L-Leucine, 4-fluoro-N-[(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-, compd. with N-cyclohexylcyclohexanamine (1:1)

Partition coefficient

Administrative data

Endpoint:

partition coefficient

Type of information:

experimental study

Adequacy of study:

key study

Study period:

December 16, 2011 - January 27, 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study has been performed according to OECD and EU guidelines and in compliance with GLP principles.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 107 (Partition Coefficient (n-octanol / water), Shake Flask Method)

Version / remarks:

(1995)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method A.8 (Partition Coefficient)

Version / remarks:

(O.J. no L142, 2008)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 830.7550 (Partition Coefficient, n-octanol / H2O, Shake Flask Method)

Version / remarks:

(1996)

Deviations:

no

GLP compliance:

yes

Type of method:

shake-flask method to: flask method

Partition coefficient type:

octanol-water

Test material

Test material information

Constituent 1

Reference substance name:

N-cyclohexylcyclohexanaminium (2S)-4-fluoro-4-methyl-2-{[(1S)-2,2,2-trifluoro-1-{4'-methanesulfonyl-[1,1'-biphenyl]-4-yl}ethyl]amino}pentanoate

EC Number:

700-778-8

Cas Number:

1064076-86-3

Molecular formula:

C21H23F4NO4S.C12H23N

IUPAC Name:

N-cyclohexylcyclohexanaminium (2S)-4-fluoro-4-methyl-2-{[(1S)-2,2,2-trifluoro-1-{4'-methanesulfonyl-[1,1'-biphenyl]-4-yl}ethyl]amino}pentanoate

Details on test material:

- Name of test material (as cited in study report): Biphenyl DCHA Salt
- Description: White powder

Study design

Analytical method:

high-performance liquid chromatography

Results and discussion

Partition coefficient

Partition coefficient 1

Type:

log Pow

Partition coefficient:

0

Temp.:

20 °C

pH:

7

Remarks on result:

other: value based on the response of the cationic part

Partition coefficient 2

Type:

Pow

Partition coefficient:

0.99

Temp.:

20 °C

pH:

7

Remarks on result:

other: value based on the response of the cationic part

Partition coefficient 3

Type:

log Pow

Partition coefficient:

0.9

Temp.:

20 °C

pH:

7

Remarks on result:

other: value based on the response of the anionic part

Partition coefficient 4

Type:

Pow

Partition coefficient:

7.1

Temp.:

20 °C

pH:

7

Remarks on result:

other: value based on the response of the anionic part

Any other information on results incl. tables

 n-octanol solubility - preliminary test

The tests performed showed that solubility of the test substance in n-octanol was between 0.102 and 0.536 g/l (visually interpreted). Based on this and the water solubility determined (see section 4.8), the shake flask method was considered suitable for determination of the partition coefficient of Biphenyl DCHA Salt.

Partition coefficient - shake flask method

Results based on response of cationic part (m/z 182.2 amu)

The Biphenyl DCHA Salt concentration of the stock solution was measured to be 0.297 g/l. Based on this, the nominal quantity of the test substance in the test samples was 0.593 mg. The recoveries based on the response of the cationic part at m/z 182.2 amu were determined according to this value.

 

The log P_owvalues calculated were within the criterion range of± 0.3 log units. Based on this, the P_ow and log P_ow of the cationic part of the test substance is given as the mean value of all measurements.

 

No test substance was detected in the pre-treated samples from the blank mixture.

Ratio n-octanol : water [v:v]	Analysed test substance concentration		Pow		log Pow	pH
	n-octanol [g/l]	water [g/l]	individual	mean
1:1	0.0421	0.0469	0.90	0.95	0.0	7.1
	0.0463	0.0461	1.0		0.0	7.1
1:2	0.0523	0.0451	1.2	1.2	0.1	7.1
	0.0509	0.0445	1.1		0.1	7.1
2:1	0.0462	0.0528	0.88	0.87	-0.1	7.1
	0.0457	0.0524	0.87		-0.1	7.1
Mean			0.99		0.0
Standard deviation			0.13

Recoveries in solutions with n-octaol:water ratio's 1:1, 1:2 and 2:1 were in the range 90 -98% of nominal quantity of the test substance in the test samples.

Results based on response of the anionic part (m/z 462.1 amu)

The Biphenyl DCHA Salt concentration of the stock solution was measured to be 0.275 g/l. Based on this, the nominal quantity of the test substance in the test samples was 0.550 mg. The recoveries at m/z 462.1 amu were determined according to this value.

 

The log P_owvalues were within the criterion range of ± 0.3 log units. Based on this, the P_ow and log P_ow of the anionic part of the test substance is given as the mean value of all measurements.

 

No test substance was detected in the pre-treated samples from the blank mixture.

Ratio n-octanol : water [v:v]	Analysed test substance concentration		Pow		log Pow	pH
	n-octanol [g/l]	water [g/l]	individual	mean
1:1	0.0725	0.0107	6.8	7.1	0.8	7.1
	0.0797	0.0108	7.4		0.9	7.1
1:2	0.104	0.0161	6.4	6.4	0.8	7.1
	0.0993	0.0156	6.4		0.8	7.1
2:1	0.0640	0.00818	7.8	7.9	0.9	7.1
	0.0655	0.00820	8.0		0.9	7.1
Mean			7.1		0.9
Standard deviation			0.70

Recoveries in solutions with n-octaol:water ratio's 1:1, 1:2 and 2:1 were in the range 91 -101% ofnominal quantity of the test substance in the test samples.

Log P_ow of the cationic and anionic part of Biphenyl DCHA Salt are different as expected based on their molecular formula.

Applicant's summary and conclusion

Conclusions:

The shake flask method was applied for the determination of the partition coefficient (Pow) of Biphenyl DCHA Salt.

The Pow value of the cationic part of the test substance was 0.99 at pH 7.0 and 20°C which corresponds with a log Pow value of 0.0.

The Pow value of the anionic part of the test substance was 7.1 at pH 7.0 and 20°C which corresponds with a log Pow value of 0.9.