Medical grade poloxamer 188 experiment declared research and development test

Medical grade poloxamer 188 experiment declaration research and development trial Poloshame 188Poluoshamu 188Poloxamer 188 H(C2H4O)a (C3H6O)b(C2H4O)aOH This product is α-hydrogen-oω-hydroxypoly(oxyethylene)a-poly(oxypropene)b-poly(oxyethylene)a block copolymer
.
It is reacted by propylene oxide and propylene glycol to form polyoxypropylene glycol, and then ethylene oxide is added to form a block copolymer
.
In the copolymer, the oxygen ethylene unit (a) is 75 to 85, the oxygen propylene unit (b) is 25 to 30, the oxygen ethylene (EO) content is 79.
9% to 83.
7%, and the average molecular weight is 7680 to 9510
.
【Properties】This product is white or off-white waxy solid; There is a slight odor
.
This product is easily soluble in water or ethanol, dissolved in absolute ethanol or ethyl acetate, and almost insoluble
in or petroleum ether.
【Identification】The infrared light absorption pattern of this product should be consistent
with the control map (spectral set 618 figure).
【Check】pH Take 1.
0g of this product, add 10ml of water to dissolve, and determine according to law (General 0631), the pH value should be 5.
0 ~ 7.
5
.
The clarity and color of the solution Take the solution under the pH and check it according to law (General 0901 and General 0902), and the color
should be clarified.
Oxyethylene 0.
1~0.
2g of this product and dissolved it with 1ml of deuterated water containing 1% sodium 4,4-dimethyl-4-silepentyl sulfonate or deuterated tri1ml containing tetramethylsilane; The sample solution is loaded into a nuclear magnetic resonance tube, if it is deuterated three as the solvent, add 1 drop of deuterated water, shake, in the NMR, from 0 to 5×10-6 scanning, to directly compare the quorum, the following formula to calculate the oxygen ethylene (EO) value: EO=3300α/(33α+58) In the formula α=(A2/A1)-1 A1 is the integral area of 1.
15×10-6 at the bimodal, representing the methyl of oxypropylene; A2 is the integral area of the composite peak at (3.
2~3.
8)× 10-6, representing the CH2O of oxypropylene, oxyethylene and CHO of oxypropylene; EO is the proportion of oxyethylene in the total molecular composition, which should be 79.
9% to 83.
7%.

Unsaturation Weigh about 15.
0g of this product after study, 50ml of precision solution, completely dissolve under magnetic stirring, let stand for 30 minutes, shake intermittently, add sodium bromide crystallization for 10g, mix under magnetic stirring for 2 minutes, immediately add 1ml of phenolphthalein indicator solution, titrate with methanol potassium hydroxide titration solution (0.
1mol/L), with blank test and initial acidity correction [take poloxamer 15.
0g, add neutral methanol (p-phenolphthalein indicator liquid is neutral) 75ml after dissolution, Neutralize potassium hydroxide titration solution (0.
1 mol/L) with methanol to p-phenolphthalein indicator solution].

The unsaturation (mmol/g) is calculated using the following formula, which must not exceed 0.
034 mmol/g
.
Unsaturation = (V for -V blank-V initial) in N/W formula V is the volume of methanol potassium hydroxide titration solution (0.
1 mol/L) consumed for the test product, blank and initial acidity, ml; N is the concentration of methanol to potassium hydroxide titration solution, mol/L; W is the weight of the sample, g
.
Average molecular weight Take the appropriate amount of this product (about equivalent to the molecular weight ×0.
002g), precision weighing, precision addition phthalic anhydride - pyridine solution 25ml, add a little zeolite, heat reflux for 1 hour, cool, rinse the condenser twice with pyridine, each time 10ml, add water 10ml, mix, plug for 10 minutes, precision add 0.
66mol/L sodium hydroxide solution 50ml, then add phenolphthalein-pyridine solution (1→100) 0.
5ml, with sodium hydroxide titration solution (0.
5mol/ L) titration, micropink, lasts 15 sec without fading, and the result of the titration is corrected with a blank test, that is, obtained
.
The average molecular weight of the test product should be 7680~9510
according to the formula.
Average molecular weight = 2000W/[(B-S)N] in the formula W is the weight of the sample, g; B is the volume of blank consumption sodium hydroxide titration solution (0.
5 mol/L), ml; S The volume of sodium hydroxide titration solution (0.
5mol/L) consumed for the test product, ml; N is the concentration of sodium hydroxide titration solution, mol/L
.
Ethylene oxide, propylene oxide and 1,4-dioxane take 1g of this product, precision weighing, placed in a headless empty bottle, precision water 5ml, sealed, as a test solution; Take ethylene oxide, propylene oxide and 1,4-dioxane in an appropriate amount, dissolve with water and quantitatively dilute to make a mixed solution containing 0.
2μg, 1μg and 1μg per 1ml, take 5ml with precision, place in a headless bottle, seal, as a control solution
。 According to gas chromatography (General Rule 0521), the capillary column with 6% cyanopropyl phenyl-94% dimethylsiloxane (or similar polarity) as the fixation liquid is a column (30m×0.
25mm, 1.
40 μm), the starting temperature is 35 °C, maintained for 5 minutes, heated at 5 °C per minute to 120 °C, maintained for 5 minutes, and then heated to 220 °C at 35 °C per minute for 5 minutes; Inlet temperature is 250°C; Detector temperature is 280°C; The equilibrium temperature of the headspace bottle is 80 °C and the equilibration time is 30 minutes
.
Take the control solution headspace injection, ethylene oxide peak, propylene oxide peak and 1,4-dioxane peak separation should meet the requirements
.
Then take the test solution and the control solution respectively headspace injection, record the chromatogram
.
According to the external standard method calculated by the peak area, the ethylene oxide content shall not exceed 0.
0001%, the propylene oxide shall not exceed 0.
0005%, and the 1,4-dioxane hexacyclic shall not exceed 0.
0005%.

