Stability lyophilized compounds

The aggregation of metrizamide in solution further reduced its osmolality to about 485 mOsm kg at 300 mgl mL [ 1 ]. Unfortunately, this agent could not be sterilized by autoclaving and, consequently, had to be lyophilized and reconstituted extemporaneously. In the mid-1970s, stable nonionic compounds such as iopamidol or iohexol superseded metrizamide. Further improvement was reached by stabilization of the hydrophilic sphere against external disruption, as shown with iobitridol [2]. 

Stability of biopharmaceutical compounds should also be determined under conditions that mimic their normal usage. For instance, the stability of reconstituted lyophilized products should be assessed with respect to time and temperature and, if applicable, light and mechanical stimuli. Likewise, the stability of a compound included in implantable devices and controlled-release microsphere formulations should be determined over the course of its required use, under conditions which mimic the heat, moisture, light, and enzymatic physiological conditions to which it... 

The majority of medicines today are formulated as tablets [1], Tablets are formulated rapidly and economically, and they have high patience compliance. Also, many compounds, such as aspirin, degrade rapidly in solution and are formulated in solid dosages to increase stability [2]. Drug substances that are oils, liquids, and solids may be formulated into capsules, tablets, lyophiles, creams, or microsuspensions. Administration may be through ingestion, injection, topical application, inhalation, and other routes. The reader may consult other texts for discussion of formulation options [1,3]. Formulations are selected for stability and the ability to best deliver the active agent to the affected area of the patient or consumer. 

If a lyophilized drug is amorphous, then knowledge of the glass transition temperature is important for stability reasons. Chemically, amorphous compounds are usually less stable than their crystalline counterparts. This is illustrated in Table 6.11, which shows some stability data for an amorphous compound (produced by lyophilization) and the crystalline hydrate... 

Table 6.11 Stability data for an amorphous (lyophilized) and crystalline hydrate form of a compound. ...

The use of the reverse phase evaporation method permits inclusion of 50 and more percent of the substance to be encapsulated from the water phase into the liposomes. Besides, a variety of methods have been developed to obtain lyophilized liposomal preparations possessing good storage stability. The in vitro release rate of different compounds from liposomes, including proteins of moderate molecular weight, is usually under 1% per hour, assuming that the incubation temperature sufficiently differs from the phase transition temperature of a given phospholipid, since the maximal permeability of liposomes is usually observed at temperatures close to the phase transition temperature of the liposomal phospholipid. In vivo, this parameter can vary within wide limits from minutes to hours and depends on the liposome membrane composition, cholesterol content, and disposition within the body. 

Before using this material in enzyme experiments, the stability of the active compound was studied using the TPNH oxidation assay. When the solution was stored at 0°C., it lost 30 to 40% of its activity in 90 minutes. The addition of Tris buffer, pH 6.8, either before or after the dye-oxidation step led to greater instability. Storage in an evacuated tube did not prevent these losses. The compound was less stable in dilute acid or alkali than it was at neutrality. Lyophilizing the solution immediately... 

---