vein of 5 grades of scorings, relative to placebo, carrying out treating with the alcohol ethoxylate of embodiment 1 purification is statistically significantly excellent (p<0.0001).
Further statistical analysis confirms, the alcohol ethoxylate of embodiment 1 purification is statistically significantly be better than placebo (p<0.0001) in following:
1) in the satisfaction for the treatment of 12 (± 2) week rear patient;
2) the last time injection after 12 (± 2) week, evaluate treatment success rate;
3) 26 (± 4) week after injection the last time, the improvement situation of vein is evaluated;
4) in the satisfaction for the treatment of 26 (± 4) week rear patient; And
5) the last time injection after 26 (± 4) week, evaluate treatment success rate.
For great majority with the alcohol ethoxylate of embodiment 1 purification (96%) or
(93%) patient treated, after injection, 3 months (Visit 4) observes the good improvement of vein or treats completely successfully the last time.After injection, 6 months (Visit 5) observes similar results the last time.
The alcohol ethoxylate of embodiment 1 purification is 96% in the treatment success rate of Visit 4, is 95%, is significantly higher than placebo at Visit 5.And
92% or 91% is respectively, slightly lower than the alcohol ethoxylate of embodiment 1 purification in the treatment success rate of Visit 4 or 5.
Great majority accept patient's satisfied or very satisfaction for treatment of the alcohol ethoxylate treatment of embodiment 1 purification, Visit 4 be 88% and Visit 5 be 84%.For
(being 64% at Visit 4, is 63% at Visit 5; P<0.0001) and placebo (being 13% at Visit 4, is 11% at Visit 5; P<0.0001), satisfied or very satisfied to treatment patient's digital display work is lower.With with
the patient for the treatment of compares, and the patient satisfaction for the treatment of with the alcohol ethoxylate of embodiment 1 purification is higher, may be because the good safety of alcohol ethoxylate of purification.
In this research, viewed modal relevant adverse events is that general obstacle (general disorder) and application position are uncomfortable, and it occurs in the patient of 73%; Next is angiopathy (vascular disorder, 52%), and skin and subcutaneous tissue obstacle (skin and subcutaneous tissue disorder, 23%).The patient treated with the alcohol ethoxylate (70%R with 73%S) with embodiment 1 purification compares, and accepts
the patient of (93%R and 96%S) occurs that the percent of general obstacle and application position discomfort (mainly stimulation, variable color and injection position pain) is higher.With with
the patient for the treatment of compares (67% (R) and 78% (S)), with the patient that the alcohol ethoxylate of embodiment 1 purification is treated, only there is angiopathy (mainly injection position hematoma and neovascularization (neovascularization)) in the patient of 52% (R) and 44% (S).In the patient treated with the alcohol ethoxylate of embodiment 1 purification, there is skin and subcutaneous tissue obstacle (such as in injection position pruritus and occur cicatrix (scar)) in the patient of 21% (R) and 20% (S); And in acceptance
in the patient for the treatment of, there is skin and subcutaneous tissue obstacle (such as injection position pruritus with occur cicatrix (scar)) in the patient of 26% (R) and 47% (S).
Note: " R " refers to for reticular veins varicose, " S " refers to for the thread varicosis of Aranea.
With accepting
the patient for the treatment of compares, in the patient treated with the alcohol ethoxylate of embodiment 1 purification, lessly observe local response hyperpigmentation (local reactions hyperpigmentation) in area for treatment, hematoma and neovascularization.
In addition, with accepting
the patient for the treatment of compares, and in the patient treated with the alcohol ethoxylate of embodiment 1 purification, occurs that patient's percent of pruritus, pain or causalgia (burning) is less at injection position.
part II pharmacokinetic study
From 22 patients participating in this research, extract outer blood sample (extra blood sample), for the plasma concentration of the alcohol ethoxylate of Evaluation operation example 1 purification.
Fig. 4 shows the relation curve of the concentration of alcohol ethoxylate in blood plasma of purification and the time after drug administration.
