KR100729479B1 - New process for the purification of aldehyde impurities - Google Patents

Abstract

Dissolving the poloxamer (s) optionally in a solvent that may contain an acid or acid mixture, and removing the aldehyde after addition of the acid if the solvent in which the poloxamer (s) is dissolved does not contain an acid, Process for the purification of poloxamers containing aldehyde impurities, in particular poloxamers designated poloxamer 188 and poloxamer 407.

Poloxamer, Method for Purifying Poloxamer, Aldehyde, Poloxamer 188, Poloxamer 407

Description

Purification of aldehyde impurities {NEW PROCESS FOR THE PURIFICATION OF ALDEHYDE IMPURITIES}

The present invention relates to a novel process for the purification of poloxamers containing aldehyde impurities, in particular poloxamers designated poloxamer 188 and poloxamer 407.

Pollock four dimmer formula _{HO- [C 2 H 4 O]} a - [C 3 H 6 O] b - [C 2 H 4 O] a -H ( In this case, a and b are the number of the respective hydrophilic and hydrophobic chains Synthetic hydrophilic ethylene oxide chains and hydrophobic propylene oxide chains.

Poloxamers can be used as surfactants, emulsifiers, solubilizers or wetting agents in various compositions. WO97 / 38675 discloses a composition comprising at least one local anesthetic, water and at least one surfactant, preferably poloxamer (s). Since poloxamers have both hydrophobic and hydrophilic regions, for example, they can be combined with local anesthetics to provide compositions having thermoreversible gelling properties.

Commercially available poloxamers usually contain relatively large amounts of aldehydes. Such aldehydes can react with active compounds, such as local anesthetics, to form unwanted compounds that must be separated from the final product. This also means that a large amount of active compound is required because the active compound may react with the aldehyde and be lost during the purification process.

Thus, there is a need for an improved purification method for lowering the aldehyde concentration in poloxamers.

The present invention relates to a method for purifying poloxamer containing aldehyde, according to which

(i) dissolving the poloxamer (s) optionally in a solvent which may contain an acid or acid mixture,

(ii) if the solvent in which the poloxamer (s) were dissolved did not contain an acid, add acid, and

(iii) remove aldehydes.

The process according to the invention the general formula containing aldehyde impurities _{HO- [C 2 H 4 O]} a - [C 3 H 6 O] b - [C 2 H 4 O] a -H ( In this case, a and b are Suitable for the purification of poloxamers each having a number of hydrophilic and hydrophobic chains). The process according to the invention is particularly suitable for the purification of LutrolF68, also called poloxamer 188, in the formula a 80 and b is 27, or LutrolF127, also called poloxamer 407, with a 101 and b 56 (above). Definitions are in accordance with USP (1995) HF18, p. 2279). The process of the invention can also be used for the purification of polymers consisting of monomers such as ethylene oxide, propylene oxide and the like containing aldehydes, as well as for the purification of poloxamer mixtures and in particular mixtures of poloxamer 188 and poloxamer 407.

The solvent used to dissolve the poloxamer may be an alcohol such as water, methanol, ethanol or propanol or any other suitable solvent. Preference is given to using water as a solvent.

The temperature of the solvent or solvent mixture and poloxamer is not critical, but the poloxamer dissolves more rapidly at temperatures below room temperature. Preferred solvent temperatures are 0 to +10 ° C.

The concentration of poloxamer in the poloxamer solution is preferably 5 to 21% by weight. More preferred concentration is 15% by weight.

The acid (s) added to the poloxamer solution may be any acid (s), but one or a mixture of two or more of hydrochloric acid, acetic acid or citric acid is preferred. More preferably, the acid is one of hydrochloric acid or acetic acid, or a mixture thereof, most preferably using acetic acid alone. After addition of the acid the pH of the solution should be between 1 and 7, preferably between 1 and 5. The amount of acid added depends on the desired pH.

The acid or acids may be added to the solvent before and after adding the poloxamer to the solvent. The reaction temperature can be room temperature or brought to a temperature of, for example, cooled, preferably 0 ° C. When poloxamer and acid are added to the solvent and the poloxamer is dissolved, it takes some time for the acid to interact, after which the aldehyde is removed from the solution by drying. Drying involves evaporating the solution to evaporate aldehydes, drying the solution on a fluidized bed, spray drying, freeze drying, vacuum evaporation or passing a gas stream such as helium or nitrogen through the solution, spray crystallization, Spray granulation or any other method known to those skilled in the art. Preferred is to evaporate the aldehyde by drying the solution on a fluidized bed whose temperature for poloxamer is less than 47 ° C. The solution can be dried more quickly by providing a higher temperature, but the temperature should not be too high because poloxamers can melt at high temperatures.

The process according to the invention is particularly suitable for removing formaldehyde, acetaldehyde and propionaldehyde in poloxamers. However, other impurities can also be removed using the method according to the invention. The method of the invention is particularly suitable for removing acetaldehyde and propionaldehyde in poloxamers.

