Formulating an Oral Suspension (part 1)
Frequently we at Velesco are approached with a request to formulate a suspension of a new compound for use in a clinical study. Often this request contains the helpful information “we mixed some drug with some 2% methylcellulose solution and dosed it to the rats without issues so this shouldn’t be a big job, right?”
Well maybe yes but probably no is the answer to that.
Formulating an oral suspension for human use is basically a balancing act. You want the drug particles to remain suspended for a reasonable length of time but you don’t want the formulation to be too thick or you won’t be able to resuspend it or easily pour it out after it’s been sitting on a pharmacy shelf for a few months. It should have an acceptable taste which is easily achieved with the flavorings that are available but do you have any idea what all the constituents of a flavor are going to do to your stability indicating HPLC method?
I can go on (and on) but instead here’s an overview of formulating an oral suspension for human use. Basically a good suspension should be formulated such that:
A standard, uniform dose is easily and consistently removed from the container.
The drug particles settle slowly and uniformly after shaking the container.
The settled solid material can be easily redispersed.
The drug particle size and distribution remain constant on storage
The suspension pours easily and completely from the container
The product does not support microbial growth.
Has an acceptable taste and “mouth feel”.
It can be easily and reproducibly manufactured over a wide range of batch sizes.
Uniformity of dose
In pharmaceutical suspensions the drug particles are typically too large to remain suspended in water and will rapidly settle to the bottom of the container. The rate of this settling (the sedimentation rate) is determined by the Stokes’ equation where particle size and vehicle viscosity can be manipulated.
Reducing particle size reduces sedimentation rate but care is needed as smaller particles have higher surface energy and so tend to flocculate to produce coarse large clumps that sediment rapidly. Flocculation can be inhibited by the addition of small amounts of a surface active agent such as Polysorbate. Suspensions where the individual drug particles remain discrete are referred to as deflocculated.
Increasing the viscosity of the vehicle reduces the sedimentation rate and this can by most easily achieved by the addition of a hydrophilic polymer such as hydroxy propyl methyl cellulose typically at levels between 1% and 3%.
Redispersing a settled product
A deflocculated suspension that settles slowly can, on extended storage, form a clay like mass which is resistant to re-suspension. In extreme cases there may be crystal growth at the junction points between the particles in this mass, this is referred to as caking and can result in a completely non-dispersible solid mass.
Additionally, whilst an increase in viscosity reduces the sedimentation rate it also increases the time and effort required to re-suspend the product and there is frequently a trade-off between the two.
Particle size and distribution
Whilst drugs formulated in suspension have, by definition, very limited solubility in the vehicle there is a constant equilibrium dissolution/precipitation of drug occurring. Whilst it is an equilibrium effect when considered at the bulk scale, at an individual particle level it is known that small particles dissolve and redeposit onto larger crystals. This effect, referred to as Ostwald ripening, causes the average particle size of the suspension to grow over time. This effect is particularly marked with frequent changes in temperature. To minimize this effect the solvating properties of the vehicle may need to be deliberately minimized e.g. by altering the pH.
USP requirements 698 & pourability
It is required that liquid products are formulated in a manner that will allow the entire contents of the container to be emptied in a reasonable time and this is detailed in USP <698>. There are two aspects to be considered, firstly that the suspension is of sufficiently low viscosity that it the container’s contents can flow out in the required period of time (30 minutes for a multi-dose container) and secondly that there is very little adherence of the suspension to the wall of the container.
The first requirement can be achieved by adjusting the amount and molecular weight of the viscosity enhancing polymer used as a suspending agent. The second by ensuring that the contact angle of the suspension vehicle on the container wall is minimized either by limiting the presence of surface active agents that may be needed to wet the drug substance particle (see manufacturability challenges later) or by choosing a container material sufficiently hydrophobic in nature.
An added advantage of minimizing the contact angle between the suspension and the container is that it eases the “pourability” of the suspension by limiting the propensity for the vehicle to adhere to the container and flow back along the outside.
In part 2 of this article we’ll develop the themes of preservation against microbial growth, taste & “mouthfeel” as manufacturability.