Dissolution development: fast-track methodology for your highly soluble, highly permeable drug

Regarded as a key quality standard, dissolution testing is a powerful tool that’s used to measure a product’s quality and product performance, report Caitlin White, Team Leader, and Melissa Nelson, Senior Group Leader, Metrics Contract Services

Recent US FDA guidance on dissolution testing highlights its critical role in ensuring that pharmaceutical drug products are safe and effective for patients.1

From a quality perspective, the FDA requires a robust dissolution method for a wide range of applications. From assessing the batch-to-batch consistency of solid oral dosage forms such as tablets to formulation development, it can sometimes provide information regarding the predictability in vivo drug release profiles as well as 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 key criteria — media, vessel volume and paddle/basket rotation speed — to be tested under the exact same methodology.

With every molecule having unique behavioral characteristics, a proper methodology must be developed that meets all FDA requirements.

In addition, having a sound dissolution development report that justifies how the method was developed and why the final conditions were selected is essential for a successful filing. So, what is the fast-track procedure to getting a method established based on this guidance?

Define the media: Study the compound. Is it highly soluble and/or in a logical pH range (from 1.1 to 6.8)? What is the pKa? Where in the gastrointestinal (GI) tract is the product supposed to be released?

Is it an immediate release or extended release product? Media selection depends on where the drug is expected to dissolve in the body. As such, 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 a minimum of 24 hours using pH 1.2, 4.5 and 6.8 media; however, pKa should be examined to ensure that the 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 conditions 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 the 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).

Starting with a 500 mL vessel volume for highly soluble compounds (>10 mg/mL) is recommended to improve the discriminating power of the method; however, the volume can be increased with appropriate justification.

Regardless of volume choice, the results obtained for different (all) strengths must be consistent. Given a low strength (15 mg) and high one (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 in 30 minutes. If the dissolution takes longer to achieve, such as 80% dissolution at 45 or 60 minutes, additional justification would be required.

Define the apparatus type and paddle speed: Basket (Apparatus 1) and paddle (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 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 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 that the appropriate conditions are established and recording/reporting dissolution development will ensure that the information is readily available when the time comes for filing
  • although sponsors often draft their own dissolution development summary, contract partners can be brought in to write a comprehensive dissolution development report on their behalf; ideally, this task occurs in the lab and is agreed upon prior to dissolution development to ensure accurate and the 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 to ensure continuous drug product quality and performance, regardless of the project or product.

Reference

  1. www.fda.gov/regulatory-information/search-fda-guidance-documents/dissolution-testing-and-acceptance-criteria-immediate-release-solid-oral-dosage-form-drug-products.