Stress testing can reveal physical and chemical changes of the active pharmaceutical ingredient (API) or other critical excipients that may occur during processing and storage. Since certain lattice types and modifications may be more prone to change than others, the appearance of phase impurities (such as crystalline API in an amorphous formulation) and different modes or rates of chemical degradation can often be associated with particular solid forms such as polymorphs, hydrates, and amorphous or disordered crystalline forms,. We conduct high-temperature, high-humidity, light-exposure, and mechanical (by grinding and compression) stress studies to identify and quantitate physical and chemical changes by a range of analytical techniques. This information is used to assess risk and define the precautions necessary to control undesired changes in the API solid form, which may include modification of formulation components and/or manufacturing steps, and appropriate packaging configurations for bulk drug product intermediates and finished materials.
Dissolution testing is commonly used as a research tool to reveal differences in performance during drug product development and as a validated control method for release testing. In early development, dissolution is often used to anticipate comparative release kinetics in biological systems. Because dissolution rates are highly dependent on the intrinsic properties of the API solid form (e.g., solubility) and the process parameters used for drug product manufacture (e.g., particle size distribution, tablet hardness, and friability), characterization of the dissolution rates of different formulations in various medias can be used to guide excipient selection and identify critical process control parameters that achieve the desired release profiles for an immediate, controlled, or modified-release formulation. While dissolution testing is most commonly applied to solid oral dosage forms, it is possible to characterize the dissolution rate (e.g., release profile for liquid oral capsules) for other delivery systems.
SSCI scientists have extensive experience conducting research-based dissolution studies for a broad range of drug products using both automated and manual sampling techniques. We work closely with each client to clearly define the goals of the study and the essential parameters required to provide discriminating test conditions, including experimental set-up and media selection. As with most studies, an understanding of the physicochemical properties of the API and the dose range of the drug product required to ensure sink conditions are important. Different types of dissolution vessels, as described in the United States Pharmacopeia (USP) for Dissolution and Drug Release are available including Apparatus 1 (basket method) and Apparatus 2 (paddle method). While typically used for studies of API solid form, dissolution studies can also be conducted using compacts with known surface area (intrinsic) and powders. Although dissolution experiments are typically conducted under sink conditions, for poorly water soluble API other factors such as non-sink conditions and precipitation can be considered.
If the dissolution method is intended to investigate biopharmaceutical properties, it is important that the aqueous media simulates the desired in-vivo environment. To this end, SSCI has expertise in the use of aqueous buffers and simulated biorelevant media, such as McIlvaine buffer to mimic Fasted State Simulated Gastric Fluid (FaSSGF), Fed State Simulated Gastric Fluid (FeSSGF), Fasted State Simulated Intestinal Fluid (FaSSIF), and Fed State Simulated Intestinal Fluids ('FeSSIF and FeSSIF-V2').
When possible, a non-validated UV-VIS method is developed to measure concentration of the API in different media. Where UV is not possible, HPLC methods can be used. For these experiments, the linear range of the UV method will be established prior to each experiment based upon an agreed upon number of standards to span the anticipated concentrations. The dissolution studies are performed at controlled temperature, such as 37 °C, using multiple experiments under the agreed upon conditions to allow for calculation of statistics, if needed. Given changes in the solid form are critical to allow for proper interpretation of dissolution data, solids samples can be examined on-site immediately after the experiment or in-situ using a Raman spectroscopy probe to monitor the solid form during the dissolution experiment.