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Video Transcript for Rheology for Generic Pharmaceuticals:
If you’re formulating a generic pharmaceutical liquid or semi-solid then you’re not don’t need to submit some evidence of what we call structural equivalence of your product to the reference listed drug or the originator’s product to the regulatory bodies, a range of real logical properties are often requested to gain a comprehensive comparison of the two formulations, we provide this as a service for our customers but if you want to do this yourself or you just want to get a better understanding of the properties involved then here’s a super quick guide.
So what are the authorities typically asking for? well here’s an example from the US FDA’s draft guidance on acyclovir common generic topical and here’s an example from the European medical agency, the EMA draft guidelines on the quality and equivalence of topical products.
So let’s put out some of the key requirements in these a complete flow curve of shear stress or viscosity versus shear rate shear stress as a measure of how hard you push a material shear rate is a measure of how fast it flows so viscosity therefore is just the ratio of how hard you push to how fast it flows the ratio of stressed shear rate so suspensions emulsions and gels all exhibit non-Newtonian shear thinning behaviour so that means their viscosity is dependent upon shear rate and the viscosity decreases at higher shear rates however you measure the viscosity across a wide range of shear rate you’re gonna get a plot that looks something like this you can see here that the non-Newtonian shear thinning only occupies the middle shear rate region but Newtonian behaviour is seen as low shear and high shear plateaus the viscosity is attained at these plateaus are known respectively as zero shear viscosity and the infinity of viscosity zero shear viscosity is particularly interesting as it can give you an idea of the mobility of suspended solids where most of my droplets went in and close to at rest condition so when the FDA asked for a complete flow curve until low or high shear plateaus are identified this is what they mean and I’m pretty certain this is what also what the ear may refer to when they quote linear portions of the curves so the bit in the middle there shear thinning region is usually a straight line so this could be fitted to a power law model but if you want to model the whole curve then you can use a modification of the power law models such as the cross or the Karo model and then that will quantify the zero shear in the infinite shear viscosity values as well incidentally notice that we’re using logged axes here this speakers on the shear rate axis a lot of interesting stuff occurs at the low end that we want to emphasize and on the y axis were the changes in viscosity for your normos and we need to fit it all in to make sense of it all if this was plotted on a linear scaling it’s gonna look like this which is next to useless okay so next is yield stress yield stress can be thought of as a strength of the soft solid structure that is created in your products as a result of a mass of interactions droplet interactions particle interactions surfactants polymers that kind of thing the yield stress is a key contributor to application properties sensory properties delivery from a container therefore it’s really important when it comes to topical products anything that goes on the skin yield stress can be measured in a number of different ways one of which is to use occsillitary stress sweeps.
Occsillitary testing comprises really cool set of techniques where you nudge your sample structure very gently and watch it bounce back in an asymmetry stress-free phase angle effectively a measure of the presence of structural changes as stresses increased an increase in phase and indicates the disruption of structure as the yield proceeds at that point we’ve identified the yield stress of the sample so next in the guidelines we see.
Linear viscoelastic response storage modulus and loss modulus as a function of frequency when we oscillate the very small stresses we operate in what we call the linear viscoelastic region for the material the storage modulus and the loss modulus are just the elastic and the viscous so the solid night on the liquid light contributions to the overall rigidity of the sample structure so if you want a simple but very unscientific explanation of storage and loss modulus then you should take a look at my video storage and loss modulus for beginners so the regulatory bodies request storage and loss modulus versus frequency in the test the sample is oscillated and a range of frequencies effectively imposing a range of deformation timescales on the sample the reason they do this is a by assessing the relative relationship between the moduli across the range of frequencies it’s possible to identify similarities or otherwise that are reflected in microstructure a typical pharmaceutical cream for example we usually exhibit what we call an elastic dominant response with G prime the storage modulus been higher than G double Prime their lost modulus across that range of frequencies so if that’s not the case for the generic version of the formulation then that suggests a lack of structural equivalence.
Okay so finally creep testing creep testing is far less popular in common than the viscosity profiling or the axillary testing methods creep testing entails applying a small stress to the sample maintaining that stress over a period of time and monitoring the strain so the amount of deformation as the experiment Pirtle proceeds so the sample has undergone an initial highly elastic deformation but eventually the deformation rate slows to a steady-state viscous flow and the plot straightens the slope in the steady-state region gives us the shear rate by dividing the applied stress by this shear rate we obtain a viscosity and because his viscosity was attained at very low stresses well into the linear viscoelastic region the viscosity is indicative of the viscosity in a close to a depressed condition now I suspect that this is the only information that the authorities take into account from a creep test but if anybody knows otherwise please let me know okay so we’ve covered some of the information here that is required by the regulatory bodies to assess the equivalence of a generic product to a reference listed drug actually gathering the data on your samples is not often the easiest of tasks and getting reliable repeatable data that’s free from artifacts can be a challenge.
If you need some help in that department then contact us come through the website at reality lab comm or drop us an email at lab our biology lab comm we’d love to help you please hit the like button if this is working for you subscribe if you want to see more videos and I look forward to seeing you at the next one
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