Performing Dissolution in <500mL

Dissolution is constantly evolving as novel dosage forms are made, and require release rate testing. One area in which dissolution needs are changing rapidly is in the area of small-volume dissolution testing. For the purposes of this discussion, I want to focus on some different approaches to testing in volumes below 500mL (the lowest volume recommended in a standard 1L dissolution vessel).

Small-volume dissolution is being required more often now due to some newer products which are challenging to perform in a conventional volume. Some of these products include:

-Low-dose solid oral formulation

-Low-dose drugs for a non-oral delivery or simulating a lower-volume environment

-Long-term release testing such as implantable devices

Depending on the volume requirements of the formulation, there are several options for testing using USP Compendial Dissolution Apparatus or making some non-compendial adaptations to a USP Apparatus. There are several good options worth consideration for USP Apparatus 1-4, and 7.

I'll start by reviewing the various options, and then get into some discussion of qualification of these systems and areas to consider.

Modifications to USP Apparatus 1 and 2

Modifications to USP Apparatus 1 and 2 are the most common approach to performing small-volume dissolution testing. While the small-volume vessels for the most part aren't compendial, they do offer a number of advantages. First, they only require modifications to dissolution units that are already in the lab so they require much less investment than a new system. There are a variety of options for modification of Apparatus 1 and 2.

There are 3 small volume vessels currently available, 100mL, 200mL, and 250mL. The vessel pictured above is the 250mL CP vessel with minipaddle. This vessel is compendial in the CP, but not yet in the other Pharmacopeia.

The small volume vessel kits can be utilized with either minipaddles, minibaskets, or a standard basket. Minimum volumes in these vessels are usually around 1/2 full, allowing you to achieve about 40mL dissolution in a 100mL vessel, 120mL in a 200mL vessel, and 150mL in the 250mL vessel.

Another small-volume adaptation to Apparatus 1 and 2 is the Enhancer Cell. This is a 200mL flat-bottom vessel (as opposed to the other vessels which are round-bottom). This system it utilized for testing semi-solid formulations such as creams and ointments and can be found in the topicals chapter in the USP.

Aside from the advantage of these modifications being less investment, they offer some additional advantages as well. These systems are easily automated with autosamplers, online UV, or Fiberoptics. This is especially useful, since manual sampling in a smaller vessel can be more challenging. These systems are also easy for a user to learn quickly, and offer easier set-up than some of the other options.

USP Apparatus 3 (Bio-Dis)

The Apparatus 3 is a compendial system which is already at a lower volume. The standard volume of this system is 300mL, and can be operate around 175mL effectively. This system is ideal when greater agitation is required, or pH changes are needed. In addition, the system also has a non-compendial 100mL vessel configuration as well. The 300mL Bio-Dis has the advantage of being a standard USP compendial device, and can be configured with automated sampling.

USP Apparatus 4 (Flow-through Apparatus)

The USP Apparatus 4 has a variety of cells available, and can be utilized in a closed loop configuration which can allow for a small dissolution volume. I believe the operational minimum is around 25mL - however, I am not as familiar with this system as I am with others - so this information could be outdated.

USP Apparatus 7 (Reciprocating Holder)

USP Apparatus 7 is a reciprocating holder system which offers a wide variety of dissolution volumes, all of which are compendial. There a 2 main types of Apparatus 7 systems - an open system which is similar to the Apparatus 3 (Bio-Dis) above and the 400-DS system which is a very low volume instrument intended for low-dose drugs with long release rates.

Apparatus 7 has a variety of holders and vessel types which allow for testing of different types of dosage forms. There are various holders which can be used for small transdermal patches, osmotic or other tablets which do not disintegrate, medical devices, and other systems.

The other Apparatus 7 system is the 400-DS. This system is the lowest dissolution volume system available, and can be used with either a 5mL or 10mL vessel. This system was made specifically for testing medical devices which require testing that takes several days or weeks. It has almost no evaporation loss due to the vessels being sealed, can be used at elevated temperatures, and with some alcohol.

As with the traditional Apparatus 7, there are a variety of holders for different types of products including stents, leads, contact lenses, small implants, etc.

This system has a built-in autosampler, and is the only system fully intended for medical devices. It is suitable for products other than medical devices, but they must be non-disintegrating. If volume requirements are very small, or test length very long, this system may be optimal.

Qualification Requirements of Small Volume Systems

Qualification procedures of small-volume systems depend upon what Apparatus is being used, and if the system is compendial or not.

Apparatus 3, 4, and 7 systems are all compendial at lower volumes. The 100mL Apparatus 3 system and some Apparatus 4 holders would be considered non-compendial, however, and would possibly need some additional checks. For the compendial Apparatus 3, 4, and 7, follow the IQOQ guidelines for installation, and manufacturer recommended system checks at 6 month intervals to ensure the system is still working as designed. There is no PVT or MQ for these systems, so an abbreviated OQ procedure is typically recommended. For non-compendial devices on the systems, it is still recommended to do the OQ procedure as best as possible as well as any additional alignment checks, etc. as needed.

For small volume Apparatus 1 and 2 systems, I recommend that the dissolution unit is qualified as a 1L system first. Once the overall system is qualified by PVT or MQ, then the 1L components can be switched with the small volume accessories. Once the change has been made, height of the paddle/basket should be set in the small volume vessels. Some checks are recommended to ensure that the small volume system is properly aligned. Not all measurements that can be done in a 1L vessel are possible in a small volume set-up, but you should be able to take a measure of upper centering and vessel and shaft verticality to give a good indication of the overall alignment of the system.

Other considerations

Small-volume devices must have proper care taken in their use as with standard dissolution equipment. Evaluation should be made to ensure that the systems are reproducible, maintain a low evaporation rate, don't have excessive vibration, or any other issues which could lead to test bias or high variability.

Evaporation is usually the biggest challenge with small-volume systems. When you're already starting off with a small volume, volume loss can pose a large analytical challenge for proper quantification as well as maintaining hydrodynamics. When considering a small volume system, weigh the length of the test with the apparatus being chosen and how the evaporation is controlled. Depending on the system used, you may be fine for hours or several days.

As always, these are a collection of my thoughts and shouldn't be taken as the opinion of Agilent or regulatory authorities. This is a very quick discussion of a complicated topic, so if you have any questions or would like more information, please let me know.

Thanks!