Several types of studies are crucial for assessing the stability of a solid state pharmaceutical.
Many drugs utilize solid state chemicals as their active pharmaceutical ingredients (APIs). In order to ensure the stability and resilience of those solid state chemicals, developers and contract manufacturing organizations (CMOs) must perform studies that analyze those chemicals’ reactions under various environmental conditions. The results of those studies are then used to optimize drug candidates’ crystallinity and purity profiles.
However, solid state reactions can take place significantly more slowly than those of solution state chemicals, and are also often more difficult to interpret. For this reason, effective solid state stability trials involve setting aside a large bulk of the chemical for testing, then subjecting that chemical to a wide range of extreme stress conditions.
In the United States, this testing must be conducted in a secure facility licensed by the US Drug Enforcement Agency (DEA), equipped with sufficient storage space, backup power, and a full range of testing and analysis equipment. A staff of scientists must also be on site, to perform quality quality assurance (QA) checks on the samples, as well as on the data gathered.
Solid state stability trials typically fall into the three following categories.
Forced degradation studies speed up the API’s breakdown in various ways.
Solid state pharmaceutical chemicals can break down due along a wide range of different kinetic pathways. In order to determine a drug candidate’s stability, extremes of temperature, chemical aggregation, mechanical force, chemical damage, and other stressors must be applied according to known and suspected degradation pathways. The API’s reactions to each stressor must be carefully recorded and analyzed at each step of the process.
Various types of forced degradation studies should be performed throughout the development process. The drug product should be tested at high- and low-dose concentrations, as well as in any configurations unique to a specific product. Each sample should be subjected to stress from high temperatures, kinetic force, and any other likely pathways of degradation; but care must be taken not to exceed the intensity of realistic potential stressors.
Throughout each stress trial, the solid state chemical should be analyzed for all likely responses to each stressor; for example, breakdown of molecular bonds, loss of chemical groups, physical weakening, changes in appearance, or any other functional or structural alterations. Some of these results may be immediately obvious, while others may only become apparent through analytical methods such as electrophoresis or chromatography.
Photolytic stability studies evaluate the API’s reactions to light and air.
Photodegradation typically results from exposure to air and sunlight, and takes the forms of hydrolysis and oxidation reactions. Unlike degradation due to kinetic factors or temperature extremes, photodegradation can occur even in ordinary storage conditions, if a pharmaceutical’s packaging material fails to provide adequate protection from sunlight. Thus, before a drug candidate is prepared for shipping, its photolytic stability must be assessed.
To initiate a photochemical reaction, the solid state chemical is bombarded with photons, whose energy is absorbed by the API’s molecules. This absorbed energy rapidly pushes the configuration of that molecular structure into an excited state, which may or may not be kinetically stable, depending on a range of chemical and environmental factors. If the molecular structure is unable to maintain its stability, it may decompose into high-energy fragments, which react with other molecular fragments as they dissipate into the surrounding environment as pollutants.
Once a chemical’s level of photolytic sensitivity has been determined, the API can be protected by introducing certain additives into the formulation, by adding packaging that filters out light at certain wavelengths, and/or by attaching warning labels that alert handlers to transport and store the drug in locations free from damaging light sources.
Oxidative stability studies examine the API’s resistance to oxidation reactions.
In an oxidation reaction, electrons are transferred between molecules, resulting in a gain of oxygen relative to other atoms. This reaction, causes the breakdown of many types of organic and inorganic molecules. The exact rate at which it occurs in a given solid-state chemical depends on many factors, including temperature and pH, as well as presence of water, certain acids, and other catalysts.
Despite the fact that oxidation poses a hazard to many drug products, its precise chemical pathways have been studied relatively little in comparison with other threats such as photodegradation. To some degree, however, this lack of research on oxidation is justified, because oxidative degradation can be mitigated simply by keeping the drug out of direct sunlight, and by adding antioxidants to the drug formulation.
In addition to evaluations on kinetic and temperature-related degradation, and photolytic and oxidative stability, some solid state pharmaceuticals may also require studies of special conditions that may lead to degradation, such as hydrolysis and other chemical reactions. These conditions can be as unique as the pharmaceutical products to which they apply, and thus must be selected and studied on an individual basis. A CMO with experience in stability studies will tailor these recommendations around the conditions of a given product and facility, in order to ensure minimal loss throughout the manufacturing phase.
In addition to being an author and speaker, Susan Thompson serves as the Technical Director of Indianapolis based VxP Pharma.