WO2021073961A1

WO2021073961A1 - Solution of cellulose in a quaternary ammonium compound and a co-solvent

Info

Publication number: WO2021073961A1
Application number: PCT/EP2020/078043
Authority: WO
Inventors: Jan-Ole MÜLLER; Bernd OSCHMANN; Holger KUENNE; Timo Witt
Original assignee: Basf Se
Priority date: 2019-10-14
Filing date: 2020-10-07
Publication date: 2021-04-22
Also published as: EP4045000A1

Abstract

A polysaccharide solution comprising a) less than 15 % by weight of cellulose based on the weight of the solution b) a quaternary ammonium compound of formula I wherein R1 to R4 independently from each other represent organic groups with 1 to 20 carbon atoms and X- represents an anion with a carboxylate group and optionally X represents chloride as anion, and c) at least 50 % by weight of acetonitrile based on the weight of the solution, characterized in that the ratio of the amount of a) cellulose to b) the quaternary ammonium compound is 1:10 to 1:3, preferably 1:7 to 1:3, more preferably 1:5 to 1:3, most preferably 1:3.5 to 1: 3.

Description

Solution of cellulose in a quaternary ammonium compound and a co-solvent

Cellulose has often been used as a biodegradable polymer for pharmaceutical and cosmetic applications due to its good biocompatibility. Pharmaceutical or cosmetic and personal care composition comprising cellulose may require low concentrations of cellulose in biocompatible solvents.

Solvents for cellulose as N-methylmorpholine-N-oxide or liquid salts known as ionic liquids are often used in the manufacturing of fibers.

Solutions of cellulose in ionic liquid are, for example, disclosed in WO 2006/108861. According WO 2006/108861 ionic liquids with heterocyclic ammonium cations are suitable as solvents for cellulose. Quaternary ammonium cations with four substituents to the nitrogen atom are also mentioned. As disclosed in WO 2006/108861, nearly any anion is a suitable anion to the ionic liquid. Carboxylates, in particular acetate, are found among the preferred anions. The dissolution of cellulose in ionic liquids with quaternary ammonium cations usually requires high temperatures. The obtained solutions remain liquid at high temperatures but solidify with falling temperature. In addition, ionic liquids such as imidazolium salts and many solvents for dissolution of cellulose used for the manufacturing of fibers must be avoided for personal care, cosmetic and pharmaceutical applications due to their missing biocompatibility. Ionic liquids are difficult to be washed out and expensive to be recycled.

US 2010/0305249 discloses cellulose solutions comprising cellulose, a tetraalkylammonium alkyl phosphate, which is, for example a tributylmethylammonium alkyl phosphate, and optionally a co-solvent. Other ionic liquids, protic or aprotic non-ionic compounds are mentioned as possible co-solvents. The list of aprotic solvents includes acetonitrile among a variety of high boiling solvents. The cellulose solutions are prepared by dissolving cellulose in the tetraalkylammonium alkyl phosphate or mixtures thereof with the co-solvent. The purpose of the co-solvent is to lower the viscosity. Due to the co-solvent, the solutions of cellulose remain liquid at lower temperatures. However, it is difficult and energy consuming to remove high boiling solvents from the solutions when required for the later technical application.

US 8901054 discloses cellulose solutions comprising cellulose and tetraalkylammonium salts. A co-solvent is used to lower the melting point of the cellulose solutions, so that the cellulose solutions can be handled and processed at lower temperatures. The preferred co solvent is acetone. JP2016044149 discloses a process of manufacturing tetrabutyl ammonium acetate followed by a step of adding an aprotic polar organic solvent which could be acetonitrile. This mixed solution can be used to dissolve cellulose.

Also from PCT-application WO 2007/049485 and Kohler et al. - “Ammonium-based Cellulose Solvents Suitable for Homogeneous Etherification”, Macromolecular Bioscience, Wiley-VCH Verlag GmbH, Vol.9, no. 9, September 9, 2009, p. 836-841 - ionic liquids are well known to dissolve cellulose.

