Registration Dossier

Administrative data

Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The experimental start date was 14 May 2019, and the experimental completion date was 16 May 2019.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report Date:
2019

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other:  EC Guideline A.8.
Version / remarks:
Partition Coefficient. March 04, 2016.
Deviations:
no
Qualifier:
according to
Guideline:
other: EC Guideline A.24.
Version / remarks:
Partition Coefficient (n-octanol/water), High Performance Liquid Chromatography (HPLC) Method. March 04, 2016.
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 107 (Partition Coefficient (n-octanol / water), Shake Flask Method)
Version / remarks:
Partition Coefficient (n-octanol/water), Shake Flask Method.
July 27, 1995.
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)
Version / remarks:
Partition Coefficient (n-octanol/water), High Performance Liquid
Chromatography (HPLC) Method. April 13, 2004.
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 830.7550 (Partition Coefficient, n-octanol / H2O, Shake Flask Method)
Version / remarks:
Partition Coefficient (n-octanol/water), Shake Flask Method. August 1996
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 830.7570 (Partition Coefficient, n-octanol / H2O, Estimation by Liquid Chromatography)
Version / remarks:
Partition Coefficient (n-octanol/water), Estimation by Liquid Chromatography. August 1996.
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of method:
HPLC method
Partition coefficient type:
octanol-water

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
White to off-white powder.
Storage Conditions: At room temperature.
Specific details on test material used for the study:
Batch (Lot) Number: 334115
Expiry date: 14 April 2020 (retest date)
Physical Description: White to off-white powder
Purity/Composition: 99.9%
Storage Conditions: At room temperature

Study design

Analytical method:
high-performance liquid chromatography

Results and discussion

Partition coefficientopen allclose all
Key result
Type:
log Pow
Partition coefficient:
ca. 3.1
pH:
ca. 2
Remarks on result:
other: Temperature not specified
Key result
Type:
Pow
Partition coefficient:
ca. 1 100
pH:
ca. 2
Remarks on result:
other: Temperature not specified
Key result
Type:
log Pow
Partition coefficient:
>= 7.2
pH:
ca. 7.5
Remarks on result:
other: Temperature not specified
Key result
Type:
Pow
Partition coefficient:
>= 16 000 000
pH:
ca. 7.5
Remarks on result:
other: Temperature not specified

Any other information on results incl. tables

PowCalculation

The Powof the test item was calculated to be 3.1x109(log Pow8.5) using the Rekker calculation method.

pKaValues

The pKavalues in the logarithm range of 1 - 14 for acidic and basic groups in the molecular structure of the test item were calculated using the Perrin calculation method. The results are given in Table 5. According to these calculations, testing of the non-ionised form would require a pH of≥12.8. The HPLC method cannot be performed at such high pH. As an alternative, it was decided to test at pH 2 in order to have the test item fully ionised and at pH 7.5 where the test item is singly charged.

 

Table 5          
pKa Values of the Test Item

Acidic

Basic

-

SUBST.-QUINUCLIDINE

pKa10.8

RRNH2+

pKa5.9

   HPLC Method

pH 2

UPLC-UV chromatograms of the test item solution and corresponding blank are shown inFigure 4 and Figure 5, respectively. In the chromatogram of the test solution, one major test item peak was observed.

The results of the HPLC method are given in theTable 6. Figure 6shows the calibration curve of the log k’ of the reference substances as function of log Pow. The equation of the regression line was: log k’ = 0.365´log Pow– 0.903 (r = 0.993, n = 12).

Table 6          
pH 2: Powof the Test Item

Substance

Retention time (min)

log Pow

Pow

tr,1

tr,2

mean

Formamide (t0)

0.608

0.612

0.610

 

 

Benzylalcohol

0.788

0.787

 

1.1

 

Nitrobenzene

0.970

0.968

 

1.9

 

Toluene

1.537

1.533

 

2.7

 

1,4-Dichlorobenzene

1.982

1.976

 

3.4

 

Biphenyl

2.649

2.642

 

4.0

 

1,2,4-Trichlorobenzene

3.054

3.045

 

4.2

 

Test item – peak 1

1.606

1.594

1.600

3.1

1.1´103

 

pH 7.5

UPLC-UV chromatograms of the test item solution and the corresponding blank are shown inFigure 7andFigure 8, respectively. In the chromatogram of the test item solution, one peak with a retention time of 23.5 minutes was observed. The shoulder on the test item peak was also observed on the peak for benzo[ghi]perylene(log Pow= 7.2) which under the same analytical conditions, eluted at 17.4 minutes. Because the shoulder was observed for both the test item and the reference substance, it was considered to be due to the column used and not

to derive from another compound. It could be safely concluded that the log Powof the test item was > 7.2 (Pow > 1.6 x107).

Applicant's summary and conclusion

Conclusions:
The HPLC method at pH 2 and pH 7.5 was applied for the determination of the partition coefficient (Pow) of Maropitant base (CJ-11,972).
The Pow and log Pow values of the test item at pH 2 and pH 7.5 were:
pH 2 pH 7.5
Pow log Pow Pow log Pow
Test item – peak 1 1.1 x 10^3 3.1 > 1.6 x 10^7 > 7.2