Nucleation freeze-drying

In precipitation reactions, powder characteristics depend on the speed of the nucleation of particles and their growth due to the mass flow to the surfaces. In freeze drying and spray drying, powder characteristics primarily depend on the size of droplets, which in turn is determined by the parameters of a nozzle and characteristics of the flow of a carrier gas. Both these methods enable one to obtain powders with very high surface area. 

J. Hallet, Nucleation and growth of the ice crystals. Advances in Freeze-Drying. Her-man-Verlag, Paris, 1966, pp. 21-38. 

Figure lb Electron micrograph of a 20% KCl solution after rapid quenching to —150°C and freeze-drying at —70°C. Note the radial crystallisation pattern, originating from the nucleation site at the centre of the picture. Modified from MacKenzie ... 

In the following discussion, emphasis is placed on the classes of solutes that are of importance in pharmaceutical freeze-drying they include salts and some water-soluble organic compounds, specifically those that can act as hydrogen-bond donors and/or acceptors. As shown in Figure 10, solutes exert a major influence on ice nucleation and, hence, also on ice crystallisation rates and crystal habits. An additional factor to be taken into account is the fate of the solutes during freeze-concentration. 

Geidobler R, Winter G (2013) Controlled ice nucleation in the field of freeze-drying Fundamentals and technology review. Eur J Pharm Biopharm 85 214—222... 

J Hallet. Nucleation and growth of ice crystals. In L Rey, ed. Advances in Freeze-drying Lyophilisation. Paris Hermann, 1966, p 33. 

It is well accepted that containers housing product temperature probes are uncharacteristic of the containers that do not have probes nucleation is enhanced by the heterogeneous surface introduced by the probe [20] and the probe leads present a heat source. Probes in containers cannot be used as an absolute indication of the conditions occurring in those containers without a probe during a freeze-drying run and should be regarded as a source of information and not used to control the system. For the processing of infectious materials probes are not included due to decontamination concerns. 

Figure 9 Freeze-drying profile showing product probe signal response due to the occurrence of ice nucleation compared to shelf temperature.

Several techniques to determine experimentally the values of the freeze-dried cake mass transfer resistance, Rp, have been reported in the literature (Pikal, 1985 Patapoff et al., 1999). They were all based on the gravimetric method used either for a single vial or for a limited number of vials. In contrast to such methods, the estimation of Rp values from the P RA model allows the determination of the mean freeze-dried product mass transfer resistance for the whole vial batch, averaging the heterogeneities of the cake structures between individual vials generated by the random nucleation phenomena. As shown in Fig. 3.6, a typical set of Rp values identified by the PRA model by... 

Different methods can be implemented for triggering the nucleation process and reducing the effect of the rather broad distribution of spontaneous nucleation temperature whitdi is one of the main causes of vial-to-vial variation of ice morphology and, consequently, of the distribution of drying times and of distributed morphology parameters in the freeze-dried product. 

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