In PCT-application WO2019/081246 the applicant has disclosed a solution of a polysaccharide comprising a quaternary ammonium compound of formula I

wherein R¹ to R⁴ independently from each other represent organic groups with 1 to 20 carbon atoms and X represents an anion with a carboxylate group and a co-solvent which was acetonitrile or acrylonitrile. Using these solutions for manufacturing synthetic cellulose fibers it was an aim to produce solutions with a high concentration of cellulose, which are not useful for certain cosmetic compositions.

In addition, it was a drawback that these solutions could not be used for manufacturing stable emulsions with cosmetic or pharmaceutic oils.

The amount of ammonium salts needed for the dissolution of cellulose should be decreased because of the high costs of these adjuvants and the high number of washing steps needed to remove the salt.

Hence it is an object of this invention to provide low concentrated biocompatible solutions of cellulose in quaternary ammonium compounds and co-solvents with minor amounts of salt. The solutions should have low viscosity, should be rid of any turbidities and should be stable at low temperatures. Especially the emulsification with oils for use of cosmetic and pharmaceutical compositions should be possible with the cellulose solutions.

These objects were solved by the present invention which relates to a polysaccharide solution comprising a) less than 15 % by weight of cellulose based on the weight of the solution b) a quaternary ammonium compound of formula I

wherein R1 to R4 independently from each other represent organic groups with 1 to 20 carbon atoms and X- represents an anion with a carboxylate group and optionally X represents chloride as anion, and c) at least 50 % by weight of acetonitrile based on the weight of the solution, characterized in that the ratio of the amount of a) cellulose to b) the quaternary ammonium compound is 1 :10 to 1 :3, preferably 1 :7 to 1 :3, more preferably 1 :5 to 1 :3, most preferably 1 :3.5 to 1 : 3.

Accordingly, the solution defined above and a process for the preparation of the solution have been found.

Detailed Description

Cellulose

Cellulose may be obtained from wood by the Kraft process, also known as Kraft pulping or sulfate process. The cellulose may also be obtained from cotton or recycled paper. Cellulose includes depolymerized cellulose and in particular microcrystalline cellulose which is obtainable as pulp from fibrous plant material.

The solution defined above comprises cellulose as polysaccharide. For further processing of these solutions in the pharmaceutical, cosmetic and personal care field it was an object to provide a cellulose concentration of less than 15 % by weight based on the weight of the solution. Preferably, the concentration of the polysaccharide in the solution is at maximum 15 % by weight, notably at maximum 10 weight %, preferably at maximum 7 % by weight, based on the total weight of the solution.

Quaternary ammonium compound

The solution further comprises the quaternary ammonium compound of formula I

wherein R1 to R4 independently from each other represent organic groups with at maximum 20 carbon atoms and X- represents an anion with a carboxylate group. The organic groups may comprise other atoms than carbon and hydrogen; for example, they may comprise oxygen, nitrogen, sulfur or chloride.

In a preferred embodiment, the organic groups do not comprise any other atoms than carbon, hydrogen, oxygen, nitrogen, sulfur and chloride.

In particular, the organic groups do not comprise any other atoms than carbon, hydrogen and oxygen. The organic groups may comprise oxygen notably in form of ether or hydroxy groups. R1 to R4 independently from each comprise 1 to 20 carbon atoms. Preferably R1 to R4 independently from each comprise 1 to16 carbon atoms, in particular 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms.

Preferably, at least two of R1 to R4 comprise at least 3 carbon atoms; more preferably at least three of R1 to R4 comprise at least 3 carbon atoms.

In a most preferred embodiment, R1 to R4 independently from each other are hydrocarbon groups with 1 to 20 carbon atoms and do not comprise any other atoms than hydrogen and carbon. The hydrocarbon group may an aliphatic group, which includes saturated and unsaturated aliphatic groups, an aromatic groups or combinations thereof such as aralkyl or alkaryl groups.

Preferred quaternary ammonium compounds are those, wherein R1 to R4 independently from each other are selected from C1 to C12 alkyl, alkenyl or alkinyl groups.

