Formulating an Oral Suspension (part 2)
In part 1 of this article I described the need to ensure the delivery of a uniform dose of a suspension, how this can be achieved and the challenges that can be encountered. In part 2 I’d like to discuss preserving against microbial growth, taste & “mouthfeel” and manufacturability.
Suppressing microbial growth
Aqueous solutions containing viscosity modifying polymers and other organic molecules are quite capable of supporting microbial growth. As the suspension will not be prepared aseptically nor sterilized it is necessary to incorporate an antimicrobial preservative and the effectiveness of the chosen preservative needs to be demonstrated.
USP chapter 51 describes the antimicrobial effectiveness testing as well as the criteria needing to be met. There are different criteria for the various formulation types; an oral suspension is a Category 3 product.
Taste & mouth feel
The need for a flavoring agent is dependent upon the solubility of the drug in the vehicle and its taste. In many suspensions as the drug is sufficiently insoluble little or no flavoring agent needs to be added. Many flavoring agents are natural products comprising a number of discrete substances and this can result in challenges with the analytical method (especially the stability indicating method) where the opportunity for co-elution of compounds is high.
Mouth feel is a consequence of particle size and shape and, normally is not a problem unless significant Ostwald ripening occurs.
Whilst notionally a simple process, there are certain aspects in the manufacture of a batch of suspension that need to be carefully considered.
It is typical to dissolve all the excipients of the formulation first. This allows for heating to be used if necessary e.g. for a preservative and possibly the polymer as well as for any significant mixing e.g. use of a high-shear mixer if it is required.
After that is completed the drug substance is added whilst mixing the vehicle. Depending on the properties of the drug a surface active agent may need to be incorporated into the formulation to allow rapid wetting of the drug particles. If the drug particles are particularly hydrophobic it may be necessary to prepare a pre-mix (slurry) of the drug in an aqueous solution of surface active agent which is then added to the bulk vehicle.
Whilst the polymer will typically dissolve quickly these long chain molecules will require time to solvate and expand to provide the necessary increase in bulk viscosity. This is usually achieved by leaving the formulated suspension to stand overnight, sometimes at refrigerated temperatures (depending on the polymer used). After this the suspension can be resuspended and filled into the final containers.
For more information about the manufacturing of oral suspensions, see the FDA Inspection Guide.