Surfactant preparation process

Abstract

An enzymatic process for the preparation of C16 alkyl polyglycosides and/or C18 alkyl polyglycosides by reacting C16 alkyl glycoside and/or C18 alkyl glycoside with a glycosyl donor containing monosaccharide residues to form an alkyl polyglycoside intermediate which can be fractionated to form an alkyl polyglycoside product, wherein the mole-average degree of polymerization mean DP) of the glycoside chains is greater than or equal to 3.0 units and the molar concentration of alkyl triglycoside (DP3) is greater than alkyl monoglycoside (DPI). The C16/C18 alkyl polyglycoside product is particularly useful in health care formulations, especially in combination with and/or as a solubilizer for active pharmaceutical ingredients (APIs).

Claims

1. An alkyl polyglycoside composition comprising C16 alkyl polyglycosides and/or C18 alkyl polyglycosides wherein the mole-average degree of polymerization (mean DP) of the glycoside chains is greater than or equal to 3.0 units, the molar concentration of alkyl triglycoside (DP3) is greater than alkyl monoglycoside (DP1), and the alkyl polyglycoside composition has a transmittance value at 400 nm of greater than 85.0% at a concentration of 1.0 wt % in an aqueous solution.

2. The composition according to claim 1 comprising 0.05 to 0.3 mole fraction of DP3 and/or the DP3:DP1 molar ratio is greater than 2.0:1.0.

3. The composition according to claim 1, further comprising an alkyl tetraglycoside (DP4), wherein the composition has an alkyl triglycoside:alkyl tetraglycoside (DP3:DP4) molar ratio of 0.2 to 2.0:1.0.

4. The composition according to claim 1 wherein the mean DP is 4.5 to 7.0.

5. A pharmaceutical composition comprising (i) 0.001 to 10.0 wt %, of at least one active pharmaceutical ingredient (API), (ii) 0.01 to 75.0 wt % of an alkyl polyglycoside comprising C16 alkyl polyglycosides and/or C18 alkyl polyglycosides wherein the mole-average degree of polymerization (mean DP) of the glycoside chains is greater than or equal to 3.0 units and the molar concentration of an alkyl triglycoside (DP3) is greater than an alkyl monoglycoside (DP1), and (iii) 15.0 to 99.99 wt % of water, wherein the pharmaceutical composition has an API recovery of greater than 87%.

Description

EXAMPLES

Example 1

(1) 1 kg of waxy barley starch was weighed into a 10 litre reactor and dispersed in 3.7 kg of water at 25 C. by means of gentle stirring. 25 ml of Thermoanaerobacter sp CGTase enzyme preparation was added (equivalent to 15 KNU-CP per kg of reaction mixture) and the temperature increased to 72 C. in order to pre-hydrolyse the starch. When the temperature reached 72 C. (after 1.5 hours), 230 ml of a 154 g l.sup.1 solution of cetearyl glucoside was added. The temperature was reduced to 63 C. and the reaction allowed to proceed at constant temperature for 5.5 hours. The enzyme was then inactivated by increasing the temperature to 91 C. and maintaining for 4.5 hours. The reaction mixture was then cooled to 20 C.

(2) Purification of the crude reaction mixture containing the alkyl polyglycoside intermediate was performed by flash chromatography, using a Biotage Isolera LS instrument. Prior to loading onto the column, the crude reaction mixture was pre-treated to remove excess oligosaccharides. 1 litre of the reaction mixture was initially heated to approximately 40 C., at which point it became visually clear. 1 litre of ethanol was slowly added, resulting in precipitation. The precipitate was separated from the supernatant by decanting, yielding 1.7 litres of supernatant. The supernatant was re-heated to approximately 40 C. and diluted with water to a final solvent composition of 20% ethanol, giving a total volume of 4.25 litres. This solution was loaded onto a 120 gram C8 flash column supplied by Acros Chemicals and elution effected using an ethanol:water gradient running from 20% to 100% of ethanol. Fractions 3 through 17 (corresponding to an eluent composition of 20-35%) were collected, pooled and concentrated on a rotavapor. Finally, the concentrate was freeze-dried, yielding alkyl polyglycoside product as a free-flowing white powder.