In particular, R1 to R4 independently from each other represent an aliphatic hydrocarbon group with at maximum 20 carbon atoms whereby at least two of R1 to R4, preferably at least three of R1 to R4 comprise at least 3 carbon atoms.

Preferred quaternary ammonium compounds are, for example, compounds wherein the quaternary ammonium cation are tetra butyl-ammonium and specifically methyl-tributyl ammonium. It was surprising that the lowest amount of ammonium salt needed to achieve the cellulose solution was noticed with methyl-tributyl ammonium. X- represents an anion with a carboxylate group. Preferred anions are anions R5-COO- wherein R5 is a saturated or unsaturated hydrocarbon group with 1 to 20 carbon atoms, notably 2 to 16, more preferably 2 to 12 carbon atoms. Preferably, R5 is a saturated or unsaturated aliphatic group, notably an alkyl group or alkenyl group.

Preferred anions X are H₃C-COO (acetate), H₂C=CH-COO (acrylate) and CH₂=CH(CH₃)- COO (methacrylate). More preferred X- is H3C-COO- (acetate). Optionally part of the component b) is a quaternary ammonium compound of formula I wherein X represents chloride as anion.

Using part of X as chloride enables a better process control for example chloride can easily be used as a tracer to verify the success of sufficient washing steps. Unfortunately, the increase of chloride as an anion results in a lower emulsification ability of the cellulose solution. Surprisingly up to 40 mol % chloride as an anion based on the mol % of X were still possible to achieve good emulsification properties.

Hence preferably 0.1 to 40 mol % of X based on the mol % of X represents chloride as anion, more preferably 60 to 99.9 mol % of X represents an anion with a carboxylate group and 0.1 to 40 mol % represents chloride, most preferably X represents of 65 to 75 mol % H3C-COO- (acetate) and 25 bis 35 mol % of chloride based on the mol % of X.

Specifically component b) is a tetra butyl-ammonium and specifically methyl-tributyl ammonium compound with X being 60 to 99.9 mol % H3C-COO- (acetate) and 0.1 to 40 mol% of chloride based on the mol % of X. More specifically component b) is a tetra butyl- ammonium and specifically methyl-tributyl ammonium compound with X being 65 to 75 mol% H3C-COO- (acetate) and 25 to 35 mol % of chloride based on the mol % of X.

The solution may comprise one quaternary ammonium compound of formula I or a mixture of different quaternary ammonium compounds of formula I. In the following the term “quaternary ammonium compound of formula I” shall include mixtures of quaternary ammonium compound of formula I, if not stated otherwise or otherwise obvious from the context.

The preparation of quaternary ammonium compounds of formula I is known. They may be pre-pared, for example, by reacting a tertiary amine with an alkylating agent. Suitable alkylating agents are alkyl halides, in particular alkyl chlorides, thus obtaining a quaternary ammonium halide. The anion may be replaced by a carboxylate anion via known anion exchange processes. Suitable processes involve the use of ion exchange resins.

In a typical anion exchange procedure, a column is loaded with a of strongly basic ion exchange resin (OH form). The ion exchange resin may be transformed into the desired carboxylate form by washing with a 1 N solution of the corresponding carboxylic acid in water or methanol until the pH of the eluate is the same as the original acid solution. 10.0 g of a quaternary ammonium halide is dissolved in a solvent, for example methanol and loaded on the column and the solution is passed over the ion exchange resin. Thereafter the ion exchange resin may further be washed with the solvent. The eluate may be concentrated by distillation, using, for example, a rotary evaporator. The crude quaternary ammonium carboxylate may be dried under reduced pressure and at temperatures of, for example, 40 to 80°C, to remove any residual solvents.

The cellulose solution is characterized in that the ratio of the amount of a) cellulose to b) the quaternary ammonium compound is 1 :10 to 1:3, preferably 1 :7 to 1:3, more preferably 1:5 to 1 :3, most preferably 1 :3.5 to 1 : 3. It was an object of the current invention to provide cellulose solutions with a minor amount of ammonium salts.

