Why is biorelevant dissolution so important?

Biorelevant dissolution tests reveal how long it takes for your drug to dissolve in gut fluids. Whereas biorelevant solubility tests use unformulated drug substance, dissolution tests require a formulated drug product. This enables the role of excipients and dosage form on drug release to be investigated.

For NCEs

Biorelevant dissolution of an NCE (New Chemical Entity) is important for formulation development, optimization and selection. By comparing drug release rates of different formulations, one with the desired profile can be identified. This is useful for both immediate release formulations as well as modified release formulations. 

Testing in Biorelevant Media can also help you understand how formulation changes may affect drug release. This is particularly useful during clinical development when formulations are being optimised and must remain bioequivalent to your clinical dosage form.

For Generic Drugs

During formulation development of a generic drug product, biorelevant dissolution tests can help identify lead formulations that match the reference formulation (originator product). Identifying the dissolution profile of the reference product you must match, and which of your test formulations comes closest to this benchmark profile, can save a lot of time and money. The use for immediate release products is outlined in the latest USP Chapter <1092>: The Dissolution Procedure: Development and Validation. The use of Biorelevant Media for modified release formulations is outlined in the EU guidance document, ‘Guideline on quality of oral modified release products (2012)’.


Dissolution results in Biorelevant Media can be used qualitatively to rank order formulations or quantitatively as part of the input for in silico modelling. This is to establish a correlation between your laboratory dissolution results and in vivo clinical results.

When is it best to perform biorelevant dissolution tests and how do I conduct them?

It is most beneficial to carry out biorelevant dissolution tests during the development of a formulated drug product before in vivo or clinical studies are carried out.

Biorelevant dissolution tests are simple and very similar to pharmacopeia dissolution studies that are carried out for measuring drug release in buffer. You simply switch the buffer in the vessels for the Biorelevant Media you want to test. Although a variety of set ups can be used, the USP 2 is by far the most popular and widely used. It allows results between laboratories to be compared with ease. There is no need to optimize the media as these physiological compositions are fixed and are based upon the physiological fluids naturally found in the gastrointestinal tract.

Single Step and Two Step dissolution tests

There are two main types of biorelevant dissolution test: Single Step and Two Step. 

The Single Step test is the simplest study and uses just one Biorelevant Medium inside the dissolution vessel.

The Two Step test uses two different types of Biorelevant Media one after the other. At first it presents the dosage form to an acidic environment which represents the fasted stomach. It then introduces it to a more basic environment which represents the fasted small intestine. This simulates the environment a drug formulation would encounter when it passes through the upper gastrointestinal tract without food (the fasted state).

Selection of the media and test type depends on the physicochemical characteristics of the drug.

For initial experiments for basic drugs and salt forms, Single Step dissolution in FaSSGF and also FaSSIF can be tested. Once the user is confident of working with Biorelevant Media, Two Step dissolution tests can be conducted. Two Step tests can give useful insights into potential drug supersaturation which can occur when a basic drug passes from stomach fluid into the small intestine.

Single Step

This method is based around the standard dissolution described in the United States Pharmacopeia <1092> The Dissolution Procedure: Development and Validation.

Equipment:

  • USP dissolution apparatus 2 with vessels heated with a water bath
  • Optional cannula filters 
  • 0.45 micrometer filters 13 mm diameter pvdf (or equivalent using filter made of PES or glass fibre)
  • 5 ml syringes and sampling needle
  • Analytical method e.g. HPLC
  • Biorelevant Media: FaSSGF or FaSSIF or FeSSIF 
  • Timer (calibrated)

Duration: 24 hours 

Actual labour time: About 8 hours (6 hour for test preparation/dissolution and 2 hours for analysis the following day)

Replicates: 6 independent replicates 

Quantity of drug needed per test: 6 doses of the drug product

Method:

  1. Prepare the selected Biorelevant Media
  2. Fill the vessels with Biorelevant Media
  3. Drop dosage form 
  4. Start paddles 
  5. Sample and filter from the Biorelevant Media
  6. HPLC analysis
  7. Plot curve

If you want to compare the dissolution of one drug product with one reference product, it is suggested to test the two products one after the other using the method outlined above. Following completion of the dissolution tests, plot both profiles and compare curves of the drug product statistically with the reference product as described in United States Pharmacopeia, Chapter <1090>: Dissolution and in vitro Equivalence.

 

Two Step

This method is based around Method A dissolution which is described in United States Pharmacopeia, Chapter <711>: Delayed Release Forms –Acid Step. 

Equipment: 

  • USP dissolution apparatus 2 with vessels heated with a water bath
  • Optional cannula filters 
  • 0.45 micrometer filters 13 mm diameter pvdf (or equivalent using filter made of PES or glass fibre)
  • 5 ml syringes and sampling needle
  • Analytical method e.g. HPLC
  • Biorelevant Media: FaSSGF and FaSSIF 
  • Timer (calibrated)

Duration: 24 hours

Actual labour time: About 9 hours (6 hour for test preparation/dissolution in two steps and 3 hours for analysis the following day)

Replicates: 6 independent replicates 

Quantity of drug needed per test: 6 doses of the drug product 

Method: 

  1. Prepare the two selected Biorelevant Media: FaSSGF and FaSSIF concentrate
  2. Fill the vessels with FaSSGF
  3. Drop dosage form 
  4. Start paddles 
  5. Sample and filter for the first step from FaSSGF
  6. Add the FaSSIF concentrate for the second step
  7. Sample and filter for the second step from FaSSIF
  8. HPLC analysis
  9. Plot curve

If you want to compare the dissolution of one drug product with one reference product, it is suggested to test the two products one after the other using the method outlined above. Following completion of the dissolution tests, plot both profiles and compare curves of the drug product statistically with the reference product as described in United States Pharmacopeia, Chapter <1090>: Dissolution and in vitro Equivalence.

 

If you have any questions on biorelevant dissolution testing please contact us: support@biorelevant.com