Poloxamers with aldehydes removed according to the methods described above are also included within the scope of the present invention.

The reduction of aldehyde in the following examples was determined according to the analytical method described below.

Analytical Method

The sample is dissolved in water and diluted. Any aldehyde present in the poloxamer is reacted with 2,4-dinitrophenylhydrazine or 3-methyl-2-benzothiazolone hydrazone at room temperature to form a derivative. After extracting the derivative with cyclohexane, the organic phase is evaporated. The residue is dissolved in the mobile phase, the derivative is separated using liquid chromatography and quantified by standard addition or external standard calibration.

The invention will now be described in more detail with the following non-limiting examples.

Example 1

Helium purging

HCl was added to water at a concentration of 0.3 mol / l, and poloxamer 407 was dissolved in HCl solution at a concentration of 5% by weight (w / w). The solution was purged with helium for 2 hours and stored at room temperature overnight. The solution was then purged with helium for another 3 hours. The solution was stored at room temperature and helium was added at a flow rate of 1 bubble / second. The amount of aldehyde was reduced by 80%.

Example 2

Nitrogen evaporation

HCl was added to water at a concentration of 0.3 mol / l, and poloxamer 407 was dissolved in HCl solution at a concentration of 5% by weight (w / w). The solution was stored at room temperature for 3 hours. 80% of the solution was evaporated using a nitrogen flow rate of 0.3 mol / l. HCl solution was added to the initial volume. The amount of aldehyde was reduced by 95%.

Example 3

Vacuum evaporation

5.5 weight percent (w / w) of poloxamer 188 and 15.5 weight percent (w / w) of poloxamer 407 were dissolved in water. After citric acid was added to pH 2.7, the solution was stored at room temperature for at least 24 hours. Then 5% by weight of the solution was evaporated using a rotary evaporator. The concentration of acetaldehyde was reduced from 135 ppm to 30 ppm and the concentration of propionaldehyde was reduced from 429 ppm to <10 ppm.

Example 4

Fluidized Bed Drying Method-Hydrochloric Acid

Poloxamer 407 was dissolved in water at a concentration of 15 wt% (w / w) and then hydrochloric acid was added to pH 2. The solution was refrigerated for 6 days. The solution was dried using fluid bed drying. The concentration of acetaldehyde was reduced from 337 ppm to 26 ppm and the concentration of propionaldehyde was reduced from 1.35 × 10 ³ ppm to 76 ppm.

Example 5

Fluid Bed Drying Method-Citric Acid

18.22 g citric acid at 50% concentration was added to 2000 g water. Poloxamer 407 was dissolved in the citric acid solution at a concentration of 15 wt% (w / w). The solution was dried in a fluidized bed. The concentrations of acetaldehyde and propionaldehyde were reduced from 358 ppm to 5 ppm and from 1.39 × 10 ³ ppm to <6 ppm, respectively.

Example 6

Fluid Bed Drying Method-Acetic Acid (Poloxamer 188)

120 g of acetic acid was added to 2000 g of water. Poloxamer 188 was dissolved in the acetic acid solution at a concentration of 15% by weight (w / w). The solution was refrigerated for 6 days. The solution was dried in a fluidized bed. Acetaldehyde concentration was reduced from 186 ppm to 8 ppm and propionaldehyde concentration was reduced from 297 ppm to <6 ppm.

Example 7

Fluid Bed Drying Method-Acetic Acid (Poloxamer 407)

120 g of acetic acid was added to 2000 g of water. Poloxamer 407 was dissolved in the acetic acid solution at a concentration of 15% by weight (w / w). The solution was refrigerated for 6 days. As the solution was dried in the fluidized bed, the acetaldehyde concentration was reduced from 358 ppm to 12 ppm and the propionaldehyde concentration was reduced from 1.39 × 10 ³ ppm to 9 ppm.

Example 8-10

Full-Scale Poloxamer 188 Purification

The poloxamer was dissolved in water and then acetic acid was added. After interacting for at least 24 hours, the solution was dried using a fluid bed dryer. To run the process faster, purified poloxamer was used as starting material in the fluid bed dryer. However, the first batch was prepared without using starting material as purified poloxamer. In the following examples the material obtained from the preceding batch was used as starting material.

Equipment and Process Parameters

Fluid Bed Dryer: Glatt GVW32 "

Filter shake: 2015

Injection nozzle: 1 * 6 heads, center, 1.8 mm

Injection nozzle position: 4 v below                 

Pump: Membrane-Pump

Process parameters Poloxamer 188 (Example 8-10) water 135 kg Acetic acid 15 kg Poloxamer 100 kg pH <2.8 Interaction time > 24 hours <1 week Starting material 100 kg Inflow air flow rate 4000-5000 ㎥ Inlet air temperature 48-52 ℃ Product temperature <47 ℃ Injection pressure 3.8-4.2 bar Injection flow rate 500-600 g / min

Analysis

Three batches of poloxamer 188 were purified according to the method of process parameters given above. The concentrations of aldehydes are given in the table below.

