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Hi everyone, I'm Laurie Lanier from Seran Bioscience and today I'll be talking beyond solubility, optimising ASD formulations for complex molecules.
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Before we jump in, let me introduce myself and Seran.
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So as she said, I'm a senior scientific writer at Seran, but I started as a technical lead in our spray drying formulation and process development team before I transition to my current role.
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Seran is a science first and data-driven CDMO in Beautiful Bend, OR.
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We have a wealth of experience and bioavailability enhancement, amorphous solid dispersions, particle engineering and oral solid dosage forms.
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We're a technical and strategic partner providing expertise, scientific expertise and flexibility required for rapid and scalable product development.
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OK.
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So today we're going to discuss designing drug products and intermediates for challenging molecules.
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As we're all aware, drug candidates are becoming more and more complex, making them more challenging to deliver orally.
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This evolving pharmaceutical landscape has changed the way we approach the design of amorphous solid dispersions.
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To understand how we have adapted our approach for challenging molecules, we will discuss how we use physiologically based biopharmaceutics models to understand and predict API absorption behaviour to guide technology selection and formulation development.
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Particularly for challenging molecules, an integrated approach is needed for the design of intermediates and drug products to meet the target product profile and the needs of the patient.
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This requires understanding the nuances of solubility and permeability limitations.
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OK, let's begin with develop the Developability Classification system or DCS.
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You may be familiar with the BCS, which is primarily designed for regulatory purposes, categorising compounds based on solubility and permeability.
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We think of the DCS as the formulators BCS, with some differences in how solubility is defined to focus on intestinal solubility to assess early candidates.
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One major difference is the division of Class 2 molecules into subcategories reflecting more absorption is typically rate limited either by dissolution or purely limited by solubility.
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And how the DCS is used to inform formulation is dependent on dose.
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For the example shown here, at low dose no enhancement is needed, it's in DCS Class 2.
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But as the dose increases, that's no longer the case.
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For the example intermediate dose, it is solubility limited.
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But permeability is fast enough that absorption may be right limited by dissolution, putting it into DCS class 2A.
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But as doses increase even higher, for this example 1000 Meg dose, even a highly permeable compound becomes limited by solubility putting it into DCS Class 2B.
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Our focus today is going to be on DCS Class 2B compounds and Class 4 compounds that are not significantly permeability limited such as complex molecules like protein degraders.
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While the DCS can identify broad bio available bioavailability limitations, there are a variety of approaches available for enabled formulations.
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So we leverage a technology selection tool that focuses on solubility enhancement.
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We can map the DCS onto the technology selection tool but first let's orient to the new representation of the plot.
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Permeability is still represented on this plot, but now it's on the Y axis down here as log P.
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And solubility is presented as a function of dose, but on the Y axis as a dimensionless dose number.
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A dose number of 1 means the dose is just soluble in the upper GI and a dose number above 1 indicates that the entire dose cannot be fully dissolved, with solubility limitation increasing as dose number increases.
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So when we fill in the rest of the technology selection guide, we can see how the recommended technology changes based on solubility and permeability.
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As expected, DCS class one and three compounds don't require any solubility enhancement as the entire dose is expected to be fully resolved.
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But for DCS Class 2 and 4 compounds, there are several technologies available.
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When a compound is known to have low solubility, the immediate thought can be to jump to an enabled formulation.
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But as this Technology Guide selection guide highlights, enabled formulations may not be necessary depending on the API properties and the target dose.
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For those numbers that are not too high above 1, particle size reduction through micronisation or nano milling may be sufficient to achieve target exposure as dissolution is the rate limiting step.
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But when solubility becomes more limiting, leveraging the amorphous form through a spray drying or hot melt extrusion allows us to access the maximum possible solubility.
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Lipid solutions are also enabling for very high target doses, but only when the compound is sufficiently soluble in lipids.
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Even this well in technology selection guide is a bit outdated as we are seeing even more compounds in this higher target dose range that's outside of the traditionally viable oral formulation space.
