Chemical Engineering Science 56 (2001) 3575–3584 www.elsevier.nl/locate/ces Development of a prototype capacitive balance for freeze-drying studies Giorgio Rovero, Sabrina Ghio, Antonello A. Barresi * Dip. Scienza dei Materiali e Ingegneria Chimica, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy Received 15 February 2000; accepted 18 January 2001 Abstract A capacitive balance that is able to work in the severe environment of a freeze-drying process has been conceived, constructed and tested. The inuence of temperature variations had to be taken into account: a model of the instrument which makes use of the temperature of several components measured by three thermocouples was developed to correct the frequency signal generated by the device and to convert it into mass; the model parameters were identied by a least-squares method from blank lyophilisation runs. This balance oers the possibility of optimising the freeze-drying process through the accurate investigation of the process kinetics. ? 2001 Elsevier Science Ltd. All rights reserved. Keywords: Instrumentation; Lyophilisation; Process control; Pharmaceuticals; Drying; Balance 1. Introduction Freeze-drying is a process where a solvent is removed from a frozen solution, suspension or cell structure through sublimation. It is widely applied to produce phar- maceuticals since it oers several advantages: the low temperature at which the process is carried out minimises any chemical decomposition and long-term stability of the product can be obtained while the specic structure obtained increases the solubility of the product and its reconstitution rate. Due to the high capital equipment costs and normally long processing time, freeze-drying is frequently regarded as an expensive process. In spite of these well known considerations, it is often not optimised for the maximum production rate. When developing a freeze-drying process the main goal is that of minimis- ing the process time within the constraints imposed by the quality specications of the product. A better under- standing of the process is a fundamental step and kinetics studies are very important to achieve this goal. Mass determination under vacuum is not an easy task; limitations to the operation of some sensors occur and the * Corresponding author. Tel.: +39-011-5644658; fax: +39-011- 5644699. E-mail address: barresi@athena.polito.it (A. A. Barresi). measure is aected by several disturbances, like buoy- ancy eects, vibrations, gas ows, temperature gradients. The eects of these disturbances have been reviewed else- where (Czanderna & Wolsky, 1980) and the character- istics of dierent types of vacuum balances in use are discussed by Robens (1985). Even more dicult is the on-line weigh measurement in a freeze-drying apparatus. Both indirect methods and direct measurements of weight loss vs. time were em- ployed to obtain kinetics data (Bruttini, Rovero, & Baldi, 1991; Liapis, Pikal, & Bruttini, 1996). The sublimation rate of frozen solutions was stud- ied by Pikal, Shah, Senior, and Lang (1983) using an electronic vacuum microbalance as a function of freezing rate, product thickness, temperature, absolute pressure and solute concentration: a cylindrical mi- crosample was isothermally freeze-dried by suspending it from one balance arm. This kind of measurement im- plied a small sample in a capillary tube, where freezing was completed very quickly after the rst ice crystals formed; a slow-freezing process which accurately im- itates vial freezing could probably not occur in that device. It can be concluded that the agreement between the vial and microbalance data remained only qualitative and might become quantitative for some materials, such as in the case where the two operating conditions have 0009-2509/01/$ - see front matter ? 2001 Elsevier Science Ltd. All rights reserved. PII:S0009-2509(01)00025-2