Cyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxylic acid, 2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-, ethyl ester, (2R,3aR,10Z,11aS,12aR,14aR)-

Particle size distribution (Granulometry)

Administrative data

Endpoint:

particle size distribution (granulometry)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 August - 08 December 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented GLP study according to the Chilworth Technology Ltd SOP n°417 using a visual microscope and Laser Diffraction Particle Size Analyser and in accordance with ISO 13320:2009 and CIPAC MT 187.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: ISO 13320-1

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: CIPAC MT 187

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of method:

Laser scattering/diffraction

Type of distribution:

volumetric distribution

Test material

Test material information

Constituent 1

Reference substance name:

ethyl (1R,4R,6S,7Z,15R,17R)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^{4,6}]octadec-7-ene-4-carboxylate

EC Number:

618-843-3

Cas Number:

923604-57-3

Molecular formula:

C37H46N4O6S

IUPAC Name:

ethyl (1R,4R,6S,7Z,15R,17R)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^{4,6}]octadec-7-ene-4-carboxylate

Test material form:

solid

Details on test material:

- Name of test material (as cited in study reports): JNJ-38970191-AAA (T003009)
- Physical state: solid
- Appearance white solid

Specific details on test material used for the study:

- Batch n°: I15AB0148
- Analytical purity: 97.8%
- Expiration date: 21 January 2017
- Storage condition: at room temperature

Results and discussion

Mass median aerodynamic diameter:

46.037 µm

Geometric standard deviation:

>= 3.57 - <= 3.645

Particle size

Particle size 1

Percentile:

D10

Mean:

7.391 µm

St. dev.:

0.051

Particle size 2

Percentile:

D50

Mean:

40.851 µm

St. dev.:

0.584

Particle size 3

Percentile:

D90

Mean:

136.511 µm

St. dev.:

1.161

Any other information on results incl. tables

Visual Microscope Analysis

(1) Standard visual observation: sample observed to be a medium and coarse white solid with clusters.

(2) 100x magnification: particles appeared to be irregular shaped crystals (smallest +/- 3 µm and largest +/- 192 µm).

(3) 400x magnification: sample was observed to be made up of single crystalline particles.

Solubility and Dispersability Test

The sample proved to be insoluble and well dispersed in silicone oil. Therefore, silicone oil was used as the suspension fluid.

Laser Diffraction Particle Size Analysis

Average volume weighted mean was determined to be 58.784 µm.

Average mode was determined to be 99.542 µm.

The Coefficient of Variation (CV) for d50 wass <3%. For d10 and d90 it was <5%. Thus the repeatability of the characteristic particles in the size distribution was within the acceptable limits according to the ISO 13320-1 test standard.

Applicant's summary and conclusion

Conclusions:

Visual examination at 100x magnification showed irregular shaped crystals between approximately 3 µm and 192 µm.
The particle size distribution of T003009 determined by the laser diffraction method led to the conclusion that the average volume weighted mean based on 5 runs was 58.784 µm and the Mass Median Aerodynamic Diameter (MMAD) based on 5 runs was 46.037 µm, whereas the average D10, D50 and the D90 were determined to be 7.391 µm, 40.851 µm and 136.511 µm, respectively.