Co-Solvent

The solution further comprises a co-solvent which is acetonitrile (boiling point 82°C). Due to its biocompatibility acetonitrile can be used for compositions in the cosmetic and pharmaceutical field. Surprisingly the amount of cosolvent could be increased while the amount of ammonium salt could be decreased although cellulose is not dissolvable in the co solvent.

The amount of the co-solvent acetonitrile in the cellulose solution of the current invention is at least 50 % by weight, preferably at least 60 % by weight, more preferably at least 80 % by weight based on the weight of the solution.

The solution may comprise further solvents such as, for example, water, alkanols or other ionic liquids. In a preferred embodiment, the solution does not comprise further protic solvents.

The solution may comprise additives, such as stabilizers, biocides, colorants or pigments.

In a preferred embodiment, the solution consists to at least 80 % by weight, preferably to at least 90 % by weight, more preferably to at least 95 % by eight and most preferred to at least 99 % by weight of the component a) polysaccharide, b) the quaternary ammonium compound of formula I and the co-solvent.

The high amount of co-solvent resulted in a reduced viscosity and increased processing feasibility, for stirring, pumping, dropping and spraying processes. Advantageous is as well the lower cost of the total mixture - while the ammonium compound is the major cost driver. Most surprisingly the inventive solution could be mixed with cosmetic and pharmaceutical oils and emollients resulting in a stable emulsion. Process of Manufacturing the Cellulose Solution

The solution may be prepared by a process wherein a mixture comprising a polysaccharide, a quaternary ammonium compound of formula I and a co-solvent comprising a nitrile group and having a boiling point below 100°C at 1 bar is prepared and kept at an elevated temperature until a solution is obtained.

The mixture may be prepared by adding the components in any order. The components may al-ready be heated before they are added to the mixture. A pre-mixture comprising not all components or not the full amount of all components may be heated and the remaining components or amounts of components may be added to the heated pre-mixture.

The mixture is prepared at normal pressure (1 bar) and a temperature of 20 to 120°C. Preferably, the mixture is heated at normal pressure (1 bar) to a temperature of 40 to 100°C and kept at this temperature under stirring until a clear solution is obtained.

Another embodiment of the invention is the process for the preparation of a cellulose solution according to the present invention wherein a mixture comprising a) up to 15 % by weight of cellulose and b) a quaternary ammonium compound of formula I at a ratio of cellulose (a) to quaternary ammonium compound (b) of 1:10 to 1:3 is dissolved in at least 50 % by weight of acetonitrile based on the weight of the solution.

The solutions are suitable for a variety of pharmaceutical and cosmetic applications. The inventive solutions of cellulose may, especially be used for the manufacturing of pharmaceutical and cosmetic emulsions. Hence the use of a cellulose solution for manufacturing cellulose containing compositions for pharmaceutical, cosmetic or personal care and an emulsion comprising the inventive solution are another embodiment of the invention.

Examples

Products used in the examples

The cellulose used was microcrystalline cellulose obtained from Sigma-Aldrich for short referred to as MCC.

Following quaternary ammonium compounds have been used: Tetra-butyl-ammonium-acetate, for short TBA-Acetate Formula:

Tri-butyl-methyl-ammonium-acetate, for short TBMA-Acetate Formula:

Tripropyl-methyl-ammonium-acetate, for short TPMA-Acetate Formula:

TBMA-Acetate has been prepared via anion exchange from TBMA-chloride obtained from Sigma Aldrich.

TBA-Acetate was either purchased from Sigma Aldrich or prepared via anion exchange from TBA-chloride obtained from Sigma Aldrich. Preparation procedure of tetrabutylammonium acetate:

Sodium acetate (34.8 g) and methanol (255.2 g) were added to a 1 L round bottom flask. The mixture was stirred at ambient temperature until a clear solution was obtained. Subsequently, a solution comprising tetrabutylammonium chloride (90.7 g) in methanol (90.7 g) was added to the reaction vessel in 10 min. The mixture was stirred for 2 h at ambient temperature. The precipitated sodium chloride was removed by filtration. The solvent was removed by rotary evaporation at 65°C. Acetonitrile (255.2 g) was added to the residue and the precipitated sodium chloride was removed by filtration. The resulting solution of tetrabutylammonium acetate in acetonitrile contains residual chloride in an amount of 25 to 35 mol%.

