1H-Pyrazolo[3,4-c]pyridine-3-carboxylic acid, 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-, ethyl ester

Particle size distribution (Granulometry)

Link to relevant study record(s)

Reference

Endpoint:

particle size distribution (granulometry)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Between 15 February and 03 March 2012.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 110 (Particle Size Distribution / Fibre Length and Diameter Distributions)

Deviations:

no

Principles of method if other than guideline:

OECD Guideline 110 (Particle Size Distribution / Fibre Length and Diameter Distributions)

GLP compliance:

yes

Type of method:

sieving

Type of distribution:

other: Sieving Screening Test, Cascade Impactor

Remarks on result:

not determinable because of methodological limitations

Percentile:

D50

Remarks on result:

not determinable

No.:

#1

Size:

< 100 other: µm

Distribution:

13.8 %

No.:

#2

Size:

< 10 µm

Distribution:

<= 5.58 %

No.:

#3

Size:

< 5.5 µm

Distribution:

<= 0.83 %

Results

Screening test (sieve method)

The results of the sieving procedure are shown in the following table:

 

Table 3.16

 

Measurement	Result
Mass of test item transferred to sieve	15.18 g
Mass of test item passed through sieve	2.10 g
Proportion of test item <100 µm	13.8 %

 

 

  

Definitive test

The results of the cascade impactor method determinations are shown as follows:

 

Determination 1

 

Table 3.17

 

Collection Stage	Particle Size Range Collected (µm)	Mass (g)
		Pre-sampling	Post-sampling	Difference
Cup 1	>10.0	86.1543	88.7816	2.6273
Cup 2	5.5 to 10.0	85.6025	85.6433	0.0408
Cup 3	2.4 to 5.5	85.9395	85.9548	0.0153
Cup 4	1.61 to 2.4	85.7216	85.7288	0.0072
Cup 5	0.307 to 1.61	85.8571	85.8573	0.0002
Filter	<0.307	75.5386	75.5404	0.0018

 

Mass of test item found in artificial throat: 0.26 g.
Total mass of test item recovered from artificial throat, sample cups and filter: 2.95 g.

Determination 2

 

Table 3.18

 

Collection Stage	Particle Size Range Collected (µm)	Mass (g)
		Pre-sampling	Post-sampling	Difference
Cup 1	>10.0	86.1168	88.6874	2.5706
Cup 2	5.5 to 10.0	85.5581	85.6647	0.1066
Cup 3	2.4 to 5.5	85.9077	85.9158	0.0081
Cup 4	1.61 to 2.4	85.6864	85.6876	0.0012
Cup 5	0.307 to 1.61	85.8565	85.8578	0.0013
Filter	<0.307	75.5343	75.5369	0.0026

 

Mass of test item found in artificial throat: 0.28 g.
Total mass of test item recovered from artificial throat, sample cups and filter: 2.97 g.

 

Determination 3

 

Table 3.19

 

Collection Stage	Particle Size Range Collected (µm)	Mass (g)
		Pre-sampling	Post-sampling	Difference
Cup 1	>10.0	86.1163	88.8757	2.7594
Cup 2	5.5 to 10.0	85.5566	85.7113	0.1547
Cup 3	2.4 to 5.5	85.9078	85.9201	0.0123
Cup 4	1.61 to 2.4	85.6859	85.6877	0.0018
Cup 5	0.307 to 1.61	85.8575	85.8579	0.0004
Filter	<0.307	75.5385	75.5419	0.0034

 

Mass of test item found in artificial throat: 0.16 g.
Total mass of test item recovered from artificial throat, sample cups and filter: 3.09 g.

 

 

Cumulative amounts

The cumulative amounts of test item found in the three determinations for the individual particle size cut-points are shown in the following table:

 

Table 3.20

 

Particle Size Cut-point (µm)	Cumulative Mass (g)			Cumulative Percentage (%)
	Determination 1	Determination 2	Determination 3	Determination 1	Determination 2	Determination 3
10.0	0.0653	0.1198	0.1726	2.21	4.03	5.58
5.5	0.0245	0.0132	0.0179	0.830	0.444	0.579
2.4	0.0092	0.0051	0.0056	0.312	0.172	0.181
1.61	0.0020	0.0039	0.0038	6.8 x 10^-2	0.131	0.123
0.307	0.0018	0.0026	0.0034	6.1 x 10^-2	8.8 x 10^-2	0.110

 

The overall cumulative percentage (%) of test item with a particle size less than 10.0 µm and 5.5 µm are shown in the following table:

 

Table 3.21

 

Particle size	Cumulative Percentage (%)
	Determination 1	Determination 2	Determination 3	Overall
<10.0 µm	2.21	4.03	5.58	≤5.58
<5.5 µm	0.830	0.444	0.579	≤0.830

Particle size data acquired for the test item is shown in the following table:

 

Table 3.22

 

Measurement		Method		Result
Proportion of test item having an inhalable particle size <100 µm		Sieve		13.8 %
Proportion of test item having a thoracic particle size <10.0 µm		Cascade Impactor		≤5.58 %
Proportion of test item having a respirable particle size <5.5 µm		Cascade Impactor		≤0.830 %

Conclusions:

Conclusion
Particle size data acquired for the test item is shown in the following table:

Table 3.22
Measurement Method Result
Proportion of test item having an Sieve 13.8 %
inhalable particle size <100 µm


Proportion of test item having a Cascade Impactor ≤5.58 %
thoracic particle size <10.0 µm


Proportion of test item having a Cascade Impactor ≤0.830 %
respirable particle size <5.5 µm

Executive summary:

Performance of the Test

Sieving Screening Test

The proportion of test item passing through a 100 µm sieve was determined using an Inclyno sieve shaker. A known mass (15.18 g) of test item was added to a 100 µm sieve fitted above a receiver pan of known mass. A lid was then secured onto the sieve and the assembled apparatus placed on the sieve shaker for a period of approximately 30 minutes. Following the shaking period, the mass of the receiver pan and collected test item was recorded and the percentage test item with a particle size <100 µm calculated as detailed in the data handling section.

Cascade Impactor

Test item (approximately 3 g) was passed into the artificial throat of a Marple Miller Cascade Impactor (MSP Corporation, Minneapolis, Minnesota, USA – Figure 3.4 - Attachment 1). During cascade impactor analysis, air was pulled through the impactor, by a vacuum pump, at a flow rate of approximately 60 L/min. The flow enters the impactor through a throat and inlet tube and accelerates through the stages. At each stage one or more nozzles direct the particle-laden airstream into a collection cup.

 

Particles larger than the cut size of that stage, impact onto the collection plate and stay in the collection cup. Smaller particles follow the airstream and are carried to the next stage. In succeeding stages the nozzles are smaller, the air velocity is higher and finer particles are collected. In the final stage the smallest particles are collected on a glass fibre filter. The mass of the collection cups and filter were recorded before and after each determination.

       

Conclusion

Particle size data acquired for the test item is shown in the following table:

 

Table 3.22

 

Measurement		Method		Result
Proportion of test item having an inhalable particle size <100 µm		Sieve		13.8 %
Proportion of test item having a thoracic particle size <10.0 µm		Cascade Impactor		≤5.58 %
Proportion of test item having a respirable particle size <5.5 µm		Cascade Impactor		≤0.830 %

Description of key information

Following measurement of particle size according to OECD Guideline 110, the following fractions were determined:

Proportion of test item having an inhalable particle size <100 µm:  13.8 %; proportion of test item having a thoracic particle size <10.0 µm: ≤5.58 %;

proportion of test item having a respirable particle size <5.5 µm: ≤0.830 %.