As seen from Figure 4, after using 5 minutes in all patients, the maximum of alcohol ethoxylate in blood plasma of embodiment 1 purification can be detected, and relevant with concentration with the volume injected of the alcohol ethoxylate of embodiment 1 purification.30 minutes to 3 hours after application, this value declined always, and is returned to its initial value, or within 6 hours, was slightly higher than initial value after application.
Therefore, when treating the patient of reticular veins (reticular vein) and Aranea thread veins (spider vein), the alcohol ethoxylate of purification of the present invention is 0.5% and 1% in concentration, and dosage demonstrates and reference substance for during 24mg at the most
equally effective, but there is better safety.Compared with placebo, the alcohol ethoxylate of purification of the present invention demonstrates the remarkable superiority in effect, and safer and can tolerate well, and does not occur local ill symptoms at injection position.
The present invention includes:
1. prepare a method for alcohol ethoxylate, comprise the steps:
1) merge DODECANOL, 1-and base catalyst, the water content in the mixture of DODECANOL, 1-and base catalyst is controlled to and is less than 0.1wt%, based on the gross weight of DODECANOL, 1-and base catalyst;
2) make oxirane contact with this mixture, oxirane and DODECANOL, 1-are reacted under described base catalyst exists, thus obtains product; With
3) make described product carry out fractional crystallization, thus obtain described alcohol ethoxylate.
2. the method for 1, wherein said fractional crystallization step comprises following operation:
A) described product is cooled to be no more than first temperature of about 15 DEG C, and then is heated to second temperature of about 20 DEG C to about 32 DEG C; With
B) centrifugal from operation material a).
3. the method for 2, wherein said first temperature is about 0 DEG C to 15 DEG C, is preferably about 5 to about 15 DEG C, more preferably from about 5 to about 10 DEG C.
4. the method for 2 or 3, wherein said second temperature is about 20 DEG C to 30 DEG C, is preferably about 25 to about 30 DEG C, more preferably from about 27 to about 29 DEG C.
5. the method any one of a 2-4, wherein operation a) in, product be cooled to the cooling rate of the first temperature to be less than about 10 DEG C/h, be preferably less than about 5 DEG C/h, be more preferably less than about 1 DEG C/h.
6. the method any one of a 2-5, wherein operation a) in, programming rate product being heated to again the second temperature is less than about 5 DEG C/h, is preferably less than about 1 DEG C/h, is more preferably less than about 0.5 DEG C/h.
7. the method any one of a 2-6, wherein centrifugally carries out at 5000 to 30000g.
8. the method any one of a 2-7, wherein centrifugal the 3rd temperature at about 20 DEG C to about 32 DEG C is carried out.
9. the method any one of a 1-8, wherein water content controls to about 0.01wt% to about 0.03wt%, based on the gross weight of DODECANOL, 1-and base catalyst.
10. the method any one of a 1-9, wherein controls water content and comprises: the mixture of DODECANOL, 1-and base catalyst is kept at least 3 hours with the pressure being less than 10 millibars the temperature of about 70 DEG C to about 130 DEG C.
11. the method any one of item 1-10, wherein said base catalyst is selected from potassium hydroxide, sodium hydroxide, Feldalat NM and their combination.
Method any one of 12. 1-10, wherein said base catalyst is potassium hydroxide.
Method any one of 13. 11-12, wherein the amount of potassium hydroxide is less than 0.5wt%, based on the gross weight of oxirane, DODECANOL, 1-and potassium hydroxide.
Method any one of 14. 11-13, wherein the amount of potassium hydroxide is 0.05wt% to about 0.1wt%, is preferably about 0.09wt%, based on the gross weight of oxirane, DODECANOL, 1-and potassium hydroxide.
Method any one of 15. 1-14, wherein reaction temperature is about 130 DEG C to about 180 DEG C, is preferably 155 DEG C to about 170 DEG C.
Method any one of 16. 1-15, wherein said base catalyst is potassium hydroxide, and its amount is about 0.09wt%, based on the gross weight of oxirane, DODECANOL, 1-and potassium hydroxide; Water content is 0.01wt% to about 0.02wt%, based on the gross weight of DODECANOL, 1-and potassium hydroxide; Reaction temperature is about 155 DEG C to about 170 DEG C; Reaction pressure is 1 to 4 bar (100kPa to 400kPa).
