Estapor Microspheres n 11 A technical newsletter published by Merck Chimie SAS - France
The Importance of Quality Methods in the Precise Sizing of Microsphere s Diameter CILAS Richard VIDAL, Cécile GENIES* Jean-Paul DUFOUR, Suzanne DESPORT, Laurent COUVIDAT** * MERCK Chimie, Center Production ESTAPOR, Zone Industrielle, rue du Moulin de la Canne, 45 300 PITHIVIERS ** Compagnie Industrielle des LASers (CILAS), 8, avenue Buffon, La Source, 45 100 ORLEANS Different characterization principles are used to measure the size of polymeric microspheres. Let us first discuss the microscopic techniques that are based on the direct observation of a sample. One method is electronic microscopy that is highly reliable but very expensive. It requires time and specific know-how in the preparation of the sample, thus making the result not immediately accessible. Therefore microscopy for the characterization of size of the particles is not easily applicable for analyses in real time. Principles of analyses known as indirect methods are also available on the market to determine the size of polymeric microspheres. Chromatographic techniques such as Hydro-Dynamic Chromatography (H.D.C.) or Field-Flow Fractionation (FF.F.) which provide a high degree of accuracy, are fast (10 to 15 minutes) and also give additional information like the molecular mass of the polymeric particles... Unfortunately, their utilization can prove to be difficult with problems like the obturation of the columns and disruption of flux, which can penalize their use for analyses in real time. Routinely, granulometric spectroscopy techniques are used. These offer the advantage of being both fast and reliable measurements for the sizing of polymeric microspheres. Taking into account the number of size measurements made daily in the ESTAPOR Laboratory, we decided to implement a strategy of regular metrological controls using a particle-size analyser in order to ensure good reproducibility in measurement. This Quality process was developed utilizing the Compagnie Industrielle des LASers (CILAS), manufacturer of the CILAS 1064 particle-size analyser with diffraction Laser (Figure 1), which is set up in the ESTAPOR laboratory. 9
The resultant factor of variation proved to be very small (less than 4% over one year). We decided it would be wise for us to calibrate the CILAS particle-size analyser each year and in order to control possible drift of measurements, every 6 months we would run a control test utilizing a set of reference quartz crystals provided by the manufacturer. Figure 1 Loading of the microspheres and overall view of CILAS 1064 particle-size analyser. Here we would like to comment on the operating software of this instrument which has the principal qualities of ease of use and user-friendliness. The software directs the operation of the instrument (ultra sonic vessel, Laser beam, pump and valves ensuring the circulation of the sample...) visualized on Figure 2. Figure 2 Graphic of CILAS 1064 particle-size analyser This operation is based on the principle of light diffraction by the particles passing through a Laser beam. The diffracted light is collected by a series of detectors, which transmit a signal proportional to the intensity of the diffracted light. The integration of this signal makes it possible to obtain the result in the shape of a distribution of particles sizes expressed in volume. It is also possible to express the results as a statistical distribution curve or as a number. This instrument, allows the analysis of Estapor microspheres with diameters greater than 0.5 µm. At the time of its installation in 1997, CILAS configured the analyser with specific programs developed for the analysis of polydisperse samples. In order to estimate the variation of the measurments over time, more than 300 samples of microspheres were taken from the various types of ESTAPOR products. Monodisperse standard latexes or monodisperse and polydisperse magnetic latexes, were analyzed and correlated with the results obtained in electronic microscopy. Monthly controls of repeatability were carried out over the period of 1 year. However, a new element recently required us to re-examine our Quality process on this instrument: the arrival on the market of a new generation of CILAS 1064 particle-size analyser, comprising of a technological advancement over the initial instrument set up in our laboratory. Indeed, this instrument integrates new components such as Laser diodes including one with a shorter wavelength allowing for better resolution as well as significant modifications in the matrices of the calculations. These diodes will gradually replace the current one and the configuration of our