# REPORT

DETERMINATION OF THE PARTICLE SIZE DISTRIBUTION OF TKA 40278 (CGI 827) Data Requirement / Test Guidelines: European Commission, ECB/TM/February 1996 Study Director: Mrs. Alessandra Tognucci Stud Corn letion Date: March 07, 2003
TestFacility: RCC Ltd Environmental Chemistry & Pharmanalytics CH-4452 Itingen/Switzerland

ClBA SPECIALTY CHEMICALS INC. CH - 4002 Basel/Switzerland RCC Stud Number: 845429 Page I of 16



### 272RCC Study Number 845429 REPORT Page 2

TKA 40278 (CGI 827) 

# GLP CERTIFICATE

The Swiss GLP Monitoring Authorities


#  ̄ Statement of GLP Compliance

It is hereby confirmed that dudng the pedod of
the following Test Facilitiesof August15-17,2000 -.August-28-29 ̄,2001 and. .... Apd115,2002 ’ "



### .....RCC Ltd ..... 4452 Itingen Switzerland were Inspected by the Federal Office of Public Health, the Swiss Agency for the Environment, Forests and Landscape and the Intercentonal Office for the Control of Medicines with respect to the compliance with the Swiss legislation on Good Laboratory Practice. Test Facilities areas of expertise* - Toxicology Division

-Environmental Chemistry and Pharmsnalytics Diyis|on

-Microbiological Diagnostics by Biotechnology & Animal Breeding Division TOX, ACC, MUT ACC, ECT, ENF, EMN, PCT, RES,OTH (Animal metabolism) OTH (Microbiology) The inspection was performed in agreement with the OECD Guidelines ~or National GLP Inspections and Audits. It was found that the aforementioned test facilities were operating tn compliance with the Swiss Ordinance relat ng to Good Laboratory Practice [RS 813.016.5] at the time they were Inspected. Federat Office of Public Health The Director

Bern, May 2002 Prof. Th. Zeitner
 ̄ TOX = Tox~cok~y ; ACC = Analy~ca} end Clinical Chernlsky ; ECT = Environmental toxlc~ on ~quat~c and teuestdal


### 273RCC Study Number 845429 REPORT Page 8

TKA 40278 (CGI 827) 

### GOOD LABORATORY PRACTICE 

# STATEMENT OF COMPLIANCE
RCC Study Number: Test Item: Study Director: Title: 845429 TKA 40278 (CGI 827) Mrs. Alessandra Tognucci Determination of the Particle of TKA 40278 (CGI 827) Size Distribution
This study was conducted in compliance with the Swiss Ordinance relating to Good Laboratory Practice, adopted February 2r~,2000 [RS 813.016.5]. This Ordinance is based on the OECD Principles of Good Laboratory Practice, as revised in 1997 and adopted November 26th,1997 by decision of the OECD Council [C(97) 186/Final]. The purity of the test item is excluded from the statement of compliance (purity available in Analytical Certificate No. 14026512-1; Ciba Specialty Chemicals Inc.).

Study Director: Tognucci

274RCC Study Number 845429 REPORT Page 4

TKA 40278 (CGI 827) 

# SIGNATURES

Study Director:

Management: 

### Dr. JSrn SchreitmQller

275Rcc Study Number 845429 REPORT Page 5

TKA 40278 (CGI 827) 

# QUALITY ASSURANCE UNIT RCC Ltd, Environmental Chemistry & Pharmanalytics, CH-4452 Itingen / Switzerland
STATEMENT 

### RCC Study Number: Test Item: Study Director: Title: 845429 TKA 40278 (CGI 827) Mrs. Alessandra Tognucci Determination of the of TKA 40278 (CGI 827) 

### Particle Size Distribution The general facilities and activities are inspected periodically and the results are reported to the responsible person and the management. Study procedures were periodically inspected. The study plan and this report were audited by the Quality Assurance Unit. The dates are given below: Dates and Types of QAU Inspections Dates of Reports to the Study Director and to the Management September 16, 2002 Study Plan September16,2002 

### January 29, 2003 Process based January 29, 2003



### (Measurement) February 28, 2003 Final report February 28, 2003 

### This statement also confirms that this finalreport

### reflects the raw data. Quality Assurance: Mrs. Diana B(~rgin

276RCCStudy Number 845429 REPORT Page 6

TKA 40278 (CG1827) 

# CERTIFICATION OF GLP AND VERIFICATION OF THE REPORT

The statement of Compliance with Good Laboratory Practice found in this report, and signed by the Study Director is truthful and accurate, and this report as provided by the testing facility is complete and unaltered.

