Suspensions, whilst not as common as tablets and capsules, are a very useful dosage form in several therapeutic areas. Typically, these active pharmaceutical ingredients (API) are associated with pediatric use, suspensions also have a valuable role to play in geriatric medicine as many elderly patients have trouble swallowing solid dosage forms.
Often, suspensions are thought to be a straightforward type of formulation. "It's just API in a viscous syrup," is a common refrain in some project meetings. Conversely, suspensions are actually very complex. Being an aqueous product, drug stability and microbial growth need to be addressed, as well as the ability to resuspend the product after many months of storage to provide the correct dose.
If you’re curious to learn more about this topic, our resident expert, Dave Barnes, Ph.D., Vice President of Scientific Affairs, has answered questions below directly from our industry colleagues, themselves.
For more in-depth background, check out his latest webinar, "The Evolution of An NCE’s Suspension Formulation, From Pre-GLP Studies To The Pharmacy Shelf."
What are critical quality attributes (CQAs) that need to be addressed for IND submission for suspension?
In my experience, the following requirements of USP Chapter 2 need to be provided: appearance, assay, related substances, deliverable volume (USP 698), and microbiology (USP 51, 61 & 62). Additionally, we usually do pH and occasionally viscosity when requested.
What is density matching?
Density matching is the process of preparing a liquid vehicle having the same density as the individual drug particles (different from the bulk or tapped density). The aim is to have the drug particles float freely in the vehicle with little to no sedimentation or floatation.
If an API is micronized, would that significantly help reduce risk of sedimentation in/of the suspension?
Using a smaller particle size API will reduce the sedimentation rate but that comes at the risk of caking which is common when a small particle size API is used.
How can one deal with gelling in suspension?
If by gelling you mean excessive viscosity in the vehicle upon standing, you may consider two options. The first option is to use polymers with a short solvation time so that the viscosity of the final product is evident in bulk prior to filling. Otherwise, the alternative is to check that the problem isn't due to caking of the API upon standing as this can give the appearance of a highly viscous vehicle upon resuspension.
Would particle size of API be influenced by the route of administration? For example, oral suspension versus intracutaneous suspensions?
Broadly speaking, APIs used in injectable formulations typically leverage a much smaller particle size than those used in oral suspensions. This is because an API for an injectable product needs to be small enough that the suspension can easily pass through a small-bore needle. An injectable product’s API must dissolve in a low volume, stationary environment meaning a small size is needed, whereas an oral suspension’s API has the stomach in which to dissolve.
For intramuscular suspension, what kind of dissolution testing is recommended?
In the FDA's dissolution method database, most suspension injections are tested using the Type IV apparatus (flow cell). For more information, read the FDA’s recently published article on the dissolution testing of injectable suspensions called “New In Vitro Methods to Understand and Mitigate Clinical Variability Associated with Injectable Suspensions” (2021).
Considering the formulation of low-solubility compounds, can the use of a Spray Dried Dispersion (SDD) be considered as formulation to be dispersed in a vehicle?
As, ideally, the API in a suspension has little or no solubility in the vehicle to avoid particle size changes on storage, the use of higher solubility forms of an API is not recommended for suspensions. If a SDD were incorporated in a suspension I would expect the polymer to dissolve quickly and the amorphous form of the API to dissolve and precipitate as a less soluble polymorph.
At what stage would you consider adding preservative to a formulation?
In my experience, any time an aqueous suspension is prepared more than 24 hours in advance of dosing, a preservative should be incorporated. While the USP technically permits unpreserved products to be held at refrigerated temperatures for up to 14 days, but I wouldn't feel comfortable doing that.
If a molecule’s suspension is sugar syrup based, what are the recommendations for preservatives and solubility of BCS class-2 API?
Preserving a suspension containing a significant amount of sucrose will require larger than normal amounts of preservative given it is a good medium for microbial growth. I'd recommend either Na Benzoate or K Sorbate as both have reasonably good solubility to allow effective antimicrobial levels to be incorporated.
What is important to consider when selecting preservative concentration in formulation?
Most preservatives have a recognized range of levels available on the internet, excipients handbook, etc. The FDA database of inactive ingredients also lists the levels used in approved products which is a useful reference point. Connect with one of our experts or review the American Pharmaceutical Review’s “Antimicrobial Preservatives Part One: Choosing a Preservative System” article, (Elder, Crowley, 2012).
In clinical trials, what is the most common method for dose adjustment of suspensions?
Typically, the dose of a suspension in a clinical trial is adjusted by volume. Oral syringes are available with adapters that allow precise volumes to be withdrawn from regular screw cap bottles. When developing suspensions for clinical use I always make sure that an oral syringe adapter is available for the bottle being considered. For additional insight into the use of oral syringes in clinical settings, submit a request to chat with our team or check out “Oral Syringes: Making Better Use of a Crucial And Economical Risk-Reduction Strategy” (Grissinger, 2013).
What does setting impurities criteria in the early clinical phase entail?
Please reference the ICH Q3(b) guideline and discuss this topic with the FDA at your pre-IND meeting.
Consider the other components in the product, will they have a high or low microbial bioburden? Will they support microbial growth? These answers will help determine whether a higher or lower level of preservative is required. Finally, bear in mind the pH of the product. Many preservatives have pH dependent activity which can affect the levels required.
It is clear suspensions are a more challenging formulation than they may appear at a first. Still, their application and value continue to remain relevant to (bio)pharmaceutical development today.
For more on suspension formulations, watch our webinar, “The Evolution of An NCE’s Suspension Formulation, From Pre-GLP Studies To The Pharmacy Shelf.”