instrument will thus become obsolete in the short-term. Due to this pending obsolescence, we decided, in close cooperation with CILAS, to carry out a study of interchangeability of the critical components so as to allow us to continue our size measurements without interruption, nor drift. After a critical analysis of the components and a comparative analysis of aspects of the calculation algorithms between the old and new generation of instruments, we launched a study on more than 100 samples representative of the whole Estapor product line. The obtained results showed a very good correlation between the two instruments for monodisperse standard latexes. But, for magnetic latexes, notable variations of measurements were identified, with increasingly important variations as the size of the particles decreased. This variation reached 10% for particles whose diameter was at 0.9 µm and quickly devolved to unacceptable values for the particles of diameters at 0,5 µm. Was this variation dependent on the technological development of the new version of CILAS particle-size analyser or quite simply on a non-homogeneous sampling of magnetic latexes? Magnetic latexes that share their structure of associating a metal core and a polymeric shell, have complex optical properties for which the theory of Mie is not applicable and the approximation of Mie 20 Figure 3 Granulometric distributions of a latex EM1 100/40. 0 0,04 0,1 1,0 X Q 3 (valeurs cumulées) /% 100 80 60 40 20 en volume 0 0,04 0,1 1,0 10,0 100,0 500,0 X (diametres) /µm 10
Your dedicated contacts (law of Fraunhofer) obliges an adapted parameter setting. After a readjustment of the SOP carried out by CILAS and by assuring homogeneous sampling, a series of comparative measurements on 30 samples representative of the various families of magnetic latexes were carried out on the two CILAS particle-size analysers. The superposition of the obtained curves for one magnetic latex, EM1 100/40, is illustrated by the diagram below and representative of the obtained results. The variations in absolute value between the measured sizes on each instrument were gathered in the table below and do not exceed 3% for some of the family of considered latexes. At the end of this last study undertaken in collaboration between Type Mean variation (%) M1 200/20 1.67 EM1 100/40 0.66 EM2 100/40 0.23 M1 070/40 & 070/60 2.75 M1 030/40 1.93 Table 1 Mean variation between the sizes of the families of latex measured with the two CILAS particle-size analysers. The information below provides you with the new phone and fax numbers and email addresses of your dedicated contacts. We will be happy to answer all your questions regarding our range of products and their applications. We also welcome your visit to our technical department and production facility. For Australia, Belgium, Denmark, Finland, France, Ireland, India, Iran, Norway, Sweden, the Netherlands and The United Kingdom please contact at Merck Chimie SAS France. M Salah Azzi - Area Sales Manager Phone : 33 1 4394 5493 - Fax : 33 1 4394 5496 E-mail : salah.azzi@merck.fr For Americas please contact at EMD Biosciences Inc. USA. M Lawrence J. Filipek - Area Sales Manager Phone : 630-355-4075 - Fax : 630-355-4075 E-mail : Lawrence.Filipek@emdbiosciences.com MERCK CHIMIE and CILAS, we developed a policy of predictive maintenance by selecting in a targeted way the subsets or parts defined as critical for the perpetuation of our instrument and subsequently the same for quality of measurement. For further information go to www.estapor.com & www.particle-size-analyser.com Estapor Product catalogue 2004/2005 Estapor has a complete and updated range of microspheres. Ask for your copy to cecile.guignard@merck.fr For Austria, Canada (Quebec), China, Germany, Greece, Hong-Kong, Israel, Italy, Japan*, Portugal, Singapore, Spain, Switzerland, Taiwan and others please contact at Merck Chimie SAS France. M Fabrice Sultan - Sales and Marketing Manager Phone : 33 1 4394 5491 - Fax : 33 1 4394 5496 E-mail : fabrice.sultan@merck.fr * For Japan, we would suggest you contact our local Merck representation (1) or their local distributor (2). 1. MERCK JAPAN Ltd. Arco Tower 5E, 8-1, Shimomeguro 1-Chome Meguro-Ku, Tokyo 153-8927. Tel : (81) 3 5434 4722 - Fax : (81) 3 5434 4706 2. MORITEX CORPORATION- 3-1-14, Jingumae Shibuya-Ku, Tokyo 150-0001. Tel : (81) 3 3401 9711 - Fax : (81) 3401 9791 For further and updated information, please visit our web site at www.estapor.com or www.merck.fr 11
EMD Biosciences Inc., Estapor Microspheres, Division Life Science Products 1658 Apache Dr. Naperville, IL 60563, USA. Phone/Fax: 630-355-4075 E-mail: lawrence.filipek@emdbiosciences.com Web-site: www.estapor.com