Recent FDA guidance* on Dissolution Testing highlights the critical role of dissolution in ensuring that pharmaceutical drug products are safe and effective for patients. Regarded as a key quality standard, dissolution testing is a powerful tool for measuring a product’s quality and product performance.

The FDA requires a robust dissolution method for current applications not only from a quality perspective, as in assessing batch-to-batch consistency of solid oral dosage forms such as tablets, but also from a development angle. It can sometimes offer predictability in in vivo drug release profiles instead of, or in addition to, quality control. The FDA guidance challenges us to look at dissolution with a renewed emphasis.

The critical takeaway is that the FDA is pressing for all strengths—media, vessel volume, and paddle/basket rotation speed—be tested under the exact same methodology. With every molecule having unique behavior, proper methodology must be developed covering all FDA requirements. In addition, having a sound dissolution development report with justification as to how the method was developed and final conditions selected is essential for a successful filing. 

So, what is the fast track to getting a method established based upon this guidance?

Define the media
Study the compound. Is it highly soluble in a logical pH range from 1.1 to 6.8? What is the pKa? Where in the GI tract is the product supposed to release? Is it immediate release or extended release? The media selection depends on where the drug is expected to dissolve in the body. So, the purpose of the drug often determines the selection of the media.

Solubility should be evaluated across the physiological pH range of 1.1 – 6.8 to support media selection. Depending on the site of absorption in the body, a higher pH must be justified. Equilibrium solubility is recommended at 24 hours, at minimum, using a pH 1.2, 4.5, and 6.8 media; however, pKa should be examined to ensure that media choice is appropriate. To meet the expected rigor for highly soluble and highly permeable compounds, the FDA says the highest proposed dosage strength for the compound should be able to dissolve in 250 mL or less in the media of choice or be able to achieve sink of 3-5 times the highest dosage unit in the target volume. Typical media choices are 0.01N or 0.1N HCl; however, the use of a buffer media can be justified as long as it falls within the physiological pH range. In addition, compatibility between media selection of multiple components must be justified.

Determine the volume
Once the target media is selected, the vessel volume should be established starting with a 500 mL vessel volume. It is preferred to start with a 500 mL vessel volume for highly soluble compounds (>10 mg/mL) to improve the discriminating power of the method; however, the volume can be increased with appropriate justification.

Regardless of volume choice, there must also be consistency throughout all strengths. Given a low strength at 15 mg and high strength of 500 mg, the method should strive to align the vessel volume across both strengths starting with 500 mL vessel volume for highly soluble compounds unless the discriminatory power can be justified at a higher volume.

For immediate release dissolution testing, the analysis is typically no more than 60 minutes and would be considered fast dissolving. The expectation for immediate release formulations is 80% (Q) dissolved by 30 minutes. If the dissolution takes longer to achieve 80% (Q) at 45 or 60 minutes, additional justification would be required.

Decide the apparatus type and paddle speed
Basket type (Apparatus 1) and paddle type (Apparatus 2) are common apparatus types used for oral solid dosage form production. Each apparatus depends on formulation and dissolution rate. The apparatus largely depends on whether the product is a tablet or capsule, or whether a sinker can be used. Additionally, the rate of dissolution or a coning observation may be a key decision maker for the apparatus choice.

Developing the method with the FDA guidance in mind, analysts can evaluate with multiple paddle speeds and basket speeds. The gold standard is 500 ml of 0.1N HCl at 100 RPM for Apparatus 1 or 50 RPM at for Apparatus 2.

Based on the FDA guidance, the following key points should be considered:

• The dissolution method development discussion should be able to justify the media, vessel volume, and paddle/basket speed. During evaluation, all parameters should be challenged to ensure the appropriate conditions are established. Recording dissolution development data in a development report will ensure that the information is readily available when the time comes for filing.
• Sponsors often draft their own dissolution development summary; however, contract partners are often brought in to write a comprehensive dissolution development report on their behalf. Ideally, this task occurs at the lab and is agreed upon prior to dissolution development to ensure accurate and timely reporting of dissolution decision making.
• Appropriate justification should be provided if 500 ml of 0.1N HCl at 100 RPM for Apparatus 1 or 50 RPM at for Apparatus 2 is not used. This includes justification for vessel volume, dissolution media buffers, apparatus speed, and specification.
• Once appropriate justification is provided, it is critical that all strengths follow the exact same methodology.

It is important to note that changes in media, vessel volume, and speed can impact the data generated in the testing. Controlling the parameters and specifying them in the test method is paramount. The FDA-based recommendations for developing the proper dissolution testing method should help ensure continuous drug product quality and performance regardless of the project or product. 

*Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances Guidance for Industry

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Melissa Nelson is a Senior Group Leader overseeing a team of 16 analytical chemists, whose focus is Release, Stability, and Formulation Development support for early phase to commercial solid oral dosage and topical projects. She has been with Metrics Contract Services for 17 years.

Caitlin White is a Team Leader at Metrics Contract Services, overseeing four analytical chemists. Her team focuses on solid oral dosage projects from early phase development to commercialization. She specializes in dissolution analyses. Caitlin has been with the company for eight years.