Batch Formaldehyde μg / g Acetaldehyde μg / g Propionaldehyde μg / g Poloxamer 188 3.8 1.4 x 10 ² 2.8 x 10 ² Example 8 Poloxamer 188 <1.9 <20 <48 Example 9 Poloxamer 188 <1.9 <20 <48 Example 10 Poloxamer 188 <1.9 <20 <48

Example 11-13

Full-Scale Poloxamer 407 Purification

The poloxamer was dissolved in water and then acetic acid was added. After interacting for at least 24 hours, the solution was dried using a fluid bed dryer. To run the process faster, purified poloxamer was used as starting material in the fluid bed dryer. However, the first batch was prepared without using starting material as purified poloxamer. In the following examples the material obtained from the preceding batch was used as starting material.

Equipment and Process Parameters                 

Fluid Bed Dryer: Glatt GVW32 "

Filter shake: 2015

Injection nozzle: 1 * 6 heads, center, 1.8 mm

Injection nozzle position: 4 v below

Pump: Membrane-Pump

Process parameters Poloxamer 407 (Examples 11-13) water 592.1 kg Acetic acid 47.4 kg Poloxamer 150 kg pH <2.8 Interaction time > 24 hours <1 week Starting material 50 kg Inflow air flow rate 4000-5000 ㎥ Inlet air temperature 48-52 ℃ Product temperature <47 ℃ Injection pressure 3.8-4.2 bar Injection flow rate 700-900 g / min

Analysis

Three batches of poloxamer 407 were purified according to the method of process parameters given above. The concentrations of aldehydes are given in the table below.

Batch Formaldehyde μg / g Acetaldehyde μg / g Propionaldehyde μg / g Poloxamer 407 5.2 3.0 x 10 ² 1.3 x 10 ³ Example 11 Poloxamer 407 <1.9 <20 <48 Example 12 Poloxamer 407 2.1 <20 <48 Example 13 Poloxamer 407 <1.9 <20 <48

The above examples show that using the method according to the invention, the concentrations of aldehydes, specifically acetaldehyde and propionaldehyde, in both poloxamer 407 and 188 are reduced. It has also been found that all acids, hydrochloric acid, acetic acid and citric acid can be used in the process of the invention. In addition, it has been demonstrated in this embodiment that the solution can be dried by many different methods such as helium purging, evaporation with nitrogen, vacuum evaporation or fluid bed drying.

Claims (21)

(i) dissolving the poloxamer (s) optionally in a solvent which may contain an acid or acid mixture, (ii) if the solvent in which the poloxamer (s) were dissolved did not contain an acid, add acid, and (iii) A process for purifying an aldehyde containing poloxamer comprising removing the aldehyde. The method of claim 1 wherein the poloxamer is one of poloxamer 188 or poloxamer 407, or a mixture thereof. The method of claim 1 wherein the solvent is water or alcohol. The method of claim 3 wherein the solvent is water. The method of claim 1 wherein the concentration of poloxamer dissolved in the solvent is from 5 to 21% by weight. The method of claim 5 wherein the concentration of poloxamer is 15% by weight. The method of claim 1 wherein the temperature of the mixture of solvent and poloxamer is below room temperature. 8. The method of claim 7, wherein the temperature of the mixture is from 0 to +10 ° C. The method of claim 1 wherein the acid is selected from hydrochloric acid, acetic acid, citric acid. The method of claim 9 wherein the acid is acetic acid. The method of claim 1 wherein the pH after adding the acid to the solution is 1-7. The method of claim 11 wherein the pH is between 1.3 and 6. The method of claim 1 wherein aldehyde is removed by passing a stream of helium or nitrogen through the solution. The method of claim 1, wherein the aldehyde is removed by vacuum evaporation. The method of claim 1 wherein the aldehydes are removed by fluid bed drying. The method of claim 1 wherein the solution is boiled to remove aldehydes. The method of claim 1 wherein the aldehydes removed are formaldehyde, acetaldehyde and propionaldehyde. 18. The method of claim 17, wherein the aldehydes removed are acetaldehyde and propionaldehyde. delete (i) dissolving the poloxamer (s) optionally in a solvent which may contain an acid or acid mixture, (ii) add acid if the solvent in which the poloxamer (s) is dissolved does not contain an acid, (iii) reacting the phloxamers with an acid solution at room temperature or lower, (Iii) removing the impurities by evaporating the solvent below the melting temperature of the poloxamers. 21. The method of claim 20, wherein said evaporating step comprises fluid bed drying at a temperature lower than 47 &lt; 0 &gt; C.