Signature of the Sponsor:

Date:



### 277RCC Study Number 845429REPORTPage 7

_TKA 40278 (CGI.___.827) 

# CONTENTS
.2 GLP CERTIFICATE .............................................................. STATEMENT OF COMPL ANCE ................................. " .................... 3 4 SIGNATURES ...................................................... ’ ’" QUALITY ASSURANCE UN T ..................................................................... CERTIFICATION OF GLP ........................................................ 6 AND VERIFICATION OF THE REPORT .................................................................... CONTENTS ............................................................... PREFACE ............................................................. " .......................... 8 9 DATA REQUIREMENT / TEST GUIDELINES ............................................. SUMMARY OF STUDY PLAN AMENDMENTS .............................................................. 9
1 PURPOSE ........................................................................................................... 10
2 MATERIAL AND METHODS ................................................................................ 10 2.1 TEST TEM ............ " ......10 2.2 PRINCIPLE OF THE TEST ........................................................................ 10 2.3 PERFORMANCE OF THE TEST.....~ .......................................................... 11 2.3.1 V~sua Exam nat on ..................................... 11 ..11 2.3.2 Test System ............................................................ 2.3.3 Preliminary Study .......................................................................... 11 2.3.3 Main Study .................................................................................... 11 2.4 DATA HANDLING ...................................................................................... 12 3 RESULTS .................................................. ’ ........................... 13 Table 1: Particle size distribution of TKA 40278 (CGI 827) ....................................... 14 Table 2: Particle size distribution of TKA 40278 (CGI 827) in % at the relevant

partcesze ....................................... Figure 1 : Particle size distribution curve of TKA 40278 (CGI 827) (1. Run) ............... 16



### 278RCCStudy Number845429 REPORT Page 8

TKA 40278 (CGI 827) 

# PREFACE
GENERAL Title: 

### Sponsor: Monitoring Scientist: Test Facility: Determination of theParticle Size Distribution of TKA 40278 (CGI 827) CIBA SPECIALTY CHEMICALS iNC. CH-4002 Basel/Switzerland Dr. Moung Sook Lee RCC Ltd Environmental Chemistry & Pharmanalytics Zelgliweg 1 CH-4452 Itingen!Switzerland

RESPONSIBILITIES Study Director: Deputy Study Director: Technical Coordinator: Reporting: Head of RCC Quality Assurance: 

### Mrs. Alessandra Tognucci Dr. Ute Schmiedel Mrs. Jos~e Gustaw, Mr. Christoph Wild Mrs. Miriam Weissenfeld Mrs. Iris WOthrich

SCHEDULE Experimental starting date: Experimental completion date: Study completion date: January 23,2003 January 24,2003 March 07,2003/wei



### ARCHIVING RCC Ltd, CH-4452 Itingen/Switzerland will retain the study plan, raw data, a sample of test item and the final report of the present study for at least ten years. No data will be discarded without the sponsor’s consent.

279RCCStudy Number 845429 REPORT Page9

TKA 40278 (CGI 827) 

# DATA REQUIREMENT / TEST GUIDELINES
This study followed the procedures indicated by the following internationally accepted guidelines and recommendations: EUROPEAN COMMISSION, Directorate General XII-JRC, Science Research and Development-Joint Research Centre. "Particle Size Distribution, Fibre Length and Diameter Distribution" Guidance Document, ECBFFM/February 1996.



# SUMMARY OF STUDY PLAN AMENDMENTS
First Amendment to Study Plan: Concerning: Alteration: Reason for Alteration: Schedule

New experimental starting and completion date Delay in study



### 280RCCStudy Number 845429 REPORT Page 10

TKA 40278 (CGI 827) 

# 1 PURPOSE
The purpose of the study was to determine the particle size distribution of TKA 40278 (CGI 827).


# 2 MATERIAL AND METHODS
2.1 TEST ITEM Data of test item as supplied by the sponsor. Identity: Product Name: Batch: Purity: Appearance: Expiration date: Storage: TKA 40278 CGI 827 KL 01/02 See Analytical Certificate, Study No. 14026512-1 Ciba Specialty Chemicals Inc Solid, slightly yellow August 30, 2004 At room temperature at about 20 °C. The test item is light sensitive.



### 2.2 PRINCIPLE OF THE TEST The above mentioned guideline contains several different methods for the determination of the particle size distribution. These methods include sieving, microscopic examination, sedimentation, gravitational settling examination, cascade impaction and laser scattering / diffraction method. In the present study the laser scattering / diffraction was applied.

