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The release rate of an active pharmaceutical ingredient (API) in semi-solid topical formulations can be affected by both structural and physical properties.

The measurement of API release is vital throughout the drug development life cycle, from early-phase clinical candidate selection to specification setting in late phase development, as well as post-approval quality control (QC) and product changes or modifications. In vitro release testing (IVRT) is becoming an ever more prevalent and essential tool to determine the release rate and diffusion of API for topical product formulations.

In vitro release testing (IVRT) explained

For all solid oral dosage forms, dissolution testing to detect physical changes in both the API and the drug product is required throughout all phases of the drug development process and lifecycle. Likewise, for non-oral dosage forms, including semi-solid topical formulations, to evaluate drug release properties, in vitro release testing is necessary.

IVRT measures the release rate of a drug by using Franz diffusion cells and a non-interactive synthetic membrane or skin. In vitro release testing methods can be developed to analyze a wide range of semi-solid dosage forms, including:

• Creams;
• Ointments;
• Lotions;
• Hydrogels;
• Suspensions;
• Topical aerosols;
• Liposomes/Ethosomes, and
• Microencapsulation.

Skin anatomy and the drug permeation process

To better understand the role of in vitro release testing (IVRT) and in vitro permeation testing (IVPT) in topical product development, knowledge of the theoretical aspects of percutaneous drug delivery is valuable, as this provides the foundation for formulation and analytical development. For any active ingredient to penetrate the skin, it must permeate the stratum corneum, and this can be achieved via one of three pathways, which are the trans appendageal transport (shunt route transport), the transcellular (intracellular) route, and the intercellular pathways. Partitioning and diffusion controls the permeation of the drug through the skin, and drugs which utilize topical routes of administration do not permeate the subcutaneous layer. Therefore, topical drug products target the stratum corneum, viable epidermis, and dermis layers. Figure 1 details the macro routes for drug permeation in skin.

Figure 1. Macro routes for drug permeation in skin

Several permeant physicochemical properties can influence the route of absorption, including:

• Partition coefficient;
• Molecular size;
• Solubility/melting point;
• Ionization, and
• Others.

For a permeant or active ingredient to penetrate the skin, it must have a small molecular weight, with the target molecular weight of a compound for skin permeation typically being less than 500 Dalton, as larger molecules are unable to pass through the corneal layer.

In vitro release testing (IVRT) guidance and applications

The US Food and Drug Administration (FDA) first released its guidance for industry, Scale-Up and Post-Approval Changes: Chemistry, Manufacturing, and Controls (CMC); In Vitro Release Testing and In Vivo Bioequivalence Documentation for Non-Sterile Semi-Solid Dosage Forms (SUPAC-SS) in May 1997. SUPAC-SS addresses non-sterile semi-solid dosage forms with intended topical routes of administration, and defines:

• Levels of change;
• Chemistry, Manufacturing and Controls (CMC) tests to support each level of change;
• Recommended in vitro release tests and/or in vivo bioequivalence tests to support each level of change, and
• Documentation to support the change.

More recently, the FDA has published several specific guidelines in an effort to overcome barriers to generic product development, as well as to improve patient care. These clearer, stricter guidelines are helping the industry with bioequivalence (BE) assessments using in-vitro release and in-vitro permeation methodologies in lieu of clinical studies, as shown in Figure 2.

Surrogate approaches to demonstrate bioequivalence (BE) for topical dermatological products

Sensitive and efficient surrogate approaches to demonstrate BE for certain topical dermatological products are provided in the following guidelines:

• Acyclovir Ointment: Q1/Q2/Q3 + IVRT;
• Silver Sulfadiazine Cream: Q1/Q2/Q3 + IVRT;
• Acyclovir Cream: Q1/Q2/Q3 + IVRT + IVPT, and
• Benzyl Alcohol Lotion: Q1/Q2/Q3 + IVRT + Lice Assay.

General definitions are as follows:

• Formulation Q1/Q2 Sameness: The test and reference listed drug (RLD) products are qualitatively and quantitatively the same.
• Q3 Similarity: The physicochemical properties of test and RLD products are similar.
• In Vitro Release Test (IVRT) Studies: The test and RLD products have an equivalent rate of API release.
• In Vitro Permeation Test (IVPT) Studies: The rate and extent of API permeation through excised human skin from the test and reference products are comparable.

Figure 2. Methods of bioequivalence (BE) for topical drug products

How Element can support your IVRT/IVPT and Q1/Q2/Q3 requirements for accelerated generic drug development

Element is equipped with the technology knowledgeable teams of pharmaceutical scientists, formulators, and organic chemists to support your IVRT/IVPT and Q1/Q2/Q3 requirements for the accelerated development of topical and generic drug products. A brief overview of our in vitro release testing (IVRT) and in vitro permeation testing (IVPT) Å·ÃÀÊìÅ®ÂÒÂ× is as follows:

Q3 (Similarity)

• Rheology;
• Particle size;
• Globule size, and
• Specific gravity, pH, and/ or water content.

IVRT and IVPT to support bioequivalence waiver and sameness testing

• Industry standard Franz vertical diffusions cells from Permegear;
• Identification of appropriate simulated membranes;
• Development of flux conditions;
• Product dose;
• Sampling intervals;
• Stirring rate, and
• Selection of receptor solution.
• Development and validation of selective and robust test methods;
• IVRT and IVPT apparatus qualification, membrane qualification, receptor solution qualification;
• Reconcile donor/acceptor part of cell;
• Designing of IVPT pilot and pivotal studies, and
• Statistical analyses of data per USP <1090>.

With proven success in Q3 sameness verification and addressing deficiencies clients have received from the FDA regarding discriminating IVRT methods and insufficient scope of development, as well as deep expertise and experience in topical and ophthalmic products, Element is the preferred partner for leading drug developers for IVRT/IVPT testing.