Physical stability solid dosage forms

The materials used in the production of hot-melt extruded dosage forms must meet the same levels of purity and safety as those used in traditional dosage forms. Most of the compounds used in the production of hot-melt extruded pharmaceuticals have been used in the production of other solid dosage forms such as tablets, pellets, and transdermals. The materials used in hot-melt extruded products must possess some degree of thermal stability in addition to acceptable physical and chemical stability. The thermal stability of each individual compound and the composite mixture should be sufficient to withstand the production process. 

The stability, both chemical and physical, of a drug may be enhanced or retarded by salt formation. For example, solid dosage forms of diclofenac contain salt forms rather than the less stable free acid. Although salt formation may result in improved dissolution rate and bioavailability of a poorly water-soluble compound, the preparation of stable salt forms for some drugs may not be feasible and the free acid or base forms may be preferred. For example, the base form of a-pentyl-3-(2-quinolinylmethoxy)benzenemethanol was selected for dosage form design because of the physical instability of its hydrochloride salt. ... 

Early on in product development, the potential for the successful development of a solid oral dosage form is assessed, based on the physicochemical properties of the API (1). Prior to solid dosage form development, it is necessary to anticipate the physicochemical properties that can have a major influence on product manufacture and performance. The early development (preformulation and early formulation development) studies should focus on these properties so as to avoid problems at later stages of development. While the molecular properties dictate the intrinsic solubility and the chemical stability of the compound, by controlling the physical form of the compound and by modifying physical properties (e.g., particle size), the dissolution rate can be enhanced with the potential for improving bioavailability. This chapter will focus on physical properties including particle characteristics, and most importantly, the physical form (i.e., solid state) of the API. 

Particle size and shape are important attributes of drug substances that can affect the dissolution rate, bioavailability, and the processing of oral solid dosage forms and the physical stability of semi-solid dosage forms. During manufacture of the bulk drug substance, the recrystallization conditions required to prepare a particular salt will inevitably influence the particle size and crystal habit conditions should be established early in the development program that routinely yield material with consistent characteristics. 

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. 

As a general rule, anhydrous forms that do not convert to the hydrate below 75% RH (at equilibrium) are likely to exhibit adequate physical and chemical stability in oral solid dosage forms. Adequate manufacturing and packaging can be designed to protect most oral solid dosage forms from exposure to >75% RH. Conversely, hydrates that do not convert to the anhydrous form until the relative humidity drops below about 20% (at equilibrium) are also likely to exhibit adequate physical stability in solid dosage forms. 

For liquid formulations that are constituted by the pharmacist or patient, a separate shelf-life will be indicated before and after constitution. Physical stability before constitution means that the constituted formulation will still perform acceptably (i.e., dissolve or disperse) within the pre-constitution shelf-life. After constitution, the stability concerns will be similar to other liquid formulations. Even for solid-dosage forms, there can be a different shelf-life for the product as shipped (potentially with more protective packaging), and as received by the patient. 

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