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TKA 40278 (CGI 827) 

## 2.3 PERFORMANCE OF THE TEST 2.3.1 Visual Examination Visual examinations were performed macroscopically and microscopically under magnification of 400, using a light microscope LEITZ, DIALUX 20, to judge the colour and the structure of the test item. For the examination under the microscope, the test item was dispersed in white spirit containing Sympatens SHO/400, placed on a slide and covered with a second slide. Details are part of the raw data and are given later in this report. 2.3.2 Test System Particle size analyser Instrument:

Particle size range: Test item dispersion: 

### "Analysette 22" COMPACT, Fritsch GmbH using a micro dispersing apparatus. The laser diffraction apparatus was checked at the beginning of the measurement using a Fritsch standard sample. The results measured are within the limits given by Fritsch. Details are not reported here but are part of the raw data. 0.3 - 300 pm 

### The test item was dispersed in white spirit containing Sympatens SHO/400 at room temperature. The mixture was ultrasonificated for 15 minutes before use.
2.3.3 Preliminary Study A solubility test was performed to choose a suitable dispersing agent. For this test it is required that the test item be both: sparingly soluble and well dispersible in the solvent. During the solubility test, white spirit containing Sympatens SHO/400 was selected as an appropriate dispersing agent for this study. A pre-saturated test item solution was prepared by transferring 0.20 g of the test item to an Erlenmeyer flask.by bringing up the volume to 1 I with white spirit and adding one drop Sympatens SHO/400. This mixture was stirred for 2 hours at room temperature and filtered with a 0.45 pm filter before use. The pre-saturated white spirit solution was used to prepare a stock dispersion (0.2 g of the test item were mixed with 10 ml pre-saturated white spirit) and for the measurement of the background of the laser diffraction apparatus. 2.3.3 Main Study The dispersing apparatus was rinsed and filled with pre-saturated white spirit. A few ml of the stock dispersion were added slowly until the absorption of the laser was reduced by about 10 %. The particle size distribution in the suspension was quantified by laser diffraction. The test was performed with two samples of the stock dispersion and each measured in duplicate. Details are part of the raw data and are summarised in Table 1 and 2.
282RCC Study Number 845429 REPORT Page 12

TKA 40278 (CGI 827) 

## 2.4 DATA HANDLING A particle size distribution curve was prepared in the range between 0.3 I~m and 300 pm. The mass median diameter (MMD) of TKA 40278 (CGI 827), which is the particle size (pm), not exceeded by 50 % of the particles was calculated. In other words, the size of 50 % of the particles are smaller than the determined value and also, that 50 % of the total sample mass is presented in particles having a diameter larger than the determined value.

283RCC StudyNumber 845429 REPORT Page 13

TKA 40278 (CGI 827) 

# 3 RESULTS
The determination of the particle size distribution of TKA 40278 (CGI 827) was performed according to the European Commission, Document ECB/TM/February 1996: "Particle Size Distribution, Fibre Length and Diameter Distribution" Guidance Document using the laser diffraction method. TKA 40278 (CGI 827) is a light beige granular powder. Under the microscope (with a magnification of 400) elongated, squared, colourless, crystalline structures were observed. A solubility test showed, that the test item is both: sparingly soluble and well dispersible in white spirit containing Sympatens SHO/400. The particle size distribution of TKA 40278 (CGI 827) was performed with two samples of the stock dispersion one measured in duplicate. The individual measurements and the results obtained using the laser diffraction of TKA 40278 (CGI 827) are summarised in Table 1 and Table 2. The tables represent rounded results obtained by using the exact measurement data. An example of the particle size distribution curve is shown in Figure 1. The results obtained during the measurements showed no relevant difference. The MMD mean value of 16.8 pm with a standard deviation of+0.05 pm is given in Table 1. The standard deviation is smaller than 5 % therefore the study is considered to be valid and no further testing is necessary. In conclusion using alaser diffraction apparatus to study the particle size of TKA 40278 (CGI 827) in the range between 0.3 pm and 300 pm the mass median diameter (MMD) was determined to be 16.8 pm. The particle size distribution was found to range from approximately 0.3 I~m to 35 pm.

284RCC Study Number 845429 REPORT Page 14

TKA 40278 (CG1827) 

### Table 1 : Particle size distribution of TKA 40278 (CGI 827)
1. Run 2. Run 3. Run mean Stand. ParticleParticle ~article Particle Dev. Size Size Size Size 

### % pm pm IJm pm [±] 5 < 1.82 < 1.80 < 2.01 < 1.9 0.116 10 < 4.95 <5.11 < 4.73 < 4.9 0.191 50 < 16.80 < 16.90 < 16.82 < 16.8" 0.053 9O < 25.21 < 25.08 < 27.53 < 25.9 1.379 *) The MMD of the test item indicates that 50 % of the particles are smaller than 16.8 pm.



