methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate compd with dimethylsulfoxide

Melting point / freezing point

Link to relevant study record(s)

Reference

Endpoint:

melting point/freezing point

Type of information:

experimental study

Adequacy of study:

key study

Study period:

September 04, 2019 to September 12, 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 102 (Melting point / Melting Range)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method A.1 (Melting / Freezing Temperature)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of method:

differential scanning calorimetry

Remarks:

and capillary method

Key result

Melting / freezing pt.:

> 135 °C

Decomposition:

yes

Remarks:

melted under decomposition starting at 135 °C

Decomp. temp.:

> 135 °C

Individual results

Melting point / melting range: Differential scanning calorimetry

Two DSC measurements in aluminium crucibles with a hole showed two endothermal effects in the temperature range of 70 – 140 °C and 160 – 260 °C. Additionally a multistage exothermal effect in the temperature range of 320 – 460 °C was observed. After the measurement the test item was a black residue. The mass loss after the DSC measurement amounted to 50 % and 48 %, respectively.

Two additional DSC measurements were performed in order to clarify the melting. The DSC measurement in an aluminium crucible with a hole up to 150 °C showed an endothermal effect in the temperature range of 80 – 140 °C, but the test item appeared unchanged after the measurement (mass loss 1 %). Whereas the DSC measurement in an aluminium crucible with a hole up to 240 °C showed two endothermal effects in the temperature range of 90 – 135 °C and 135 – 240 °C and the test item changed into a yellow solidified melt (mass loss: 25 %).

The results of the DSC measurements are summarized in Table 1.

 

Table 1: DSC measurements

Ident No.	Test item / mg	Starting temperature / °C	Final test temperature / °C	Temperature range / °C	Crucible	Observations after the measurement
38800	10.84	25	500	70 – 135 (endothermal) 160 – 260 (endothermal) 320 – 460 (multistage exothermal)	Aluminium with a hole	Test item was a black residue; mass loss: 50 %
38801	6.90	25	500	80 – 140 (endothermal) 160 – 250 (endothermal) 320 – 460 (multistage exothermal)	Aluminium with a hole	Test item was a black residue; mass loss: 48 %
38802	10.42	25	150	80 – 140 (endothermal)	Aluminium with a hole	Test item was a light yellow solid; mass loss: 1 %
38803	9.23	25	240	90 – 135 (endothermal) 135 – 240 (endothermal)	Aluminium with a hole	Test item was a yellow solidified melt; mass loss: 25 %

                    

Due to these results, it was assumed that the second peak in the temperature range of 135 – 240 °C belonged to the melting. Because of a mass loss of 25 % after the DSC measurement up to 240 °C additional measurements with the capillary method were performed in order to clarify the melting behavior.

 

Melting point / melting range: capillary tube in a metal block

Two measurements with the capillary method were performed to clarify the results of the DSC measurements. Since the measurements were performed only as a verifying screening a high heating rate of 10 K/min was chosen and therefore the absolute temperature values derived with the capillary method are not as accurate as the DSC results. For both measurements the filling height of the test item was approximately 5 mm. The results are summarized in Table 2.

Table 2: Results of the capillary method

No.	Set point / °C	Heating rate / K/min	End point / °C	Remarks
1	100	10	250	100 °C: Test item appeared unchanged Approx. 202 °C: Test item changed partly into a light-yellow liquid (start of melting) Approx. 210 °C: Bubble formation (test item rose partly up in the melting tube) Approx. 217 °C: Test item was completely molten into a yellow liquid
2	100	10	250	100 °C: test item appeared unchanged Approx. 120 °C: Test item started to soften Approx. 120 °C to 203 °C: Continuous softening of the test item Approx. 203 °C: Test item changed partly into a light-yellow liquid (start of melting) Approx. 211 °C: Bubble formation (test item rose partly up in the melting tube) Approx. 216 °C: Test item was completely molten into a yellow liquid.

               

Under consideration of the results from the DSC measurements and the capillary method it was concluded that the test item melted under decomposition starting at 135 °C. The decomposition (bubble formation and mass loss) could have been caused by an evaporation of the DMSO (Dimethyl sulfoxide, boiling point: 189 °C ), that is included in the test item as solvate (Test item: BAY 1021189 (Vericiguat) DMSO-Solvat).

 

Executive summary:

The test item BAY 1021189 (Vericiguat) DMSO-Solvat melted under decomposition starting at 135 °C. The decomposition (bubble formation and mass loss) could have been caused by an evaporation of the DMSO, that is included in the test item as solvate.

Description of key information

The test item BAY 1021189 (Vericiguat) DMSO-Solvat melted under decomposition starting at 135 °C. The decomposition (bubble formation and mass loss) could have been caused by an evaporation of the DMSO, that is included in the test item as solvate.