Method any one of 17. 1-16, also comprises other purification step.
The method of 18. 17, wherein said other purification step comprises:
With gas bleed from the material of fractional crystallization more than 30 minutes, then keep more than 5 hours in the temperature of 50 DEG C to 100 DEG C and the pressure that is less than 20 millibars.
The alcohol ethoxylate of 19. 1 kinds of purification, comprising:
There is the compound of following structural formula (I),
Wherein n is the integer of 1 ~ 23, and meansigma methods is 7.8 to 9.8;
The mean molecule quantity of the alcohol ethoxylate of wherein said purification is about 530 to about 620;
The alcohol ethoxylate of described purification has monomodal molecular weight distribution in the molecular weight ranges of 180 to 1160;
Molecular weight is the total amount of formula (I) compound of about 620 to about 760 is about 27.5wt% to 31wt%, based on the gross weight of formula (I) compound; And
The total amount that molecular weight is greater than formula (I) compound of about 980 is less than 3wt%, based on the gross weight of formula (I) compound.Desirably, the alcohol ethoxylate of this purification is prepared by the method for item 1.Preferably, the method for item 1 comprises the feature any one of a 2-18 further.
The alcohol ethoxylate of the purification of 20. 19, its middle-molecular-weihydroxyethyl is that formula (I) compound of about 610 to about 640 accounts for about 8.0wt% to about 9.0wt%, molecular weight is that formula (I) compound of about 660 to about 690 accounts for about 7.5wt% to about 8.5wt%, and/or molecular weight is that formula (I) compound of about 700 to about 730 accounts for about 6.5wt% to about 7.5wt%, separately based on the gross weight of formula (I) compound.
21. 19 or 20 the alcohol ethoxylate of purification, the total amount of its Chinese style (I) compound is more than 96wt%, based on the gross weight of the alcohol ethoxylate of described purification.
The alcohol ethoxylate of the purification of 22. any one of 19-21, the alcohol ethoxylate of wherein said purification also comprises the impurity composition that total amount is less than 2wt%, based on the gross weight of the alcohol ethoxylate of described purification.
The alcohol ethoxylate of the purification of 23. 22, wherein said impurity composition comprises and is selected from ethylene glycol, diethylene glycol, Polyethylene Glycol, formaldehyde and has formula C
10h
21(CH
2cH
2o)
mthe composition of the compound of OH, wherein m is 0 or positive integer.
24. 22 or 23 the alcohol ethoxylate of purification, the wherein said impurity composition amount of comprising is less than the ethylene glycol of 50ppm, based on the gross weight of the alcohol ethoxylate of described purification.
The alcohol ethoxylate of the purification of 25. any one of 22-24, the wherein said impurity composition amount of comprising is less than the diethylene glycol of 100ppm, based on the gross weight of the alcohol ethoxylate of described purification.
The alcohol ethoxylate of the purification of 26. any one of 22-25, the wherein said impurity composition amount of comprising is less than the Polyethylene Glycol of 1wt%, based on the gross weight of the alcohol ethoxylate of described purification.
The alcohol ethoxylate of the purification of 27. any one of 22-26, the wherein said impurity composition amount of comprising is less than the formaldehyde of 5ppm, based on the gross weight of the alcohol ethoxylate of described purification.
28. the alcohol ethoxylate of the purification of any one of item 22-27, what the wherein said impurity composition amount of comprising was less than 1wt% has formula C
10h
21(CH
2cH
2o)
mthe compound of OH, based on the gross weight of the alcohol ethoxylate of described purification.
The alcohol ethoxylate of the purification of 29. any one of 19-28, the alcohol ethoxylate of wherein said purification has the following character of at least one: refractive index is about 1.4 to about 1.5; Saponification number is about 0.05% to about 0.5%, particularly 0.05% to about 0.3%; Peroxide value is about 0.01% to about 0.3%; PH value is about 6.5 to about 7.1; Cloud point in water is about 80 to 90 DEG C; Water content is less than 1wt%; Hydroxyl value is about 90 to 100.