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Our talk is, our talk today will focus on this range with intermediate log P but high target doses where lipid solutions are not a viable option, but an amorphous form can be enabling.
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So traditionally development of an ASD has focused on preventing rapid crystallizers from precipitating out to the crystalline solubility through precipitation inhibition.
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We think of a spring and parachute model of performance where we spring up to the amorphous solubility, then slow down precipitation enough to maintain super saturation above the crystalline solubility.
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But many new compounds do not rapidly crystallise, and precipitation inhibition is not required because they already sustain the amorphous solubility on their own.
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In this traditional framework that should be sufficient to enhance bioavailability without a more complex formulation needed because the amorphous solubility is the maximum possible solubility of the drug in the intestine.
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So preventing precipitation shouldn't be needed to improve bioavailability for slow crystallizers.
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But we see time and again that formulation as an ASD for these slow crystallizers can significantly impact performance.
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So when we compare ASDs to amorphous API in a bio relevant non sync dissolution test as shown here, often we see results with a higher apparent solubility of the ASD above the amorphous solubility.
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In this two stage biorelevant non sync dissolution test, we assess performance in vitro by dosing test articles above solubility limit into and simulated gastric fluid and then transferring to a simulated intestinal fluid by dilution.
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Well this is an imperfect test as it doesn't simulate permeation.
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It allows us to understand the super saturation happening in the intestine and in this state, ASD is an example of achieving higher apparent solubility than the amorphous form, and that happens through speciation.
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You may be aware of speciation, but let's talk through it and see how it relates to drug absorption.
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So when an ASD dissolves in the lumen, several species can form.
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You have pure drug species such as solubilizer, free drug aggregates and large drug crystals.
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You can also have micelles with bile salts and drug polymer colloids.
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To be absorbed, species must diffuse through the lumen and the mucus layer lining the epithelium, referred to as the unstirred water layer, and then pass to the epithelium.
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So there are two stages to permeation, first diffusion through the unstirred water layer and then passage to the epithelium.
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Both of these stages are driven by a concentration gradient.
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Therefore, absorption of a drug is a function of both solubility and permeability.
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The areas in this diagram represent the relative diffusion rates showing that while all species can diffuse to the unstirred water layer, it's not practically possible for larger species.
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During the time scale of intestinal transit and due to the pathways of epithelia permeation, only free drug can permeate through the epithelium to be absorbed in the bloodstream.
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So the solubility governing the rate of absorption is limited to the amorphous solubility as that's what's the maximum possible solubility in this unstirred water layer.
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But as drug polymer colloids cannot be absorbed or practically diffuse through entirely through the unstirred water layer, they do not directly contribute to solubility and permeation.
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But instead drug can diffuse out of these colloids and into the unstirred water layer when drug is depleted through the epithelium permeation, thereby sustaining maximum possible concentration gradient to enhance absorption through what we call rapid resupply.
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OK, with this illustration of speciation absorption in mind, how does the increased apparent solubility of ASDs translate in vivo? While the CDMO we can't share confidential in vivo results, there are two different scenarios we see in PK studies, both of which have this in vitro result here.
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So in scenario one, the ASD outperforms the amorphous API as we expected based on that higher apparent solubility.
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But in scenario 2, the ASD and the amorphous API performs similarly, which we did not predict in an in vitro dissolution. Drug polymer colloids are formed in both scenarios and the amorphous solubility is still the maximum driving force for diffusion.
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So what is happening? In the first scenario where the amorphous API underperforms the ASD.
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The formation of drug polymer colloids rapidly resupplies free drug to replace what's diffused through the unstirred water layer and permeates epithelium.
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And we know from this that the right living step for diffusion is diffusion through the unstirred water layer because having those drug polymer colloids makes a big difference in the absorption.
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But in the second scenario where the ASD and the amorphous API perform similarly, the rate living step for absorption is the epithelium free drug is not rapidly permeating through the epithelium.
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So it's not being rapidly depleted and there's rapid resupply.
