tert-butyl {(1S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl]-1-[3-hydroxyadamantan-1-yl]-2-oxoethyl}carbamate

Partition coefficient

Administrative data

Endpoint:

partition coefficient

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Between 07 February and 15 March 2012.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method A.8 (Partition Coefficient)

Version / remarks:

- using the shake-flask method, designed to be compatible with Method A8 Partition Coefficient of Commission Regulation (EC) No 440/2008 of 30 May 2008 and Method 107 of the OECD Guidelines for Testing of Chemicals, 27 July 1995.

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

using the shake-flask method, designed to be compatible with Method A8 Partition Coefficient of Commission Regulation (EC) No 440/2008 of 30 May 2008 and Method 107 of the OECD Guidelines for Testing of Chemicals, 27 July 1995.

Deviations:

no

GLP compliance:

yes

Type of method:

shake-flask method to: flask method

Partition coefficient type:

octanol-water

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

Identification: BMS-528235-01
Description: Off white powder
Batch: 1L63487N
Purity: 98.6 %
Expiry Date: 27 November 2014
Storage Conditions: Room temperature in the dark

Results and discussion

Partition coefficient

Type:

log Pow

Partition coefficient:

77.2

Temp.:

23 °C

Remarks on result:

other: The partition coefficient of the test item has been determined to be 77.2 at 23.0 ± 1.5 °C, log10 Pow 1.89. Testing was carried out at approximately neutral pH with the test item in a non-ionised form.

Details on results:

Due to the tabular nature of this information & to retain the integrity & coherence of the original Harlan Laboratories Ltd. Study report please see section “Any other information on results incl. tables”

Any other information on results incl. tables

Results

Preliminary assessment

The log₁₀P_owwas calculated to be 2.53.

 

The full KOWWIN calculation is presented in Appendix 3 (Attachment 2).

Please see Attachment 3 for the Typical Chromatography.

The mean peakareasobtained for the standard, stock and sample solutions are shown in the following two tables:

 

Table 3.14– Organic Phase

 

Solution	Mean PeakArea
Standard 46.8 mg/L	1.3286 x 10^7
Standard 41.2 mg/L	1.1477 x 10^7
Sample 1	1.0698 x 10^7
Sample 2	1.0613 x 10^7
Sample 3	1.0489 x 10^7
Sample 4	1.0494 x 10^7
Sample 5	1.0647 x 10^7
Sample 6	1.0828 x 10^7
Stock solution A	1.0777 x 10^7
Stock solution B	1.0869 x 10^7

 

Table 3.15– Aqueous Phase

 

Solution	Mean PeakArea
Standard 10.3 mg/L	2.8336 x 10^6
Standard 10.2 mg/L	2.8922 x 10^6
Sample 1	2.9865 x 10^6
Sample 2	3.0493 x 10^6
Sample 3	3.0080 x 10^6
Sample 4	2.8994 x 10^6
Sample 5	3.1892 x 10^6
Sample 6	2.9993 x 10^6

 

 

The total weights (mg) and analysed concentration (mg/L) of the respective phases are shown in the following table:

 

Table 3.16

 

Sample Number	Organic Phase		Aqueous Phase			% Recovery
	Analysed Concentration (mg/L)	Weight (mg)†	Analysed Concentration (mg/L)	Weight (mg)†	pH
1	3.88 x 10^3	291	50.3	3.77	7.3	100
2	3.86 x 10^3	289	49.8	3.73	7.3	99.6
3	3.82 x 10^3	145	50.1	3.81	6.2	99.9
4	3.82 x 10^3	176	50.9	4.69	6.9	100
5	3.87 x 10^3	348	48.7	2.19	7.0	99.2
6	3.92 x 10^3	298	50.2	1.91	6.9	101

 

pH of n-octanol saturated water:       7.5
Temperature:                                     23.0 ± 1.5 °C

 

The partition coefficient determined for each sample is shown in the following table:

 

Table 3.17

 

Sample Number	Organic/Aqueous Volume Ratio	Partition Coefficient	Log10Pow	Mean Partition Coefficient
1	1:1	77.2	1.89	77.3
2		77.4	1.89
3	1:2	76.2	1.88	75.6
4		75.0	1.88
5	2:1	79.4	1.90	78.8
6		78.2	1.89

 

Mean P_ow: 77.2                      log₁₀P_ow: 1.89                       P_owstandard deviation : 1.53

 

† From analysis of the respective phase

 

           

Validation

Organic phases: The linearity of the detector response with respect to concentration was assessed over the concentration range of 0 to 114 mg/L. This was satisfactory with a correlation coefficient (r²) of 1.000 being obtained.

 

Aqueous phases: The linearity of the detector response with respect to concentration was assessed over the concentration range of 0 to 23.3 mg/L. This was satisfactory with a correlation coefficient (r²) of 1.000 being obtained.

Applicant's summary and conclusion

Conclusions:

The partition coefficient of the test item has been determined to be 77.2 at 23.0 ± 1.5 °C, log10 Pow 1.89.

Executive summary:

The determination was carried out using the shake-flaskthod, designed to be compatible with Method A8 Partition Coefficient of Commission Regulation (EC) No 440/2008 of 30 May 2008 and Method 107 of the OECD Guidelines for Testing of Chemicals, 27 July 1995.

Conclusion

The partition coefficient of the test item has been determined to be 77.2 at 23.0±1.5°C, log₁₀ P_ow 1.89.