(1R,2S,3S,4R)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Particle size distribution (Granulometry)

Administrative data

Endpoint:

particle size distribution (granulometry)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 April 2018 - 07 June 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

ISO 13320 (Particle size analysis - Laser diffraction methods)

Version / remarks:

ISO 13320:2009

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: CIPAC MT 187

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Chilworth Technology Ltd SOP n°417

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:

(2S,3S)-3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]bicyclo[2.2.2]octane-2-carboxylic acid

EC Number:

821-184-6

Cas Number:

1777721-60-4

Molecular formula:

C13H15ClFN3O2

IUPAC Name:

(2S,3S)-3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]bicyclo[2.2.2]octane-2-carboxylic acid

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study reports): JNJ-63757096-AAA (T003689)
- Physical state: solid (powder)
- Appearance: white powder

Specific details on test material used for the study:

- Batch n°: I16ED2695
- Expiration date: 28 May 2018 (retest date)
- Purity: 99.3% (based on UHPLC)
- Storage condition of test material: At room temperature

Results and discussion

Mass median aerodynamic diameter:

304 µm

Geometric standard deviation:

>= 2.011 - <= 2.064

Particle size

Particle size 1

Percentile:

D10

Mean:

90 µm

St. dev.:

2.78

Remarks on result:

other: Average result is calculated from the entirety of data captured in each run and is not a simple arithmetic mean.

Particle size 2

Key result

Percentile:

D50

Mean:

252 µm

St. dev.:

4.52

Remarks on result:

other: Average result is calculated from the entirety of data captured in each run and is not a simple arithmetic mean.

Particle size 3

Percentile:

D90

Mean:

444 µm

St. dev.:

6.15

Remarks on result:

other: Average result is calculated from the entirety of data captured in each run and is not a simple arithmetic mean.

Any other information on results incl. tables

Visual Microscope Analysis

(1) Standard visual observation: sample observed to be a coarse, gritty, free flowing white powder.

(2) 10 objective lens: particles appeared to be irregular shaped crystals with some agglomerations present (smallest +/- 10 µm and largest +/- 480 µm).

(3) 40 objective lens: sample was observed to be made up of single crystalline particles.

Solubility and Dispersability Test

The sample was well dispersed in both silicone oil and sunflower oil. Both solvents were tested as dispersant with sunflower oil selected as the final disperant.

Laser Diffraction Particle Size Analysis

Using the identified parameters, the particle size was analysed over the range 0.01 µm to 3500 µm.

The average Volume weighted Mean was 261 µm and the mode was 301 µm. The Coefficient of Variation for d50 was <3%; d10 and d90 were <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:

Observation using 10 objective lens showed irregular shaped crystals (between approximately 10 µm and 480 µm) with some agglomeration.
The particle size distribution of T003689 determined by the laser diffraction method led to the conclusion that the average volume weighted mean based on 5 runs was 261 µm and the Mass Median Aerodynamic Diameter (MMAD) based on 5 runs was 304 µm, whereas the average D10, D50 and the D90 were determined to be 90 µm, 252 µm and 444 µm, respectively.