Comparative examples for the dissolution of cellulose from WQ2019/081246:

Example 1 of WO2019/081246 (comparative): Dissolution of MCC in TBA-Acetate, solvent acrylonitrile 20.0 milligram (mg) of MCC and 180.0 mg of tetrabutylammonium acetate were added to a 3 milliliter (ml) vial. 0.5 ml (405 mg) of acrylonitrile were added and the mixture in the open vial was stirred at 100 °C until a clear solution was obtained. The solution remained clear after cooling to room temperature (21 °C).

In an alternative method for the preparation of the acrylonitrile comprising solution 20.0 mg of MCC and 180.0 mg of tetrabutylammonium acetate were added to a 3 ml vial. Thereafter 0.2 ml (157 mg) of acetonitrile were added and the open vial was stirred at 75°C. A clear, colorless solution was obtained after 10 minutes and acetonitrile the solvent was allowed to evaporate. After solidification of the sample, 0.2 ml_ of acrylonitrile were added and a clear colorless solution was obtained within 3 min. With the alternative method, an increase of viscosity caused by polymerization of acrylonitrile at higher temperatures can be avoided.

Example 3 of WO2019/081246 (comparative): Dissolution of MCC in TBMA-Acetate 20.0 mg of MCC and 180.0 mg of tributylmethylammonium acetate were added to a 3 ml vial. 0.1 ml (79 mg) of acetonitrile were added and the mixture was stirred at 80 °C until a clear, colorless solution was obtained.

Example 7 of WO2019/081246 (comparative): Dissolution of MCC in TBA-Acetate 60.0 mg of MCC and 180.0 mg of tetrabutylammonium acetate were added to a 3 ml vial. 0.1 ml (79 mg) of acetonitrile were added and the mixture was stirred at 80 °C until a clear, colorless solution was obtained.

Examples according to the current invention:

Procedure for the dissolution of cellulose (examples #1 - #5, #9, and examples #19 - #21) Cellulose (29.5 g) was added to a solution of tetrabutylammonium acetate (95.3 g) in acetonitrile (160 g) and stirred for 30 min at ambient temperature. The temperature was increased to 65°C and the solvent was removed under reduced pressure. Acetonitrile (300 g) was dosed to the vessel over a period of 9 h at a temperature of 65°C to obtain a clear, colorless solution. The obtained solution (424.8 g) with a composition of cellulose / TBAAc / acetonitrile (6.9 / 22.4 / 70.6 wt%) was further diluted with acetonitrile and TBAAc to yield the desired composition.

Procedure for the dissolution of cellulose (examples #6 - #18)

Cellulose (3.0 - 13.0 wt%) was added to a solution of tetrabutylammonium acetate (8.4 - 36.5 wt%) in acetonitrile (100 - 300 mL) and stirred for 30 min at ambient temperature. The temperature was increased to 65°C and the solvent was removed under reduced pressure. Acetonitrile (50.1 - 88.6 wt%) was dosed to the vessel over a period of 9 h at a temperature of 65°C to obtain a clear, colorless solution.

Specific example for emulsification of a cellulose solution according to example #16:

1.0 ml of cellulose solution in TBAAc/MeCN (10 wt.% MCC) was emulsified in 4.0 ml of dicaprylyl ether containing 0.05 g of a surfactant mixture AB of Arlacel P 135 (39,7%) / Span 85 (39,7%) / Span 80 (10,35) / CremophorA6 (10,3 %) using an Ultraturrax rotor-stator device (30s, 10 000 rpm).

Method for determininq the feasibility of emulsification:

Preparation procedure of MCC-TBAAc-MeCN-solution (for E1 and E2)

1.92 g of a cellulose solution comprising 7.8% MCC : 26.0% TBAAc : 66.2g MeCN were added to a vial. 3.65 g of solution of 27.4 wt % tetrabutylammonium acetate in acetonitrile and 24.42 g acetonitrile are mixed and dropwise added to vial with the cellulose solution while stirring. The resulting clear solution comprises 0.5% MCC : 5.0% TBAAc : 94.5% MeCN.

