Influence of controlled nucleation by ultrasounds on ice morphology of frozen formulations for pharmaceutical proteins freeze-drying

Nakagawa, Kyuya; Hottot, Aurélie; Vessot, Séverine; Andrieu, Julien

doi:10.1016/j.cep.2006.03.007

Cited by 137 publications

(68 citation statements)

References 13 publications

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“…After freeze drying, the former sample was found to have larger pores than the latter. Nakagawa et al 141 reported the influence of controlled nucleation by US on the ice morphology of a frozen formulation of pharmaceutical proteins prior to freeze drying. The US treatment increased the temperature of nucleation; consequently, the mean ice crystal diameter was augmented and the primary freeze drying rate was accelerated.…”

Section: Applications Of Afps In Food Technology and Perspectivesmentioning

confidence: 98%

Ice Morphology: Fundamentals and Technological Applications in Foods

2009

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Freezing is the process of ice crystallization from supercooled water. Ice crystal morphology plays an important role in the textural and physical properties of frozen and frozen-thawed foods and in processes such as freeze drying, freeze concentration, and freeze texturization. Size and location of ice crystals are key in the quality of thawed tissue products. In ice cream, smaller ice crystals are preferred because large crystals results in an icy texture. In freeze drying, ice morphology influences the rate of sublimation and several morphological characteristics of the freeze-dried matrix as well as the biological activity of components (e.g., in pharmaceuticals). In freeze concentration, ice morphology influences the efficiency of separation of ice crystals from the concentrated solution. The cooling rate has been the most common variable controlling ice morphology in frozen and partly frozen systems. However, several new approaches show promise in controlling nucleation (consequently, ice morphology), among them are the use of ice nucleation agents, antifreeze proteins, ultrasound, and high pressure. This paper summarizes the fundamentals of freezing, methods of observation and measurement of ice morphology, and the role of ice morphology in technological applications.

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Section: Applications Of Afps In Food Technology and Perspectivesmentioning

confidence: 98%

Ice Morphology: Fundamentals and Technological Applications in Foods

2009

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“…335 It should be noted that the size and homogeneity of ice crystals will differ signifi cantly, depending on the type and concentration of other additives present in the protein solution. 338 On the other hand, a lower freezing rate may facilitate crystallization of other solution components, promoting potential crystallization -induced protein aggregation. 339 Freezing -induced pH change is another major cause for protein aggregation due to selective crystallization of certain buffering species.…”

Section: Freeze -Thawmentioning

confidence: 99%

External Factors Affecting Protein Aggregation

Wang

Speaker

2010

Aggregation of Therapeutic Proteins

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The behavior of biotherapeutic proteins is signifi cantly different from small molecule drugs both in liquid and solid states, especially in terms of physical stability. One such property is the high tendency of protein molecules to aggregate under a variety of conditions. The aggregation tendency is arguably the most common and troubling manifestation of protein instability during the development of protein biotherapeutics. 1 Protein aggregates usually exhibit either reduced or, in many cases, no biological activity. 2 -5 A clear correlation was established between loss of recombinant factor VIII (rFVIII ) and its degree of aggregation as shown in Fig. 4.1 . 6 To achieve effective prevention or inhibition of protein aggregation, it is of paramount importance to understand all the possible factors that affect or control the protein aggregation process.Many factors have been identifi ed and reported in the literature affecting the process and rate of protein aggregation. These factors can be roughly divided into two major categories: internal (protein structure related) and external (protein environment related). Chapter 3 in this book has focused extensively on factors that belong to the fi rst category. This chapter focuses on the external factors that affect the process and rate of protein aggregation. To facilitate discussion, these external factors are further divided into the following sections: (1) temperature; (2) solution conditions and composition (pH, buffer type and concentration, ionic strength, excipients and level, protein concentration, metal ions, denaturing and reducing agents, impurities, organic solvents, containers/closures, sources of proteins, sample treatment, and analytical methodologies); (3) processing steps (fermentation/expression,

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“…Recently, various methods (alternative to the shelf-ramped freezing) have been proposed to make this process less unpredictable [3][4][5][6][7][8][9][10][11][12][13][14]. Among these include the following: electrofreezing [4], ultrasound [5][6][7][8], depressurization method [9] and ice fog technique [10][11]. All these methods were found to give a dramatic reduction in cycle duration and improve the homogeneity of the batch as a whole, thus ensuring similar product characteristics in all the vials of the batch.…”

Section: Introductionmentioning

confidence: 99%

Impact of vacuum-induced surface freezing on inter- and intra-vial heterogeneity

Oddone

Bockstal

Beer

et al. 2016

European Journal of Pharmaceutics and Biopharmaceutics

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This paper aims to study the impact of freezing on both within-batch (inter-vial) and withinproduct (intra-vial) heterogeneity. This analysis has been carried out using two freezing protocols, the conventional shelf-ramped method and the Vacuum Induced Surface Freezing, and placebo formulations containing both crystallizing (mannitol) and amorphous (lactose and sucrose) excipients. The freezing conditions (i.e., the temperature of freezing, the temperature and time of the equilibration phase, and the filling volume) were found to have a dramatic impact on both the within-batch and the within-product homogeneity. Overall, we observed that the control of freezing can effectively minimize the variability in product characteristics, and moisture content, within the same batch. In addition to more uniform production, the control of freezing was found to be fundamental to achieve a more uniform product than that produced by the shelf-ramped freezing method. The influence of the freezing protocol on the crystallization process of mannitol was also investigated, showing that the temperature of freezing plays a key role in the formation of the mannitol polymorphs. Chemical compounds studied in this articleMannitol (PubChem CID: 96011), Lactose (PubChem CID: 6134), Sucrose (PubChem CID: 5988).

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Influence of controlled nucleation by ultrasounds on ice morphology of frozen formulations for pharmaceutical proteins freeze-drying

Cited by 137 publications

References 13 publications

Ice Morphology: Fundamentals and Technological Applications in Foods

Ice Morphology: Fundamentals and Technological Applications in Foods

External Factors Affecting Protein Aggregation

Impact of vacuum-induced surface freezing on inter- and intra-vial heterogeneity

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