Why is biorelevant solubility so important?
Biorelevant solubility is one of the most important physiochemical properties to know when developing an orally administered drug molecule. It reveals how much drug is likely to dissolve within the intestinal fluids or, in other words, the concentration of soluble drug that is in the intestinal fluids. As explained in the Biopharmaceutical Classification System, solubility in combination with permeability influences the amount of drug that can be absorbed. This fundamental in vitro information can then be used to calculate an estimate of how much of an expected dose will dissolve in vivo.
Understanding the biorelevant solubility of a new drug can help compound selection, selection of the physical form (salt or polymorph) and pre-clinical formulation development. It can indicate if a formulation to increase drug solubility may be needed. If the drug has low solubility in Biorelevant Media, it can also predict how risky the development challenge would be if the drug were selected as a clinical development candidate. New drugs that are difficult to formulate take considerably longer and have much higher development costs.
For generic drugs, biorelevant solubility tests are generally much less important because the drug has already been commercialised. It is therefore known that the solubility of the drug product is sufficient to make the drug absorbable. In these cases, it is more typical to start with biorelevant dissolution tests.
When should biorelevant solubility tests be performed?
It is most beneficial to carry out these simple tests on an unformulated NCE drug substance before starting formulation development. Profiling your NCE’s biorelevant equilibrium solubility during preformulation studies can provide the necessary information to help guide the compound’s development.
Which Biorelevant Media should I test in?
Media selection depends upon the aim of your test. First of all, decide if you want to study the solubility of the drug in fasted (without food) state, fed state (with food) or both conditions. Fasted state media (e.g. FaSSIF) are usually measured because the fasted state is the benchmark condition for most drug dosing studies. This is because it is more convenient to administer a dosage form after drinking a glass of water and without eating food.
However, if you also want to establish drug solubility in the presence of food, then testing in media that simulate fed state fluids is also important. For drugs with low water solubility, to support labelling claims it is mandatory that clinical studies exploring the effect of food on drug exposure is carried out. Preliminary fed state solubility results can provide an early indication if your drug could be affected by the intake of food before you carry out the first fed state clinical trials.
Why is the location of the gastrointestinal fluids important?
You can also decide which Biorelevant Media to use based on the gastrointestinal fluid location you want to study. Although drug absorption can occur throughout the gastrointestinal tract, most of the dose of an immediate release drug is usually absorbed in upper small intestinal fluid because of the larger surface area available for absorption. Therefore, knowing the drug solubility in media that simulate small intestinal fluid (FaSSIF) is typically most important for any drug intended for immediate release.
How do I conduct a biorelevant solubility test?
A biorelevant solubility test is very easy to do. It’s similar to a study that you would carry out for measuring an NCE’s solubility in water. You simply use the Biorelevant Media of your choice instead of water.
Shake flask method
Using the shake flask method to measure equilibrium solubility of an NCE prior to starting formulation development is most common because of its simplicity and reproducibility. It uses small lockable vials and Biorelevant Media in the vials incubated with the test drug. The method below determines drug solubility up to 1 mg/ml. In general, if a drug has solubility of at least 1 mg/ml and a dose less than 250 mg it is likely to be soluble in gastrointestinal fluid.
Equipment (for determining solubility of one drug (assumes n=2 individual replicates)):
- 2 x 5 mL lockable vials
- 1 x oscillating shaker in an oven or incubator
- 2 x 0.45 μm filters
- 2 x 5 mL plastic syringes and two needles (23 Gauge)
- Analytical method indicating stability e.g. HPLC
- 10 mL of each Biorelevant Medium you want to test your drug in
Duration: Estimated 30 hours
Actual labour time: About 3 hours (1 hour for test preparation and 2 hours for analysis)
Replicates: At least 2 independent replicates (vials) for each Biorelevant Medium
Quantity of drug needed per test: Approximately 20 mg (for duplicate drug solubility and for HPLC)
An outline of the shake flask method is provided below and also referred to in Chapter <1092> of USP 38- NF33 (2015): Development and Validation of Dissolution Tests, Section 1.2 Determining Solubility and Stability of Drug Substance in Various Media at 37°C.
- Prepare the Biorelevant Medium
- Weigh drug in a lockable vial
- Add Biorelevant Medium to the drug in vial
- Shake and incubate sample
- Let the undissolved drug sediment
- Filter the sample
- Analyse dissolved drug by HPLC
- Calculate the drug concentration in the selected Biorelevant Medium
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