。 Ethylene glycol, diethylene glycol and triethylene glycol Take 1.
0g of this product, precision weighing, placed in a 10ml measuring flask, precision plus internal standard solution (take 1,3-butanediol appropriate amount, precision weighing, add ethanol to dissolve and quantitatively dilute to make a solution containing 0.
1mg per 1ml) 1ml, dilute with ethanol to the scale, shake well, as a test solution; take another ethylene glycol, diethylene glycol and triethylene glycol appropriate amount, precision weighing, Dissolve and quantitatively dilute with ethanol to make a mixed solution containing 0.
1mg per 1ml, take 1ml with precision, place in a 10ml measuring bottle, add 1ml of internal standard solution with precision, dilute with ethanol to the scale, shake well, and use it as a control solution
。 According to gas chromatography (General Rule 0521), the capillary column with 50% phenyl-50% dimethyl polysiloxane (or similar polarity) as the fixing liquid is a column (30m×0.
53mm, 1.
0 μm), the starting temperature is 60 °C, maintained for 5 minutes, heated at a rate of 10 °C per minute to 100 °C, then heated to 170 °C at a rate of 4 °C per minute, and finally warmed to 290 °C at a rate of 30 °C per minute for 30 minutes; Inlet temperature is 270°C; The detector temperature is 290°C
.
Precise quantity of 1 μl of the test solution and the control solution are each injected into the gas chromatograph to record the chromatography
.
According to the internal standard method based on the peak area, the content of ethylene glycol, diethylene glycol and triethylene glycol shall not exceed 0.
01%.

Dibutyl hydroxytoluene (measured when marked as containing dibutyl hydroxytoluene) Take an appropriate amount of this product, weigh it precisely, add ethanol to dissolve and quantitatively dilute to make a solution containing 100mg per 1ml, as a test solution; Take another appropriate amount of dibutylhydroxytoluene control, weigh it precisely, add ethanol to dissolve and quantitatively dilute to make a solution containing 20μg per 1ml, as a control solution
。 According to gas chromatography (General Rule 0521), the capillary column with 50% phenyl-50% dimethyl polysiloxane (or similar polarity) as the fixed liquid is a column (30m×0.
53mm, 1.
0 μm), starting at 60 °C, maintained for 5 minutes, heating at 10 °C per minute to 100 °C, then heating at 4 °C per minute to 180 °C, and finally heating at 30 °C per minute to 290 °C for 30 minutes; Inlet temperature is 270°C; The detector temperature is 290°C
.
Precise quantity of 1 μl of the test solution and the control solution are injected into the gas chromatograph to record the chromatography
.
According to the external standard method based on the peak area, the content of dibutyl hydroxytoluene shall not exceed 0.
02%.

Moisture Take this product, according to the moisture determination method (general rule 0832 first method 1) to determine, the moisture content shall not exceed 1.
0%.

Blazing residue Take 1.
0g of this product, inspect according to law (General Rule 0841), and the residual residue shall not exceed 0.
4%.

Heavy metals: Take the residues left under the incineration residue and inspect them according to law (General Rule 0821 Second Law), and the heavy metals shall not exceed 20
parts per million.
Arsenic salt Take 1.
0g of this product, add 5ml of hydrochloric acid and 23ml of water, shake to dissolve, check according to law (General 0822 First Law), should comply with the provisions (0.
0002%)
.
Bacterial endotoxin (for injection) Take this product, check according to law (general rule 1143), the amount of endotoxin contained in each 1mg should be less than 0.
012EU
.
【Category】Pharmaceutical excipients, solubilizers and emulsifiers, etc
.
【Storage】Shading, airtight preservation
.