30. the alcohol ethoxylate of the purification of any one of item 19-29, the alcohol ethoxylate of wherein said purification has following character:
Acid number is less than 0.2;
Saponification number is less than 0.5%;
Peroxide value is less than 0.5%; And
Water content is less than 1wt%.
31. 1 kinds of pharmaceutical compositions, it comprises the alcohol ethoxylate of purification described in an any one of 19-30.
The pharmaceutical composition of 32. 31, also comprises pharmaceutically useful diluent and/or excipient.
The alcohol ethoxylate of purification described in 33. any one of 19-30 or the application of the pharmaceutical composition of item 31 or 32 in the cirsoid medicine of preparation treatment.
The alcohol ethoxylate of purification described in 34. any one of 19-30 or the application of the pharmaceutical composition of item 31 or 32 in the uterus of preparation treatment jenny (comprising people) and/or the medicine of diseases of fallopian tubes.
The alcohol ethoxylate of purification described in 35. any one of 19-30 is as the purposes of nonionic emulsifier and/or cosurfactant.
36. the alcohol ethoxylate of purification described in any one of item 19-30 is as the purposes of the additive of people's care product.
The purposes of 37. 36, wherein people's care product comprises hair conditioner product, such as shampoo, hair-care agent, facial cream and body frost.
Although describe the present invention with reference to exemplary embodiment, it will be appreciated by those skilled in the art that and can to carry out various change when not deviating from scope of the present invention and its key element can be replaced with equivalent.In addition, when not deviating from essential scope of the present invention, can multiple improvement be carried out, being adapted to instruction of the present invention to make particular condition or material.Therefore, this means the present invention and is not limited to the disclosed particular implementation as expection enforcement best mode of the present invention, but the present invention will comprise the whole embodiments fallen within claims scope.
Claims (14)
1. pharmaceutical composition, it comprises the alcohol ethoxylate of purification, and the alcohol ethoxylate of described purification comprises:
There is the compound of following structural formula (I),
Wherein n is the integer of 1 ~ 23, and meansigma methods is 7.8 to 9.8;
The mean molecule quantity of the alcohol ethoxylate of wherein said purification is about 530 to about 620;
The alcohol ethoxylate of described purification has monomodal molecular weight distribution in the molecular weight ranges of 180 to 1160;
Molecular weight is the total amount of formula (I) compound of about 620 to about 760 is about 27.5wt% to 31wt%, based on the gross weight of formula (I) compound; And
The total amount that molecular weight is greater than formula (I) compound of about 980 is less than 3wt%, based on the gross weight of formula (I) compound.
2. the pharmaceutical composition of claim 1, its middle-molecular-weihydroxyethyl is that formula (I) compound of about 610 to about 640 accounts for about 8.0wt% to about 9.0wt%, molecular weight is that formula (I) compound of about 660 to about 690 accounts for about 7.5wt% to about 8.5wt%, and/or molecular weight is that formula (I) compound of about 700 to about 730 accounts for about 6.5wt% to about 7.5wt%, separately based on the gross weight of formula (I) compound.
3. the pharmaceutical composition of claim 1 or 2, the total amount of its Chinese style (I) compound is more than 96wt%, based on the gross weight of the alcohol ethoxylate of described purification.
4. the pharmaceutical composition of any one of claim 1-3, the alcohol ethoxylate of wherein said purification also comprises the impurity composition that total amount is less than 2wt%, based on the gross weight of the alcohol ethoxylate of described purification.
5. the pharmaceutical composition of claim 4, wherein said impurity composition comprises and is selected from ethylene glycol, diethylene glycol, Polyethylene Glycol, formaldehyde and has formula C
10h
21(CH
2cH
2o)
mthe composition of the compound of OH, wherein m is 0 or positive integer.
6. the pharmaceutical composition of claim 4 or 5, the wherein said impurity composition amount of comprising is less than the ethylene glycol of 50ppm, based on the gross weight of the alcohol ethoxylate of described purification.
7. the pharmaceutical composition of any one of claim 4-6, the wherein said impurity composition amount of comprising is less than the diethylene glycol of 100ppm, based on the gross weight of the alcohol ethoxylate of described purification.
