Liquid drug product, physical stability

The need for a multidose formulation may also dictate the use of a solid-state formulation. As the name implies, multidose products are intended to provide the patient with a product that contains several doses of the therapeutic within one container. Multidose formulations contain preservatives to kill any bacteria and prevent mold growth that may result from repeated entry into the drug product. Phenol and benzyl alcohol are two widely used preservatives in protein-based parenteral pharmaceuticals. Frequently, the addition of a preservative to the formulation compromises the long-term stability of the drug product, typically because the protein becomes physically unstable and/or exhibits oxidation. If the formulation scientist can obtain sufficient short-term stability (e.g., 2 weeks) for a formulation containing a preservative, then the use of a solid-state product may enable production of a multiuse formulation. In this case, the preservative is NOT added to the liquid bulk used to prepare the solid state. Instead, when the solid-state formulation is reconstituted prior to use, a preservative is included in the water for reconstitution. Thus the final product to be used is a multidose formulation that will experience only short-term exposure to the preservative. 

Knowledge about the chemical and physical stability of a candidate drug in the solid and liquid state is extremely important in drug development for a number of reasons. In the longer term, the stability of the formulation will dictate the shelf life of the marketed product, however, to achieve this formulation, careful preformulation work will have characterized the compound such that a rational choice of conditions and excipients is available to the formulation team. 

If the drug is insufficiently soluble to allow delivery of the required dose as a solution (the maximum delivered dose for each nostril is 200 p,L), then a suspension formulation will be required. There are additional issues for suspension products, for example crystal growth, physical stability, resuspension, homogeneity and dose uniformity. Suspension products will also require information on density, particle size distribution, particle morphology, solvates and hydrates, polymorphs, amorphous forms, moisture and/or residual solvent content and microbial quality (sterile filtration of the bulk liquid during manufacture is not feasible). 

Physical instability of liquid formulations involves the formation of precipitates, less-soluble polymorphs, adsorption of the drug substances onto container surfaces, microbial growth, and changes in product appearance. Evaluation of product acceptability is subjective and includes properties such as color, odor, taste, and clarity. Dye stability depends on the... 

---