Freeze-dried formulations

712 injection, powder, lyophilized, for suspension, extended release. 

Shelf-life specifications of a suspension dosage form include redispersabihty upon storage. However, there is no official method to test this, and most manufacturers design their own methods, chiefly requiring some t q)e of subjective shaking. The stability of the suspensions is partly dependent on the particle size in suspension. This can be measured using techniques, such as laser diffraction or Malvern Mastersize (19). As the stabilized suspension is mostly in a flocculated form due to the electrolytes added to it, it may be necessary to apply sonification in the study of particle sizes. 

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Vromans, H., Schalks, E. J. M. Comparative and predictive evaluation of the stability of different freeze dried formulations containing an amorphous, moisture-sensitive ingredient. Drug Dev. Ind. Pharm., 20 (5), p. 757-768, 1994... 

Pikal, M. J., Dellermann, K., Roy, M. L Formulation and stability of freeze-dried proteins Effects of moisture and oxygen on the freeze-dried formulation of human growth hormones. Developments in Biological Standardization, Vol. 74, p. 21-38. Acting Editors Joan C. May - F. Brown. S. Karger AG, CH-4009 Basel (Switzerland), 1992... 

Chang, B.S., G. Reeder, and J.F. Carpenter, Development of a stable freeze-dried formulation of recombinant human interleukin-1 receptor antagonist. Pharm Res, 1996.13(2) 243-9. 

While formulation of proteins in solution or suspension are less costly to produce, not all therapeutic proteins can be stably stored in solution or suspension, even when refrigerated (4°C) or frozen (-20°C). In those cases freeze-dried formulations of proteins may be used as an alternative. Freeze-drying or lyophifization typically produces an amorphous form of... 

There are no published studies which examine the significance of pH shifts on quality attributes of freeze-dried formulations of small molecules. However, Costantino et al. (14) reported that lyophilized organic compounds containing protein functional groups (amino-, carboxylic-, and phenolic-) exhibit pH memory that is, the ionization state of the solid, as reflected by the FTIR spectrum, is similar to that of the aqueous solution from which the compound was freeze dried. 

Of course, it is common (and often desireable) to have both amorphous and crystalline phases present in a freeze-dried formulation. This is particularly relevant to freeze-dried proteins, where the lyoprotectant is present in the amorphous state, and another component, such as glycine or mannitol, is present as a crystalline solid in order to impart mechanical integrity and pharmaceutical elegance to the lyophilized solid. 

Kett et al. [1.162] studied Tg in freeze-dried formulations containing sucrose as a function of relative humidity and temperature during storage by TMDSC and ther-mogravimetric analysis. Craig et al. [1.163] found it helpful to asses the relaxation behavior of freeze-dried amorphous lactose by MTDSC. Relaxation times were calculated from measurements of Tg, and the magnitude of the relaxation endotherm. Scannnig was performed at 2°C/min with a modulation amplitude of 0.3 °C and a period of 60 s. 

Kett, V.L., Craig, D.Q.M., Deutsch, D. Thermal analzsis of freeze-dried formulations. In Proc.NATAS Annu. Conf. Thermal Anal. Appl., 27th, pp. 618-623,... 

Fernandez-Urrusuno et al. [30] reported on development of a freeze-dried formulation of CT/TPP nanoparticles loaded with insulin. They tested various cry-protective agents for their ability to maintain the original size/charge of particles upon reconstitution. The best medium appeared to be 5 % trehalose or sucrose. This was confirmed with unloaded nanoparticles from System 2 (Fig. 16). The original suspension, without the trehalose addition, exhibited a size of 185 nm (SD 25 nm). 

Fernandez-Urrusuno R, Romani D, Calvo P, Vila-Jato JL, Alonso MJ (1999) Development of a freeze-dried formulation of insulin-loaded chitosan nanoparticles intended for nasal administration. S.T.P. Pharma Sci 9 429-436... 

M. J. Pikal, K. Dellerman and M. L. Roy, Formulation and stability of freeze-dried proteins effects of moisture and oxygen on the stability of freeze-dried formulations of human growth hormone. Dev. Biol. Stand. 74. 21-38 (1991). 