8. the pharmaceutical composition of any one of claim 4-7, the wherein said impurity composition amount of comprising is less than the Polyethylene Glycol of 1wt%, based on the gross weight of the alcohol ethoxylate of described purification.
9. the pharmaceutical composition of any one of claim 4-8, the wherein said impurity composition amount of comprising is less than the formaldehyde of 5ppm, based on the gross weight of the alcohol ethoxylate of described purification.
10. the pharmaceutical composition of any one of claim 4-9, what the wherein said impurity composition amount of comprising was less than 1wt% has formula C
10h
21(CH
2cH
2o)
mthe compound of OH, based on the gross weight of the alcohol ethoxylate of described purification.
The pharmaceutical composition of 11. any one of claim 1-10, the alcohol ethoxylate of wherein said purification has the following character of at least one: refractive index is about 1.4 to about 1.5; Saponification number is about 0.05% to about 0.5%, particularly 0.05% to about 0.3%; Peroxide value is about 0.01% to about 0.3%; PH value is about 6.5 to about 7.1; Cloud point in water is about 80 to 90 DEG C; Water content is less than 1wt%; Hydroxyl value is about 90 to 100.
12. the pharmaceutical composition of any one of claim 1-11, the alcohol ethoxylate of wherein said purification has following character:
Acid number is less than 0.2;
Saponification number is less than 0.5%;
Peroxide value is less than 0.5%; And
Water content is less than 1wt%.
The pharmaceutical composition of 13. any one of claim 1-12, also comprises pharmaceutically useful diluent and/or excipient.
The application of pharmaceutical composition in the cirsoid medicine of preparation treatment of 14. any one of claim 1-13.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410564470.0A CN104666283B (en) | 2010-06-10 | 2010-06-10 | Prepare the method and product of alcohol ethoxylate |
| HK15107853.4A HK1207287A1 (en) | 2010-06-10 | 2015-08-14 | A method of manufacturing alcohol ethoxylate and products |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410564470.0A CN104666283B (en) | 2010-06-10 | 2010-06-10 | Prepare the method and product of alcohol ethoxylate |
| CN201010196908.6A CN102276429B (en) | 2010-06-10 | 2010-06-10 | Method for preparing alcohol ethoxylate and product |
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| CN201010196908.6A Division CN102276429B (en) | 2010-06-10 | 2010-06-10 | Method for preparing alcohol ethoxylate and product |
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| CN104666283A true CN104666283A (en) | 2015-06-03 |
| CN104666283B CN104666283B (en) | 2019-01-08 |
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| CN (1) | CN104666283B (en) |
| HK (1) | HK1207287A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997038961A1 (en) * | 1996-04-16 | 1997-10-23 | Imperial Chemical Industries Plc | Non-ionic surfactant compositions |
| CN1762948A (en) * | 2005-09-16 | 2006-04-26 | 陕西天宇制药有限公司 | Polycinnamic alcohol production formula and its preparation process |
-
2010
- 2010-06-10 CN CN201410564470.0A patent/CN104666283B/en active Active
-
2015
- 2015-08-14 HK HK15107853.4A patent/HK1207287A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997038961A1 (en) * | 1996-04-16 | 1997-10-23 | Imperial Chemical Industries Plc | Non-ionic surfactant compositions |
| CN1762948A (en) * | 2005-09-16 | 2006-04-26 | 陕西天宇制药有限公司 | Polycinnamic alcohol production formula and its preparation process |
Non-Patent Citations (2)
| Title |
|---|
| DAVID M. ECKMANN: "Polidocanol for Endovenous Microfoam Sclerosant Therapy", 《EXPERT OPIN INVESTIG DRUGS》 * |
| JAGGI RAO ET AL.: "Double-Blind Prospective Comparative Trial between Foamed and Liquid Polidocanol and Sodium Tetradecyl Sulfate in the Treatment of Varicose and Telangiectatic Leg Veins", 《DERMATOL SURG》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| HK1207287A1 (en) | 2016-01-29 |
| CN104666283B (en) | 2019-01-08 |
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