(3) The alkyl polyglucoside intermediate and alkyl polyglucoside product were subjected to the test procedures described herein, and exhibited the following properties;

(4) a) Alkyl Polyglucoside Intermediate:

(5) i) DP1=0.23 mole fraction. ii) DP2=0.16 mole fraction iii) DP3=0.13 mole fraction. iv) DP4=0.12 mole fraction v) DP4 to DP10=0.40 mole fraction. vi) Mean DP=3.7 glucose units. vii) Increase in mean DP (over starting material)=2.6 glucose units. viii) Glucose conversion=4.6 wt %. ix) Transmittance=22.9%. x) API Solubility: Budesonide=0.272%. Progesterone=0.178%. xi) API Transmittance: Budesonide=18.7%. Progesterone=19.8%. Dexamethasone=17.1%. xii) Insulin Stability: Recovery after 12 weeks.

(6) TABLE-US-00004 No Agitation With Agitation 25 C. 25 C. 40 C. 40 C. 25 C. 25 C. pH 6.8 pH 7.4 pH 6.8 pH 7.4 pH 6.8 pH 7.4 61.0% 70.9% 23.2% 73.9% 32.2% 26.7%
b) Alkyl Polyglucoside Product: i) DP1=0.02 mole fraction. ii) DP2=0.01 mole fraction. iii) DP3=0.11 mole fraction. iv) DP4=0.21 mole fraction. v) DP4 to DP10=0.83 mole fraction. vi) DP11 to DP15=0.03 mole fraction. vii) Mean DP=5.6 glucose units. viii) Increase in mean DP (over intermediate)=1.9 glucose units. ix) Transmittance=96.8%. x) API Solubility: Budesonide=0.395%. Progesterone=0.260%. xi) API Transmittance: Budesonide=77.9%. Progesterone=87.9%. Dexamethasone=84.3%. xii) API Recovery at 60 C. for 3 months: Budesonide in Suspension=98.5%. Budesonide in Solution=95.8%. xiii) Insulin Stability: Recovery after 12 weeks.

(7) TABLE-US-00005 No Agitation With Agitation 25 C. 25 C. 40 C. 40 C. 25 C. 25 C. pH 6.8 pH 7.4 pH 6.8 pH 7.4 pH 6.8 pH 7.4 90.9% 91.4% 67.8% 83.7% 75.3% 75.3%

(8) For comparison purposes, polysorbate 80 was also subjected to some of the test procedures described herein, and exhibited the following properties; i) API Solubility: Budesonide=0.195%. Progesterone=0.083%. ii) API Recovery at 60 C. for 3 months: Budesonide in Suspension=96.9%. Budesonide in Solution=85.9%. iii) Insulin Stability: Recovery after 12 weeks.

(9) TABLE-US-00006 No Agitation With Agitation 25 C. 25 C. 40 C. 40 C. 25 C. 25 C. pH 6.8 pH 7.4 pH 6.8 pH 7.4 pH 6.8 pH 7.4 72.9% 86.4% 19.9% 47.7% 43.6% 57.5%

Example 2

(10) 317 kg of water was charged into a 1,000 litre reactor. 80 kg of potato maltodextrin (DE=1) and 2.9 kg of cetearyl glucoside were added to the reactor at ambient temperature under stirring. The temperature of the reactor was increased to 65 C. under continuous stirring. After reaching the target temperature, 0.2 kg of Thermoanaerobacter sp. CGTase enzyme preparation was added (equivalent to 1.5 KNU-CP per kg of reaction mixture) and the reaction allowed to proceed for 24 hours. The reaction was stopped by heating the reaction mixture to 95 C. and maintaining for 2.5 hours. The solution was then cooled to 30 C. and preservative was added. Finally, the reaction mixture was cooled to ambient temperature. The crude reaction mixture containing the alkyl polyglucoside intermediate was then purified as described in Example 1 to produce the alkyl polyglucoside product. In addition, Fractions 20 through 40 (corresponding to an eluent composition of 50-70%) were collected, pooled and concentrated on a rotavapor. This concentrate was freeze-dried, yielding alkyl glycoside side-product as a free-flowing white powder.

