Ryan Klein, Director R&D at Tergus

We have previously touched on the dramatic increase in the use and application of in vitro release testing (IVRT) during the development of topical products (See the September 23, 2014 blog post). As a follow up in an upcoming blog series, we’ll consider the technical aspects of IVRT, briefly introduce the most common apparatus used to perform the experiment, and review a basic strategy for developing robust and reproducible methods while reviewing the major assumptions and most basic considerations underlying the technique.

Conceptually, IVRT for a semi-solid dosage form is a simple experiment, and typically uses an equally simple apparatus to perform the experiment – the vertical diffusion cell (VDC). The VDC is comprised of two compartments: a donor chamber that holds the formulation during the course of the experiment, and a receptor chamber that contains an appropriately selected receiving medium and serves as the sampling site during the experiment. The receptor chamber is designed to maintain a constant temperature via either a water jacket or dry heating compartment. Between the donor and receptor chambers sits an appropriately selected synthetic membrane which acts as a holding surface for the formulation, and serves as a demarcation between the two chambers. During 2014, the USP published Chapter based on input from leaders in industry, academia, and regulatory agencies that describes the VDC in greater detail. The USP chapter recommends specific dimensions for the apparatus as well as additional characteristics for consideration. The document is an excellent resource for those unfamiliar with the technique.

Although the concepts behind IVRT and the apparatus used are fairly simple, developing methods quickly and efficiently is a different story. Semi-solid formulations are extremely diverse in their physical and rheological characteristics. The drug substances contained within them cover an extremely wide range of hydrophobicity and aqueous solubility, and the strength of approved products and those under development can be as low as 0.01% w/w, and as high as 10% w/w (a one thousand fold range). This diversity precludes the implementation of a standard and simple method development strategy and requires some careful consideration and rigorous paper exercise before jumping into the lab to start the first experiments. Below are a number of questions that should be addressed and considered before starting the work. The answers to these questions will allow the development of an optimal strategy and design of experiments to allow rapid development of robust and reproducible methods which we’ll explore in the coming weeks.

1. What is the strength of the product?
2. What is the expected range of sample concentrations? An approximate range can be determined by considering the strength of the product, the volume of the receptor chamber, and the targeted percentage of drug substance that will be released from the product during the experiment.
3. Is there an analytical method capable of accurately measuring the drug substance across the range of expected concentrations?
4. Is the drug substance hydrophobic or hydrophilic, and what is the approximate aqueous solubility?
5. Is the drug substance ionizable? What are the pKa values? What pH would provide the greatest solubility?
6. Are there solvents or surfactants that might preferentially solubilize the drug substance?
7. What type of semi-solid formulation is the product (i.e. cream, lotion, ointment, etc.)?
8. What is the aqueous solubility of the major excipients in the drug product?
9. How viscous is the drug product? (Viscosity will impact the diffusivity of the drug substance within the product and may impact the selection of the receiving medium.)
10. What is known about the excipients and their impact on the physicochemical properties of the dosage form?