SSCI carries out preclinical and clinical stability studies on drug substance and drug products through our full service solid state and chromatography/dissolution groups. We develop chromatographic, dissolution, and solid-state methods for material assessment and conduct accelerated stress testing on site with GMP ICH stability storage at AMRI sites or preferred vendors. With our class leading solid-state characterization we are able to help guide our clients to the best solid form and dosage form for their API and help them determine risks that may impact a development program.
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.
In Vitro Comparative Analysis
SSCI has expertise in assessment of the performance characteristics of various drug products in a laboratory setting. Using tools such as dissolution, diffusion, and disintegration, assessment of abuse deterrence through alcohol-induced dose dumping and bioequivalence can be performed. In vitro bioequivalence studies can be performed for various non-absorbed drugs, topical and oral drugs, locally acting emulsions and suspensions, as well as transdermal patches. In vitro comparative studies can also be used to demonstrate equivalency in manufacturing process or site changes, multi-strength product equivalency, and marketing advantage studies.
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 developing and 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. Different types of dissolution equipment, as described in the United States Pharmacopeia (USP and USP ) for Dissolution and Drug Release are available including Apparatus 1 (baskets), Apparatus 2 (paddles), and Apparatus V (paddle over disk) Rotating disk (USP ) is available to study API solid form dissolution, using compacts with known surface area and powders. 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. 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’).
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.
In order to assess membrane permeability for various combination products, we employ side-by-side diffusion. Franz vertical diffusion cells are used for evaluation of drug release from semi-solid dosage forms. SSCI scientists are experienced at the development and conduct of these studies.
A wide variety of quantitation tools are available to measure concentration of the API in different media from the various in vitro comparative analysis techniques. In situ monitoring via a UV dip probe may be used for selected media. When possible, a non-validated UV-VIS method is developed. HPLC methods can also be developed and used. For these experiments, the linear range of method will be established which is appropriate to each experiment. These studies are performed at controlled conditions (i.e. temperature, and stirring speed), using sufficient replicates to allow for calculation of statistics, if needed.