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

Particle size distribution (Granulometry)

Administrative data

Endpoint:

particle size distribution (granulometry)

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

Qualifier:

equivalent or similar to guideline

Guideline:

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

Version / remarks:

The method used is based on a procedure designed to comply with that given in ‘Particle Size Distribution, Fibre Length and Diameter Distribution’, June 1996 European Commission technical guidance document, which satisfies the requirements of OECD Guideli

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 distribution:

other:

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

Particle size

Particle size 1

Percentile:

D50

Remarks on result:

other: Not applicable(migrated from fields under 'Mass median diameter' as D50 percentile. No source field for Standard deviation.)

Particle size 2

Mean:

other: Not Applicable

Particle size distribution at different passages

Particle size distribution at different passages 1

No.:

#1

Size:

< 100 µm

Distribution:

27.9 %

Particle size distribution at different passages 2

No.:

#2

Size:

< 10 µm

Distribution:

0.233 %

Particle size distribution at different passages 3

No.:

#3

Size:

< 5.5 µm

Distribution:

0.156 %

Any other information on results incl. tables

Results

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

 

Table 3.18

 

Measurement	Result
Mass of test item transferred to sieve	19.93 g
Mass of test item passed through sieve	5.56 g
Proportion of test item <100 µm	27.9 %

 

 

 

Definitive test (cascade impactor method)

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

 

Determination 1

 

Table 3.19

 

Collection Stage	Particle Size Range Collected (µm)	Mass (g)
		Pre-sampling	Post-sampling	Difference
Cup 1	>10.0	86.1153	88.5606	2.4453
Cup 2	5.5 to 10.0	85.5530	85.5553	0.0023
Cup 3	2.4 to 5.5	85.9031	85.9065	0.0034
Cup 4	1.61 to 2.4	85.6836	85.6839	0.0003
Cup 5	0.307 to 1.61	85.8546	85.8561	0.0015
Filter	<0.307	75.5387	75.5402	0.0015

 

Mass of test item found in artificial throat: 0.69 g.
Total mass of test item recovered from artificial throat, sample cups and filter: 3.14 g.

Determination 2

 

Table 3.20

 

Collection Stage	Particle Size Range Collected (µm)	Mass (g)
		Pre-sampling	Post-sampling	Difference
Cup 1	>10.0	86.1145	88.5350	2.4205
Cup 2	5.5 to 10.0	85.5557	85.5582	0.0025
Cup 3	2.4 to 5.5	85.9035	85.9040	0.0005
Cup 4	1.61 to 2.4	85.6831	85.6841	0.0010
Cup 5	0.307 to 1.61	85.8552	85.8552	0
Filter	<0.307	75.5371	75.5393	0.0022

 

Mass of test item found in artificial throat: 0.62 g.
Total mass of test item recovered from artificial throat, sample cups and filter: 3.05 g

 

Determination 3

 

Table 3.21

 

Collection Stage	Particle Size Range Collected (µm)	Mass (g)
		Pre-sampling	Post-sampling	Difference
Cup 1	>10.0	86.1172	87.9666	1.8494
Cup 2	5.5 to 10.0	85.5543	85.5566	0.0023
Cup 3	2.4 to 5.5	85.9041	85.9048	0.0007
Cup 4	1.61 to 2.4	85.6829	85.6845	0.0016
Cup 5	0.307 to 1.61	85.8552	85.8561	0.0009
Filter	<0.307	75.5353	75.5361	0.0008

 

Mass of test item found in artificial throat: 1.15 g.
Total mass of test item recovered from artificial throat, sample cups and filter: 3.01 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 3.22

 

Particle Size Cut-point (µm)	Cumulative Mass (g)			Cumulative Percentage (%)
	Determination 1	Determination 2	Determination 3	Determination 1	Determination 2	Determination 3
10.0	0.0090	0.0062	0.0063	0.286	0.203	0.210
5.5	0.0067	0.0037	0.0040	0.213	0.121	0.133
2.4	0.0033	0.0032	0.0033	0.105	0.105	0.110
1.61	0.0030	0.0022	0.0017	9.5 x 10^-2	7.2 x 10^-2	5.7 x 10^-2
0.307	0.0015	0.0022	0.0008	4.8 x 10^-2	7.2 x 10^-2	2.7 x 10^-2

 

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 3.23

 

Particle size	Cumulative Percentage (%)
	Determination 1	Determination 2	Determination 3	Mean
<10.0 µm	0.286	0.203	0.210	0.233
<5.5 µm	0.213	0.121	0.133	0.156

 

Applicant's summary and conclusion

Conclusions:

Too few particles were of a size less than 10.0 µm to allow accurate assessment of the mass median aerodynamic diameter.

Executive summary:

The method used is based on a procedure designed to comply with that given in ‘Particle Size Distribution, Fibre Length and Diameter Distribution’, June 1996 European Commission technical guidance document, which satisfies the requirements of OECD Guideline 110, 12 May 1981.

Conclusion

Table 3.24

 

Measurement	Method	Result
Proportion of test item having an inhalable particle size <100 µm	Sieve	27.9 %
Proportion of test item having a thoracic particle size <10.0 µm	Cascade Impactor	0.233 %
Proportion of test item having a respirable particle size <5.5 µm	Cascade Impactor	0.156 %