Sink condition is mentioned a lot when it comes to dissolution testing, but its importance is often left out. The background and relevance of this topic is further described and discussed by  , Dissolution Product Specialist at Agilent. This information was initially posted on Ken's LinkedIn page.

Sink condition is the ability of the dissolution media to dissolve at least 3 times the amount of drug that is in your dosage form. Having sink conditions helps your dissolution have more robustness as well as being more biologically relevant. Why is 3 times the magic number when it comes to sink condition? This value comes out of the Noyes-Whitney equation, one form of which is displayed below:

Where the terms are:

• R = Dissolution Rate
• k2 = Intrinsic Dissolution Rate
• D = Diffusion Coefficient
• S = Surface Area
• v = Volume
• h = Thickness of Stagnant Layer
• Cs = Saturation Constant of API
• Ct = API Concentration at Time t

Looking at this equation, we see that the Dissolution Rate (R) is proportional to the term (Cs - Ct). This is the difference of the concentration at saturation compared to the concentration at a given time. So, the closer our concentration gets to saturation, the slower the dissolution rate becomes. You can see this same thing happen when you make sugar water - the first scoop may need no mixing and goes readily in solution, but the 10th scoop requires mixing and heating and quite a bit of time.

In a patient, drug product is not typically getting anywhere near saturation, and this slowing of the dissolution rate is not experienced. The dosage form is moving through the body and we are eating and drinking throughout the day. So, when we are testing in vitro, we must minimize this artificial issue. This is where the importance of sink condition is demonstrated.

• If sink conditions are met, then at the beginning of the dissolution the (Cs-Ct) term would be 3-0. At the end of the dissolution, you would be at 3-1 or 2. Over the course of the dissolution, your dissolution rate would be slowed by only 1/3 due to the drug already dissolved in solution. At this level, we see an impact to the dissolution curve, but not one that is excessive.
• If sink conditions are not met, it becomes more challenging to match in vivo performance (since in vivo doesn't experience saturation). This could also present robustness issues in your dissolution method. For robustness, this is important because relatively minor day to day changes will have greater impacts when you're not meeting sink. For example, if an analyst uses 910 mL of media vs. 890 mL, or the temperature is 36.5°C vs. 37.5°C, and so on - this variability can have greater impact than it would otherwise.

It should also be noted that there are existing and validated dissolution methods which do not meet, or are below, sink conditions. This certainly isn't preferred, but is allowed if you've sufficiently demonstrated the method to be effective. If you aren't meeting sink conditions, then there are a few ways to improve the solubility of your product:

1) Change the API - if still in the early stages of formulation development, you may be able to find an API with better solubility, such as one complexed with a salt.
2) Adjust the pH of the dissolution media.
3) Add surfactants - be sure to try multiple types. SLS/SDS is most popular, but has a lot of challenges associated with it. CTAB, Tween, Triton X, and others are all commonly used and effective.
4) Increase volume of dissolution media - larger vessel systems (e.g., 2-liter) are available from some dissolution vendors.
5) Add alcohol - this is generally a last resort, so don't rush to this as a solution.

I hope this was helpful, and please let me know if you have any questions. There are many more details related to this complex topic, so feel free to contact our team of experts at dissolution.hotline@agilent.com for more clarification or support.

DE24178104