1-[([[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl)oxy]pyrrolidine-2,5-dione

Stability in organic solvents and identity of relevant degradation products

Link to relevant study record(s)

Reference

Endpoint:

stability in organic solvents and identity of relevant degradation products

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2018-09-06 to 2019-02-07

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

other: European Commission: Guidance for Generating and Reporting Methods of Analysis in Support of Pre-registration Data Requirements for Annex II (Part A, section 4) and Annex III (Part A, section 5) of Directive 91/414, SANCO/3029/99 rev. 4 (11/07/00)

Deviations:

yes

Remarks:

The mean RF of the calibration curve during formulation analyses vs validation had a relative difference of 26.78%. This may be caused by the instrument configuration. As a calibration curve is used for quantification this does not impact results.

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

- Batch n°: I16FD3167
- Analytical purity: 98.2%
- Expiration date: 26 October 2018 (retest date)
- Storage condition: In refrigerator (2-8°C)

Test substance stable:

yes

Transformation products:

no

Accuracy of preparation : The concentrations analysed in the formulations at 10 mg/mL (mid) and 200 mg/mL (high) were in agreement with target concentrations (i.e. mean accuracies between 85.00% and 115.00%).The concentrations analysed in the formulations at 1 mg/mL (low) were slightly below the criterion (i.e. mean accuracy of 83.61%).

Stability: Analysis of the formulations at 1 mg/mL (low), 10 mg/L (mid) and 200 mg/mL (high) after storage yielded a relative difference of ≤ 10.00% when stored at room temperature under normal laboratory light conditions for at least 6 hours. Based on this, the formulations were found to be stable during storage at room temperature under normal laboratory light conditions for at least 6 hours. When stored in the refrigerator for 14 days the relative difference of the formulation at 1 mg/mL was  -14.49%. The relative difference of the formulation at 10 and 200 mg/mL was  ≤ 10.00%.

Stability test at room temperature under normal laboratory light conditions for 6 hours

Group	Date of analysis	Analysed conc [mg/mL]- t=0 [1]	Analysed conc  [mg/mL] - t=6h	Relative difference [%]
Low	25 Sep 2018	0.836	0.842 [2]	0.75
Mid	25 Sep 2018	8.93	9.13 [3]	2.63
High	25 Sep 2018	205	200 [4]	-2.35

[1] Mean of six samples at t=0 taken at 10%, 50% and 90% height.

[2] Mean of two samples at t=6 hours taken at 50% height. Individual results were 0.823 and 0.861 mg/mL.

[3] Mean of two samples at t=6 hours taken at 50% height. Individual results were 8.77 and 9.56 mg/mL.

[4] Mean of two samples at t=6 hours taken at 50% height. Individual results were 206 and 195 mg/mL.

Stability test for 14 days in the refrigerator

Group	Date of analysis	Analysed conc [mg/mL]- t=0 [1]	Analysed conc  [mg/mL] - t=6h	Relative difference [%]
Low	09 Oct 2018	0.836	0.715 [2]	-14.49
Mid	09 Oct 2018	8.93	8.11 [3]	-9.18
High	09 Oct 2018	205	203 [4]	-0.90

[1] Mean of six samples at t=0 taken at 10%, 50% and 90% height.

[2]  Mean of two samples at t=6 hours taken at 50% height. Individual results were 0.743 and 0.687 mg/mL.

[3] Mean of two samples at t=6 hours taken at 50% height. Individual results were 8.85 and 7.37 mg/mL.

[4] Mean of two samples at t=6 hours taken at 50% height. Individual results were 201 and 205 mg/mL.

Conclusions:

Trial formulations (not used for dosing) were prepared in vehicle (acetonitrile) at 1 mg/mL (low), 10 mg/mL (mid) and 200 mg/mL (high) and analysed to determine the accuracy and stability of the test item in formulations:

The concentrations analysed in the formulation at mid and high target level were in agreement with target concentrations. The mean accuracy of the formulation at low target level was just below the criteria (i.e. 83.61%).

Formulations at the entire range were stable when stored at room temperature under normal laboratory light conditions for at least 6 hours.

Formulations at mid and high target level were stable when stored in the refrigerator for 14 days. Formulations at low target level were not stable for 14 days in the refrigerator.

Description of key information

Formulations (prepared in acetonitrile) at the entire range were stable when stored at room temperature under normal laboratory light conditions for at least 6 hours.

Formulations at mid and high target level were stable when stored in the refrigerator for 14 days. Formulations at low target level were not stable for 14 days in the refrigerator.