Solid 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. 

The ability of many drugs to form salts affords the formulation scientist increased scope to optimize drug product performance. The formation of a drug salt can alter physicochemical properties such as physical and chemical stability, solid state characteristics such as crystal form, melting point, enthalpy, solvation, hygroscopicity, which in turn impact on processability, dissolution rate, and bioavailability, without... 

Some new drug substances exist in different crystalline forms that differ in their physical properties. Polymorphism may also include solvation or hydration products (also known as pseudopol5rmorphs) and amorphous forms. Differences in these forms could, in some cases, affect the quality or performance of the new drug products. In such cases, the bioavailabUity stability can be altered requiring choice of specific stable solid dosage forms. 

Polymorphic purity of solid drug substances is an important parameter for consideration in pharmaceutical formulation. Since different polymorphs or crystalline forms of the same drug exhibit different physical properties, chemical stability, solubility, dissolution rate, and possibly bioavailability, the presence of the alternative (metastable) crystal form(s) may have an adverse impact on the manufacturing and in vivo performance of the drug product. 

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. 

Impact of Solid-State Characteristics to the Physical Stability of Drug Substance and Drug Product... 

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