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It's kind of extraneous to increasing the rate of absorption.
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In scenario one, the way we would approach formulation design if we need this from polymer colloids is that we try our best to enhance that formulae and that colloid formation and increase that apparent solubility in vitro.
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But in scenario 2, when that kind of increase in parent solubility isn't making much of a difference in bioavailability and ASD may still be valuable for other reasons such as stability, food effects or manufacturability.
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So formulation design should focus on those aspects as increasing apparent solubility will have little effect.
10:27
As formulators, we want to produce the best formulation possible, so sometimes we'll chase minimal improvements in bioavailability to the detriment of the final drug product design, and we want to prevent that from happening because that can lead to downstream issues like increased PIL burden and poor stability.
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These scenarios are visible through in vivo data, but it is possible to develop this understanding before and in vivo study through a BPBM.
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Using the framework of the fraction absorbed classification system, we can predict the rate lettering step for absorption based on the physiological parameters and API properties that impact the fraction absorbed.
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Fraction absorbed is tied directly to solubility and permeability.
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It's a function of three dimensionless numbers, the dose number, dissolution number, and permeation number.
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As we discussed earlier, the dose number is an indicator of how soluble the dose is, with a dose number of 1 indicating the dose is just soluble in the upper GI, with solubility limitations increasing as a dose number increases.
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The dissolution number and permeability number are both defined as a function of as a function of intestinal transit time, this TBS here, and a rate coefficient that can be predicted using molecular properties such as molecular weight and charge. And these numbers can be used to predict the fraction absorbed based on dose.
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But beyond predicting the fraction absorbed, they can be leveraged to categorise a compound based on the rate limiting step for absorption.
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Absorption can be limited by dissolution and permeability or solubility, whichever process is the slowest in relation to the other two.
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The solubility limitations can be further categorised into two scenarios, solubility limited by permeability through the epithelium and solubility limited through diffusion through the unstirred water layer.
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This assessment can be done before in vivo studies using molecular properties of the drug and in vitro data and forming formulation design before dosing in a PK study.
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So let's walk through a brief example using itraconazole as a model compound.
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It's a well it's a known Class 2 compound with poor aqueous solubility available commercially as an ASD. A 200 milligram dose falls into the DCS Class 2 B.
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So when we use FACS analysis, we can determine that the absorption of itraconazole is limited by the diffusion through the unstirred water layer.
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Therefore, formulation optimization to promote the formation of colloidal species can be critical to achieving maximum of bioavailability.
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In this example, two different SDD formulations were evaluated in biorelevant dissolution testing.
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The SDDs were dosed at biorelevant doses above the limit of solubility.
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While both formulations achieve an apparent solubility above that of the amorphous solubility, there's a significant difference in the measured solubility for the HPMCAS-M SDD and the PDP-VA SDD.
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In addition, we compared it to the same formulations created but not by spray drying, but through hot melt extrusion.
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And those particle properties also make a significant difference in the formation of those colloids, which affects the super saturation of the formulation itself.
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This difference is attributable to the formation of those drug colloids and in this example of these species are a little unstable, but the precipitation down, hence why they're precipitating down to the amorphous solubility.
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But the presence of those colloids significantly impacts the apparent solubility and is predicted by FACS analysis to impact bioavailability in vivo.
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Leveraging its understanding of speciation and when and how it may impact performance can be critical to the effective development of an ASD.
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There's a lot more detail and nuance we don't have time to cover today, but I hope I've highlighted for you why understanding the nuance of solubility, how solubility is limited for low solubility compounds is crucial to understanding how to design an enable formulation, particularly for complex molecules.
14:26
Beyond precipitation inhibition the formation of drug polymer colloids can be critical for enhancing bioavailability, but not in all cases.
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A simple PBBM can be used to identify rate limiting steps for absorption prior to in vivo studies, and design of an enabled intermediate needs to consider the final drug product in an integrated approach to ensure the best drug product for the patient.
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Thank you so much for time.
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I'd love to answer any questions you may have.