Control of the Primary Drying

As stated in the introduction, the control of a freeze-drying process, with the goal to reduce the time required to reach the desired amount of residual solvent, is a challenging task due to the impossibility of measuring in-line the variables of interest, that is, the product temperature and the residual solvent content 

The main drawback of all these model-based algorithms is that they require that the model describes perfectly the dynamics of the process and that all the parameters and all the variables of the process are known. As this seldom happens, it is necessary to use one of the techniques described in Section 4.3 to monitor the primary drying in order to know the value of the temperature of the product, that is the controlled variable, and, thus, to calculate the control action. 

The first automatic control systems proposed date back to the early 1960s, and were based either on the barometric temperature measurement of the batch or on the monitoring of the resistivity of one or more sampled vials. Even if they had many limitations, and up to recent times were never really applied in industrial applications, especially those of the second kind, they introduced the concept of modem closed-loop control, and some control strategies that are still vahd (Nail and Gatlin, 1985 Jennings, 1999). 

A simple control system for the shelf temperature based on the BTM output was first proposed by Neumarm (1961) and then described by Oetjen et al. (1962). Neumann (1963) later proposed a simple control system where chamber pressure is manipulated in order to maintain the product at the desired temperature this was obtained either by means of a throttling valve cormecting the chamber to the 

In a patent by Lambert and Wang (2003) it is proposed to monitor in-line the cake resistance by inserting a tube in some vials and measuring the pressure drop of an inert gas it is suggested that the results from the measuring system are used to provide a control signal to a control system, but it seems difficult to really apply the proposed method, even in a laboratory apparatus. 

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N. Daraoui, P. Dufour, H. Hammouri 2007 Model predictive control of the primary drying stage of a freeze drying of solutions in vials a apphcation of the MPC CB software (part 1). The 5th Asia-Pacific Drying Conference, Hong Kong, China, 2 883-888. 

Sadikoglu, H., Ozdemir, M., Seker, M., 2003. Optimal control of the primary drying stage of freeze drying of solutions in vials using variational calculus. Drying Technol. 21 1307-1331. 

In practice, at the beginning of the primary drying stage, more than 90% of the water in the initial solution has frozen. The ice is then removed by sublimation. Unlike the freezing process, ice sublimation is amenable to some measure of control. The heat flow to the ice front must be adjusted to balance exactly the heat absorbed by the sublimation of ice at the operating temperature of sublimation. In this chapter, we discuss the contributing mechanisms by which heat is transferred from the shelves of the freeze-drier to the ice front and the mechanisms by which water vapour is transferred to the condenser (mass transfer), and their relative contributions to the overall sublimation process. 

H Sadikoglu. Dynamic modeling and optimal control of the primary and secondary drying stages of freeze drying of solutions in trays and vials. PhD dissertation. University of Missouri-Rolla, Rolla, MO, 1998. 

Consequently, the PRA method for non-invasive temperature estimation seems to be quite reliable during the first half of the primary drying period and thus allows an efficient on-line and in situ control of the mean product temperature. Nevertheless, due to possible reduction in the sublimation surface at the end of the primary drying period, all the models tend to underestimate the sublimation temperature so that, for thermosensible products like therapeutic proteins, extreme caution should be taken when using this method during this primary drying end period. 

Each spray-dried droplet forms a single particle whose size is determined by the droplet size, the dissolved solids of the feed solution, and the density of the resulting solid particle. For a given formulation and process, both the solid content and density of the powder remain constant within a batch and from batch to batch therefore, the distribution of the primary particle size is determined by the droplet size distribution. A narrowly distributed particle size can be achieved with a well-designed atomizer and controlled process parameters. 

Sections (4 xm thick) of formalin-fixed and paraffin-embedded ovarian tissue are mounted on silane-coated slides and air-dried for 24hr at 3°C (Davidson et al., 2000). They are deparaffinized, rehydrated, placed in 0.01 M sodium citrate buffer (pH 6.0), and heated twice for 5 min each in a microwave oven. 2H5 antibody (PharMingen, Becton Dickinson, San Jose, CA) is used at a concentration of 2 p,g/ml to detect sialyl Lex antigen. Staining is performed with labeled avidin-biotin. Negative controls consist of the exclusion of the primary antibody, while positive controls consist of carcinomas that have been shown to be immunoreactive for the antigen in earlier studies. 

If skin is placed in a water bath under controlled conditions [14] the primary barrier to transdermal delivery, the epidermal membrane comprising the stratum corneum and viable epidermis, can be readily removed and used to analyze the penetration and diffusion of materials. Figure 18.3a and Figure 18.3b show the appearance of human breast epidermal membrane, with epidermis facing uppermost, following application of the cylindrical dry-etch and pyramidal wet-etch silicon microneedles, respectively. In each case the microneedles are clearly shown to pierce the stratum corneum and viable epidermis to facilitate controlled access of molecules to the target region of skin. 

Searles, J.A., Carpenter, J.F., Randolph, T.W. The ice nucleation temperature determines the primary drying rate of lyophilization for samples frozen on a temperature-controlled shelf. PDAJ. Pharm. Sci. Technol. 90, 860-871, 2001... 

The next stage in processing ceramic films from solutions is the development of structure. There are two types of structure development to consider (1) the structure of the primary aggregate or polymer, and (2) the structure that develops upon gelation. It is possible to control both t5T)es of structure development through the chemistry of the precursor solutions. The control of structure is essential to the final microstructure of the dried gel. 

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