Polymers such as dextrans could provide many desirable properties (e.g., high 7g and T ) to the freeze-dried formulation. Therefore, it is essential that future research address the theoretical and practical aspects of protein/polymer phase separation and develop the mechanistic insight to prevent this phenomenon during lyophilization. Also, as part of this effort, it is important to discern why other polymers (e.g., PVP and BSA) that protect labile proteins apparently do not phase-separate from the protein during lyophilization. 

Figure 5 Effect of excipients on the storage stability of freeze-dried human growth hormone (hGH). Samples were stored for I month at 40°C. Solid bars, aggregation (primarily dimer). Hatched bars, chemical degradation via methionine oxidation and asparagine deamidation. The glass transition temperatures of the initial freeze-dried formulations are given above the bars when a gla.ss transition temperature could be measured by DSC. The glycine mannitol formulation is a weight ratio of hGH glycine mannitol of 1 1 5, the dex-tran formulation is 1 6 hGH dextran 40, none means no stabilizer, and the others are 1 1 hGH stabilizer. All formulations contain sodium phosphate buffer (pH 7.4) at 15% of the hGH content. Initial moisture contents are all ==1%. (Data from [4].)...

Miyata K, Kakizawa Y, Nishiyama N, Yamasaki Y, Watanabe T, Kohara M, Kataoka K (2005) Freeze-dried formulations for in vivo gerre delivery of PEGylated polyplex micelles with disulfide crosslinked cores to the liver. J Corrtrol Release 109 15—23. 

Other methodologies may be employed for specific drug products. For microencapsulated, spray-dried, and spray-freeze-dried formulations, an assessment of the particle size may be critical. Lyophilized, spray-dried, and spray-freeze-dried formulations must be... 

Freeze drying, also known as lyophilization, is a process in which water is sublimated from the product after freezing. This process can be used in many different ways to achieve the same end point. In one of the freeze-drying formulation methods, drug is physically trapped in a water-soluble matrix (water-soluble mixture of saccharide and polymer, formulated to provide rapid dispersion, and physical strength), which is freeze dried to produce a product that dissolves rapidly when placed in the mouth. The ideal candidate for this kind of manufacturing method would be a molecule that is chemically stable and water insoluble, with a particle size lower than 50 In another method, lyophili-... 

Table 2 gives some examples of excipients used as stabilizers for proteins in freeze-dried formulations. Among others, saccharides are the most widely used excipients for stabilizing freeze-dried therapeutic proteins. There are exceptions to the need for stabilizing excipients, e.g., recombinant (ot-Antitrypsin was stable when freeze-dried alone or with lactose, sucrose, and polyvinylpyrrolidone. ... 

Izutsu, K. Yoshioka, S. Stabilization of protein pharmaceuticals in freeze dried formulations. Drug Stabil. 1995, 1, 11-21. 

Pyne A, Chatterjee K, Suryanarayanan R. Solute crystallisation in mannitol-glycine systems. Implications on protein stabilisation in freeze-dried formulations. / Pharm Sci 2003 92(11) 2272-2283. 

Blood substitute stabilizer stabilizer for freeze-dried formulations sucrose crystallization modifier. 

The assessment of stability in biotechnology-derived products such as peptides for preformulation is similar to that of the small-molecule drug. Degradation subjected to hydrolysis, oxidation, and deamination influenced by pH, temperature, and buffer species may be studied in the same manner. Protein in solution is not inherently stable. As chemical reactions are retarded in the solid state, a freeze-dried formulation is more suitable for protein product. 

It is also essential to consider the glass transition temperature of the freeze-dried product, particularly with a view to predicting physical and chemical storage stability. The relationship between the physical stability of freeze-dried formulations and Tg must be considered not only in terms of recrystallization but also of product collapse. For example, te Booy et al. (119) showed that storage of sucrose-containing freeze-dried formulations above Tg may result in product shrinkage, collapse, or excipient recrystallization. 

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