Freeze-drying formulation development

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. 

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... 

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. 

Pikal, M.J. Dellerman, K.M. Roy, M.L. Formulation and stability of freeze dried proteins effects of moisture and oxygen on the stability of freeze dried formulations of human growth hormone. Develop. Biol. Standard 1991,... 

In summary, in this chapter we will discuss the freeze-drying formulation characterization, which is the first step and the most important step in developing a freeze-drying cycle. All of the characterization discussion will focus on a crystalline matrix type of formulation. In the discussion, we will follow the order given below ... 

X Ma, DQ Wang, R Bouffard, A MacKenzie. Characterization of murine monoclonal anitbody to tumor necrosis factor (TNF-MAb) formulation for freeze-drying cycle development. Pharm Res 18(2) 196-202, 2001. 

The development of freeze-drying for the production of blood derivatives was pioneered during World War II (96,97). It is used for the stabilization of coagulation factor (98,99) and intravenous immunoglobulin (IgG iv) products, and also for the removal of ethanol from intramuscular immunoglobulin (IgG im) solutions prior to their final formulation (Fig. 2). 

Therefore, freeze-drying should be carried out at the highest allowable product temperature that maintains the appropriate attributes of a freeze-dried product. This temperature depends on the nature of the formulation. Process development and validation requires characterizing the physical state of the solute, or solutes, that result from the freezing process and identifying a maximum allowable product temperature for the primary drying process [20,21]. 

Most proteins are not sufficiently stable in aqueous solution to allow formulation as a sterile solution. Instead, the protein is freeze-dried and reconstituted before use. Development of a freeze-dried protein formulation often requires special attention to the details of the freezing process (potential pH shifts and ionic strength increase with freezing) as well as to potential loss of activity with drying. Formulation additives, such as sugars and polyhydroxy compounds, are often useful as cryoprotectants and lyoprotectants. Residual moisture may also be critical to the stability of the dried preparation [33],... 

Chang, B. S., Fuscher, N. L. The development of an efficient single-step freeze-drying cycle for interleukin-1 receptor antagonist formulation. Pharm. Res. vol. 12, No. 6, p. 831-837, 1995... 

Vries et al. [3.59] described the development of a stable parenteral dosage form of the cytotoxic drug E 09. E 09 dissolves poorly in water and its solution is unstable. With the addition of 200 mg of lactose per vial containing 8 mg of E 09, an optimum formulation was developed with respect to solubility, dosage of E 09 and length of the freeze drying cycle. DSC studies have been used to select the most effective parameters. The freeze dried product remains stable for 1 year when stored at 4 °C in a dark environment. 

Until atmospheric spray-freeze-drying equipment becomes commercially available, the development of formulation will be mainly based on the Trial and Error approach, and the validation of the classical lyophilization procedure will remain difLcult. 

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