(11) The alkyl polyglucoside intermediate, alkyl polyglucoside product and alky polyglucoside side-product were subjected to the test procedures described herein, and exhibited the following properties;

(12) a) Alkyl Polyglucoside Intermediate:

(13) i) DP1=0.22 mole fraction. ii) DP2=0.17 mole fraction. iii) DP3=0.14 mole fraction. iv) DP4=0.12 mole fraction. v) DP4 to DP10=0.40 mole fraction. vi) Mean DP=4.3 glucose units. vii) Increase in mean DP (over starting material)=3.2 glucose units. viii) Glucose conversion=4.8 wt %.
b) Alkyl Polyglucoside Product: i) DP1=0.000 mole fraction. ii) DP2=0.001 mole fraction. iii) DP3=0.17 mole fraction. iv) DP4=0.24 mole fraction. v) DP4 to DP10=0.79 mole fraction. vi) DP11 to DP15=0.04 mole fraction. vii) Mean DP=5.3 glucose units. viii) Increase in mean DP (over intermediate)=1.0 glucose units.
c) Alkyl Polyglucoside Side-Product: i) DP1=0.49 mole fraction. ii) DP2=0.32 mole fraction. iii) DP3=0.10 mole fraction. iv) DP4=0.05 mole fraction. v) DP5 to DP15=0.04 mole fraction. vi) Mean DP=1.9 glucose units. vii) No phase separation in the emulsion stability test (phase separation occurred overnight using 0.5 wt % cetearyl glucoside as emulsifier).

Example 3

(14) 8.041 kg of water was charged into a 10 litre reactor. 0.2205 kg of cetearyl glucoside and 1.733 kg of -cyclodextrin undecahydrate were added to the reactor at 75 C., left stirring overnight, and then 6 ml of Thermoanaerobacter sp CGTase enzyme preparation was added (equivalent to 1.8 KNU-CP per kg of reaction mixture). The reaction was allowed to proceed for 28 hours and the enzyme was then inactivated by increasing the temperature to 98 C. and maintaining for 3 hours. The reaction mixture was then cooled to 60 C. and diluted to 50% with 99.9% ethanol for storage.

(15) Purification of the crude reaction mixture containing the alkyl polyglycoside intermediate was performed by flash chromatography, using a Biotage Isolera LS instrument. Prior to loading onto the column, 340 ml crude reaction mixture was diluted to 20% ethanol in 1 litre volume by addition of Milli-Q water and 99.9% ethanol. The mixture was heated to approximately 70 C., at which point it became visually clear. This solution was loaded onto a 120 gram C8 flash column supplied by Acros Chemicals and elution effected using an ethanol:water gradient running from 20% to 100% of ethanol. Fractions 4 through 17 (corresponding to an eluent composition of 20-35%) were collected, pooled and concentrated on a rotavapor. Finally, the concentrate was freeze-dried, yielding alkyl polyglycoside product as a free-flowing white powder.

(16) The alkyl polyglucoside intermediate and alkyl polyglucoside product were subjected to the test procedures described herein, and exhibited the following properties;

(17) a) Alkyl Polyglucoside Intermediate:

(18) i) DP1=0.30 mole fraction. ii) DP2=0.17 mole fraction iii) DP3=0.10 mole fraction. iv) DP4=0.11 mole fraction v) DP4 to DP10=0.41 mole fraction. vi) Mean DP=3.7 glucose units. vii) Increase in mean DP (over starting material)=2.7 glucose units. viii) Glucose conversion=15.7 wt %.
b) Alkyl Polyglucoside Product: i) DP1=0.00 mole fraction. ii) DP2=0.01 mole fraction. iii) DP3=0.14 mole fraction. iv) DP4=0.22 mole fraction. v) DP4 to DP10=0.82 mole fraction. vi) DP11 to DP15=0.03 mole fraction. vii) Mean DP=5.7 glucose units. viii) Increase in mean DP (over intermediate)=2.0 glucose units. ix) Transmittance=96.7%.

(19) The above examples illustrate the improved properties of the alkyl polyglucoside product, alkyl polyglucoside side-product, and uses thereof according to the present invention.