Tetrasodium (1-hydroxyethylidene)bisphosphonate

Particle size distribution (Granulometry)

Administrative data

Endpoint:

particle size distribution (granulometry)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Testing was conducted between 25 May 2010 and 26 May 2010.

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:

2010

Report date:

2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

,

Deviations:

no

Remarks:

,

Principles of method if other than guideline:

See guideline.

GLP compliance:

yes (incl. QA statement)

Type of distribution:

other: Cascade impactor

Test material

Test material information

Constituent 1

Reference substance name:

Tetrasodium (1-hydroxyethylidene)bisphosphonate

EC Number:

223-267-7

EC Name:

Tetrasodium (1-hydroxyethylidene)bisphosphonate

Cas Number:

3794-83-0

Molecular formula:

C2H8O7P2.4Na

IUPAC Name:

tetrasodium (1-hydroxyethane-1,1-diyl)bis(phosphonate)

Constituent 2

Reference substance name:

BRIQUEST ADPA-60SH

IUPAC Name:

BRIQUEST ADPA-60SH

Constituent 3

Reference substance name:

Tetrasodium (1-hydroxyethylidene) bisphosponate

IUPAC Name:

Tetrasodium (1-hydroxyethylidene) bisphosponate

Details on test material:

Sponsor's identification :BRIQUEST ADPA-60SH
Description : white powder
Chemical name :Tetrasodium (1-hydroxyethylidene) bisphosponate
Empirical formula :C2H8O7P2.4Na
CAS number : 3794-83-0
Batch number :A6SL20D1
Purity : 84.8% w/w
Date received :14 May 2010
Expiry date : 20 April 2012
Storage conditions :room temperature, in the dark

A Certificate of Analysis as supplied by the Sponsor, see attachments.

Results and discussion

Particle size

Particle size 1

Percentile:

D50

Remarks on result:

other: Too few particles were of a size less than 10.0 µm to allow accurate assessment of mass median aerodynamic diameter.(migrated from fields under 'Mass median diameter' as D50 percentile. No source field for Standard deviation.)

Particle size 2

Remarks on result:

other: Not applicable

Particle size distribution at different passages

Particle size distribution at different passages 1

No.:

#1

Size:

< 100 µm

Distribution:

67.1 %

Particle size distribution at different passages 2

No.:

#2

Size:

< 10 µm

Distribution:

7.18 %

Particle size distribution at different passages 3

No.:

#3

Size:

< 5.5 µm

Distribution:

2.78 %

Any other information on results incl. tables

Results

Screening test (sieve method)

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

Measurement	Result
Mass of test item transferred to sieve	10.11 g
Mass of test item passed through sieve	6.78 g
Proportion of test item <100 µm	67.1%

Definitive test (cascade impactor method)

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

Determination1

Collection Stage	ParticleCollected (µm)	Mass (g)
		Pre-sampling	Post-sampling	Difference
Cup 1	>10.0	86.3210	88.8677	2.5467
Cup 2	5.5 to 10.0	85.7391	85.8888	0.1497
Cup 3	2.4 to 5.5	86.1810	86.2123	0.0313
Cup 4	1.61 to 2.4	85.9141	85.9266	0.0125
Cup 5	0.307 to 1.61	86.0565	86.0641	0.0076
Filter	<0.307	75.6451	75.6901	0.0450

Mass of test item found in artificial throat: 0.02 g.
Total mass of test item recovered from artificial throat, sample cups and filter: 2.81 g.

Determination 2

Collection Stage	ParticleCollected (µm)	Mass (g)
		Pre-sampling	Post-sampling	Difference
Cup 1	>10.0	86.3207	88.9300	2.6093
Cup 2	5.5 to 10.0	85.7391	85.8375	0.0984
Cup 3	2.4 to 5.5	86.1812	86.2058	0.0246
Cup 4	1.61 to 2.4	85.9143	85.9235	0.0092
Cup 5	0.307 to 1.61	86.0562	86.0615	0.0053
Filter	<0.307	75.6445	75.6710	0.0265

Mass of test item found in artificial throat: 0.03 g.
Total mass of test item recovered from artificial throat, sample cups and filter: 2.80 g.

Determination 3

Collection Stage	ParticleCollected (µm)	Mass (g)
		Pre-sampling	Post-sampling	Difference
Cup 1	>10.0	86.3212	88.8894	2.5682
Cup 2	5.5 to 10.0	85.7394	85.8633	0.1239
Cup 3	2.4 to 5.5	86.1815	86.2122	0.0307
Cup 4	1.61 to 2.4	85.9146	85.9285	0.0139
Cup 5	0.307 to 1.61	86.0570	86.0637	0.0067
Filter	<0.307	75.6457	75.6671	0.0214

Mass of test item found in artificial throat: 0.07 g.
Total mass of test item recovered from artificial throat, sample cups and filter: 2.8348 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:

Particle Size Cut-point (µm)	Cumulative Mass (g)			Cumulative Percentage (%)
	Determination 1	Determination 2	Determination 3	Determination 1	Determination 2	Determination 3
10.0	0.2461	0.1640	0.1966	8.75	5.85	6.94
5.5	0.0964	0.0656	0.0727	3.43	2.34	2.57
2.4	0.0651	0.0410	0.0420	2.31	1.46	1.48
1.61	0.0526	0.0318	0.0281	1.87	1.13	0.991
0.307	0.0450	0.0265	0.0214	1.60	0.945	0.755

 

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:

Particle size	Cumulative Percentage (%)
	Determination 1	Determination 2	Determination 3	Overall Result
<10.0 µm	8.75	5.85	6.94	7.18
<5.5 µm	3.43	2.34	2.57	2.78

 Discussion

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

Sampling for the cascade impactor determinations was performed by rolling the test item container for approximately ten minutes then sampling from the top, middle and bottom.

The inhalable fraction is defined as the mass fraction of particles which can be inhaled by nose or mouth, the thoracic fraction is defined as the mass fraction of particles that passes the larynx and the respirable fraction is defined as the mass fraction of particles that reaches the alveoli.

Applicant's summary and conclusion

Conclusions:

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

Measurement Method Result
Proportion of test item having an inhalable particle size <100 µm Sieve 67.1%
Proportion of test item having a thoracic particle size <10.0 µm Cascade Impactor 7.18%
Proportion of test item having a respirable particle size <5.5 µm Cascade Impactor 2.78%

Executive summary:

Particle size data have been acquired using a procedure designed to comply with the European Commission technical guidance docunt 'Particle Size Distribution, Fibre Length and Diater Distribution' (June 1996), which satisfies the requirents of OECD Guideline 110. The results are as follows:

Measurent	Method	Result
Proportion of test item having an inhalable particle size less than 100 µm	Sieve	67.1%
Proportion of test item having a thoracic particle size less than 10.0 µm	Cascade Impactor	7.18%
Proportion of test item having a respirable particle size less than 5.5 µm	Cascade Impactor	2.78%