Preparation procedure of MCC-TBAAc-ACN-solution (for E5 and E6)

43,43 g of a solution of 27.4 wt % tetrabutylammonium acetate in acetonitrile were added to a 100 mL round bottom flask. While stirring at 400 rpm 1.32 g MCC were added to the TBAAc- solution and dissolved. In a rotary evaporator acetonitrile was then removed at 65°C and 3 mbar. The remaining solid was cooled to room temperature and dissolved in 26.78 g acrylonitrile (ACN).

The resulting yellow-colored solution comprises 3.3% MCC : 29.8% TBAAc : 66,9% ACN Emulsification

A surfactant solution AB - comprising Arlacel P 135 (39,7 wt %), Span 85 (39,7 wt %), Span 80 (10,35 wt %) and Cremophor A6 (10,3 wt %) - is dissolved in dicaprylyl ether (Cetiol OE). The cellulose system (dissolved cellulose) is added to the surfactant/oil system and dispersed using an Ultraturrax rotor-stator device for 30 seconds at 13 000 rpm.

Examples E1 to E4 resulted in fine dispersed emulsion systems with a stability of at least one day while the examples E5 and E6 immediately separated after a few seconds.

The success of the emulsification process of example # 10 was monitored by light microscopy. Feasibility for emulsification according to the current invention was achieved when stable droplets can be observed under the microscope and no significant coagulation has occurred (see figures 1 - Images of emulsification test according to example #10. Left: Before emulsification (two phases), middle: immediately after emulsification, right: 24 h after emulsification.- and figure 2 - Light microscopy image of emulsion obtained from example #10.

Claims

1. A polysaccharide solution comprising a) less than 15 % by weight of cellulose based on the weight of the solution b) a quaternary ammonium compound of formula I

wherein R1 to R4 independently from each other represent organic groups with 1 to 20 carbon atoms and X- represents an anion with a carboxylate group and optionally X represents chloride as anion, and c) at least 50 % by weight of acetonitrile based on the weight of the solution, characterized in that the ratio of the amount of a) cellulose to b) the quaternary ammonium compound is 1:10 to 1:3, preferably 1:7 to 1:3, more preferably 1:5 to 1 :3, most preferably 1 :3.5 to 1 : 3.

2. A solution according to claim 1 wherein R1 to R4 in formula I independently from each other represent an aliphatic hydrocarbon group with 1 to 20 carbon atoms.

3. A solution according to claim 1 or 2 wherein at least two of R1 to R4 represent an aliphatic hydrocarbon group with at least 3 carbon atoms.

4. A solution according to any of claims 1 to 3 wherein X- is acetate.

5. A solution according to any of claims 1 to 4 wherein component b) is a methyltributylammonium salt or a tetrabutylammonium salt.

6. A solution according to claims 1 to 5, wherein X represents 0.1 to 40 mol % chloride as anion based on the mol % of X.

7. A solution according to any of claims 1 to 6 wherein the amount of cellulose is less than 15 % by weight, preferably less than 10 % by weight, more preferably less than 6 % by weight based on the weight of the solution.

8. A solution according to any of claims 1 to 7 wherein the ratio of the amount of a) cellulose to b) the quaternary ammonium compound is 1:10 to 1:3, preferably 1:5 to 1:3, more preferably 1:3.5 to 1: 3.

9. A solution according to any of claims 1 to 8 wherein the amount of acetonitrile is at least 60 % by weight based on the weight of the solution

10. Process for the preparation of a cellulose solution according to any of claims 1 to 9 wherein a mixture comprising a) up to 15 % by weight of cellulose and b) a quaternary ammonium compound of formula I at a ratio of a:b of 1:10 to 1:3 is dissolved in at least 50 % by weight of acetonitrile based on the weight of the solution.

11. Use of a cellulose solution according to claims 1 to 9 for manufacturing cellulose containing compositions for pharmaceutical, cosmetic or personal care application.

12. An emulsion comprising the solution according to claims 1 to 9.