### 285RCC Study Number 845429 REPORT Page 18

TKA 40278 (CGI 827) 

### Table 2: Particle size distribution of TKA 40278 (CGI 827) in % at the relevant particle size

1. Run 2. Run 3. Run Mean Stand. pm 

### Dev.

% % % % < 0.3 < 0.5 0,37 0.45 0.29 0.37 

### 0.08 < 1.0 2.29 2.49 2.27 0.24 < 2.0 5.47 

### 5.47 4.98 

### 5.31 0.28 < 3.0 7.44 7.34 6.99 7.26 

### 0.24 < 4.0 8.85 8.72 

### 8.74 8.77 0.07 

### < 5.0 10.06 9.88 10.46 10.13 0.30 < 6.0 

### 11.21 10.92 12.20 

### 11.44 0.67 

### < 7.0 12.40 

### 11.96 14.05 12.80 1.10 

### < 8.0 13.77 13,16 

### 16.10 14.34 

### 1.55 < 9.0 

### 15.48 14.69 18.46 16.21 1.99 

### < 10.0 17.74 16.77 21.24 

### 18.58 2.35 < 11.0 20.68 19.58 24.47 21.58 2.57 < 12.0 24.33 23.17 28.12 25.21 2.59 < 13.0 28,61 27.43 32.13 29.39 2.45 < 14.0 33.64 32.54 36.53 34.24 2.06 

### < 15.0 39.24 38.27 

### 41.19 39.57 

### 1.49 < 16.0 45.07 44.26 45.97 

### 45.10 0.86 < 17.0 51.22 

### 50.61 50.87 

### 50.90 0.31 < 18.0 57.31 56,90 55.73 56.65 0.82 < 19,0 

### 63.15 62.93 60.44 62.17 

### 1.51 < 20.0 68.92 68.87 

### 65.11 67.63 

### 2.19 < 22.0 78.73 

### 78.91 73.49 77.04 3.08 < 24.0 86.18 86.45 80.49 84.37 3.37 < 26.0 

### 91.71 91.98 86,22 89.97 3,25 < 28.0 95,80 96.02 90.96 94.26 2.86 < 30.0 97.93 98.08 

### 94.11 96.71 2.25 < 35.0 

### 100.0o 100.00 98.95 99.65 

### 0.61 < 40.0 100.00 100.00 100.00 100.00 0.00 < 45.0 100.00 100,00 100.00 100.00 0.00 < 50.0 100.00 100.00 100.00 I00.00 0.00 286RCC Study Number 845429 REPORT Page 16

TKA 40278 (CGI 827) 

### Figure 1: Particle size distribution curve of TKA 40278 (CGI 827) (1. Run)

FRITSCH PARTICLE SIZER A N A L Y S E T T E 2 ? RCC ~d, 

### 13 I 01-24.2003 112:181 RCC Study No 845429 ’TKA 40278 (CG1827) ’In Petroleumbenzin (60-80°C) ’RCC No 128115 / Batch KL 01/02 ’l.Zugabe. 1. Msssung ~4.01.2003 I UserlD LAB/22 ISarN°" SN3165I

Me~3berelch 0.31 [,um] - 300.74 [pm] Pumpe 100 [rpm] Aufl5sung 62 MeSkan&le ( 17 mm/ 114 mm ) ROhrer 2 [rpm] Absorption 7.00 [%] Ultraschall 0 Dauerder Messung 12 [Scans] Mo<:le]l Independant Fraunhofer Berechnung aktiv. Inte rpolationswerte... C:XA22WlN~RITSC Hk03_50.FPS ****** % < 0.80 ,urn 0.37 % < 0.50 ,urn 2.29 % < 1,00 ,urn 5.47 % < 2.00 pm 7.44 % < 3.00 pm 8.85 % < 4,00 .urn 10,06%< 5.00 pm 11~21%< 6.00 #m 12.40%< 7,00 ,urn 13.77%< 8.00 pm 15.48%,< 9.00 pm 17,74%< 10.00 pm 20.68%< 11,00 ,urn 24,33%< 12,00pm 28,61%< 18.00 pm 33,64%< 14.00 .urn 89.24%< 15.00,urn 45.07%< 16.00 pm 81.22%< 17.00 pm 57,31%< 18.00pm 63.15%< 19,00 pm 68,92%< 20,00 pm 78.73%< 22.00pm " 86,18%< 24,00 ,urn 91,71%< 26,00 .urn 95.80%< 28,00pm 97,93%< 30.00 pm 100.00’/o < 35,00 pm 100.00% < 40.00pm 100.00% < 45.00 ,urn 100.00’~ < 50,00 pm Interpolationswerte_. C:~,22WIN~RITSCH~5_90PERC.FPV 5.00%< 1.82 pm 10,00%< 4,95 ,urn 50,00%< 16.80 .um 90,00% <25.21 pm

lOO 9o 8o 7o OO 5o 4o 3o lO o 

### 287 2O 18 18 14 12 10 8 4 2 0 

## ~’oo mOO tp.m]