bioequivalence in a sense so you can use the population simulator within Gastro Plus to test the upper and lower ranges of the dissolution specifications that you are likely to see and see if those are bioequivalent so a way to use the software together both DDDPlus and GastroPlus - to really check and make sure that those that variability is notgoing to be key in vivo what is DDDplus it's a software program that allows you to simulate dissolution so you can simulate the dissolution rate for active pharmaceutical ingredients and excipient both and as such you can specify the particle size distribution for both the API and excipients-- you can setcertain excipients to be solubilizers or disintegrates that kind of thing we have a variety of dosage form models so IR models for powder solution tablet capsule see our models for swellable matrices and then also we have some new formulation models which we're going to talk about here today we do a fulldynamic microclimate pH calculation at the surface of the API crystals and the excipients-- and also a full pH calculation of the bulk phase pH basedon the equilibrium pH calculations in the system and we also do that for ournew formulation models which I'll show a little bit later so based on this for this pH calculation we have to take into account the composition of all acids bases and salt equivalent so you know we're tracking through the simulations you know sort of what the concentrations are of the buffers and calculating the pH we have various different apparatuses that you can choose from usp 1, 2 for an open or closed loop configuration andthen microdisk profiler from Piatt we have a multi-stage or what we call phase dissolution experiment option where you can set you know like a gastric to intestinal buffer or transit experiment up so if you have you know drug dissolving at pH 1.2 then you can have it translate transfer to a you know an intestinal buffer at ph 6.5 we also have updated our my self facilitated dissolution so you know we you can model bio relevant surfactants you can model QC dissolution surfactants like SLS or tween but we also in this version have allowed you to model more than two surfactants and also in the dissolution phase experiments you can specify buffers with different surfactants and that will automatically be tracked in and utilized for the calculations of solid ability formulation models this was these were the formulation models available in version 5 of the software I'll show you the new ones and for forversion 6 here in a minute but you know in version 5 at least we had powder tablet capsule beat IR bead coding a delayed release coated tablet and CR controlled release matrix tablets and a bilayer tablet again the experimental apparatus of shown here the USP one USB to USB for flow through an open or closed loop in the P ion micro dis profiler are available we have some new we have a new ASD model artificial stomach duodenum apparatus model that we've added here to a TV +6 and we'll show that here in a minute of course once you've run a simulation and set that all up you can you know output the results in several ways and/or analyze the formulation in several ways you can simply plot the percent release versus time for the different excipients and the active ingredient at the pH changes in the micro and the microclimate and in the bulk fluid you can do virtual trials to look at your dissolution variability based on processor content uniformity you can do PSA analysis to look at you know what would happen if I changed the particle size a certain amount or you know pH of the media a certain amount and then f1 and f2 calculations can be done as well so that gets us to that's you know the introduction of the software getting familiar familiarized with what it is and now i'm going to go into the new features of in version 6 so the main new features here are going to be we'regoing to talk about three new apparatuses we have the artificial stomach duodenum membrane dissolution and the biphasic dissolution a few newtools so we have batch processing F 1 and F 2 tool so you can read in a bunchof diff and in vitro profiles and calculate F 1 F 2 and then improve multistage.
Dissolution experiments also new models of new models for long-acting injectable PLGA microspheres solution model for precipitation and then see ourcode at bead model so the first thing we're going to talk about is the artificial stomach duodenum model so on the drop-down for apparatus type you can now select artificial stomach duodenum model it allows you to model three compartment ASD model which is similar to like the literature experiments you find that have been published by Pfizer Lilly University of Michigan that kind of thing where you have an initial drug dose to the stomach it the drug gets emptied via at some rate the gastric emptying time here and then it gets pumped into the duodenum volume which is held constant at a given volume and then the pump that pumps the the fluid out of the duodenum into the genom is you know automatically adjusted such that the duodenum stays at that constant volume and then the waste compartment just collects all the buffer flows from the upper compartments into this waste or jus genom compartment inthe model you have the ability to select the initial buffer for every single compartment so initial buffer would be just the initial concentration of all the buffers in the stomach duodenum and waste compartment and then you also have buffers or reservoir buffers is what we call them where you can pump in fresh buffer into the stomach the duodenum or the waste compartment typically you would be pumping in two or four times concentrated facet in the duodenal compartment to counteract the acid changes there that are occurring based on the gastric emptying and then again you have the the choice to you know set your initial volumes of the system if you you can use constant pH mode so you could set the PHS of each compartment orthe software will automatically dynamically calculate the concentrationof all the buffers salts in in each compartment and calculate the pH you know using the equilibrium equations you can set the buffer flows transit time for a solid dosage form so this would be for like an IR tablet you canset if it's manually moved from compartment to compartment otherwise the solids that are dissolved will not let not necessarily dissolve will call them released into the fluid will transit based on the transit times of the system based on the gastric emptying and the flow rates and the buffers so this is is really a you know one of our new models that allows you to you know really look at the transit between compartments and the precipitation that happens in going from the stomach to the duodenum compartment for like a basic drug let's let's say for instance and we have one example onequick example of how how this is done for zone where we have where we able to pull out pull out literature for the to build a gastro plus model so we have the volume of distribution the clearance the permeability of this compound and we have information regarding the pKa and log P from ad predictor we were able to find solubility data in literature for across the pH ranges so we were able to build a nice dissolutionmodel for for and gastro Plus model for this compound so we took some literature data for the ASD where they looked at the tablet of 30 dosing that into the stomach and then watching it dissolve fully into the stomach then trends transferred to the duodenum and then be collected in the compartment and we looked at that and try to calculate the particle size of the API and the precipitation rate which were unknown values in the system so we use the five-minute initial gastric emptying rate as the training set to calculate the particle size and the precipitation rate and then we applied that same values to the seven point five millimeter and ten minute initial gastric empty so with that the default parameters on the left for just 25 microns particle size the default since we didn't know the particle size we optimized it and and then calculated the precipitation time in zone as it goes from high solubility environment in the gastric the red to the do sorry duodenum compartment the yellow and then the collection and the jus general compartment so we found that a precipitation time of about 2,000 seconds 2,200 seconds was what was needed to fit that data set we also it's not shown here but we also found simple precipitation assays where they just Do into a vessel and watched it precipitate and those precipitation times ranged from a hundred seconds to a thousand seconds so in this case the ASD model did seem to provide may be a little bit more realistic precipitation times than a more simple experiment we then applied those parameters to the faster gastric emptying times and and you know we got fairly decent results with the same parameters so we then tried to use those within a gastro plus model to simulate the precipitation.
Comments
Post a Comment