Excipients, lyophilized formulations

TABLE 5.8. Examples of excipients used to enhance protein stability in solution and lyophilized formulations... 

Dubost, D., Kaufman, M., Zimmerman, J., Bogusky, M. J., Coddington, A. B., Pitzenberger, S. M. Characterization of a solid state reaction product from a lyophilized formulation of a cyclic heptapeptide. A novel example of an excipient induced oxidation. Pharm Res 13 1811-1814 (1996). 

Yoshioka, S. Aso, Y. Kojima, S. Sakurai, S. Fujiwara, T. Akutsu, H. Molecular mobility of protein in lyophilized formulations linked to the molecular mobility of polymer excipients, as determined by high resolution C sohd-state NMR. Pharm. Res. 1999, id (10), 1621-1625. 

S. Yoshioka, Y. Aso, and S. Kojima, The effect of excipients on the molecular mobility of lyophilized formulations, as measured by glass transition temperature and NMR relaxation-based critical mobility temperature, Pharm. Res. 16, 135-140(1999). 

Various methods, including dilferential scanning calorimetry (DSC), dielectric relaxation spectrometry, and NMR, are known to be useful to determine molecular mobility of freeze-dried formulations [16,17]. The glass transition temperature (Tg) has been used as a measure of molecular mobility of lyophilized formulations, since it indicates the critical temperature of a-relaxation for amorphous polymer materials. Freeze-dried formulations containing polymer excipients can be considered to exhibit low molecular mobility without a-relaxation at temperatures below Tg. 

Figure 4 shows the of lyophilized formulations containing various polymer excipients as a function of relative humidity [26], As relative hymidity increased, for each formulation decreased. Formulations containing a, S-poly (vV-hydroxyethyl)-L-aspartamide (PHEA), methylcellu-lose (MC), and hydroxypropylmethylcellulose (HPMC) exhibited comparable r io values at lower humidities than formulations with dextran and carboxymethylcellulose sodium salt (CMC-Na). This indieates that the formulations containing PHEA, MC, and HPMC contain highly mobile protons at a lower temperature than the formulations containing dextran and CMC-Na at the same humidity. 

As described above, the Ti of carbons in protein and excipient molecules can provide important information on the molecular mobility of lyophilized formulations. Similarly, the Ti, of carbons is useful as a measure of molecular mobility. Figure 16 shows the x of methine carbons in a lyophilized formulation containing dextran, calculated from the observed Tip according to equation (5). The x of methine carbon at 60%RH is of the same order as the x i of methine protons described in Section II.B. 

Once the protein is purified, it will be formulated to produce the drug product. This could be as simple as diluting the protein in phosphate-buffered saline, or as complex as addition of excipients and lyophilization. The mark of... 

Inclusion of a cryoprotectant in the formulation can stabilize the protein during the freezing and drying stages of lyophilization.17 Excipients frequently... 

The finished form is a sterile, lyophilized powder formulated with tri-methamine, mannitol, and sucrose as excipients. 

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