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6 Formulation design Manufacturing process design Virtual patient population (PBPK, PDPK) API physical properties Dosage parameters Target release profile Manufacturing parameters Dosage regimen Patient population parameters Pharmacokinetic, pharmacodynamic response prediction Target vs predicted API release profile prediction Drug (API) Design modification logic

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9 ManufacturesGrades Particle Size, m Moisture, % Loose Bulk Density, g/cc FMCAvicel PH101503.0-5.00.26-0.31 JRS Vivapur 101 65-- 0.26-0.31 Emcocel 50M0.25-0.37 AKC PH-101 502.0-6.0 0.22 UF-7110.21 KG-8020.12 KG-10000.29 FMCAvicel PH-1021003.0-5.00.28-0.33 JRS Vivapur 102 100-- 0.28-0.33 Emcocel 90M0.25-0.37 AKCPH-102902.0-6.00.30 FMC = FMC BIOPOLYMERS AKC = Asahi Kasei Corporation JRS = J Rettenmaier & Shne GmbH and Co.KG

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10 40 data points from 9 sources E 0 : mean = 7.1 GPa stdev = 1.9 GPa rsd = 0.27 Variation due to natural variation, testing method, other? Need standardized, trustworthy source of data.

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11 Excipients - MCC Products - PH101 Lots - Lot # 1 Properties - particle size Test method - Light scattering Equipment - Malvern USP compendial category Actual product on the market

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12 Catalog of properties and measurements Raw data, chemical & test descriptions Measurement presentation of data Derived from raw data e.g., particle size, histogram Tools for usage e.g., how to ID excipients to solve problems User Interface

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19 2 components 9% active 2 components 30% active 3 components 9% active, 2% additive

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20 Void Structure

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22 Density variations in a tablet due to processing conditions (friction). PROCESS Flow around tablet (2-D approx.) ENVIRONMENT Simulation of erosion and dissolution considering the heterogeneous density distribution + Effects of FLOW Drug Release profile PERFORMANCE X-ray CT

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24 Tablet represented on Cartesian grid Each cell is assigned: o Number and size of particles o Active particle dissolution coefficient o Solvent penetration coefficient o Distance to nearest tablet surface Values assigned as simple concentrations radii and representative coefficients Tablet/Bulk fluid interface handled via level set Moving boundary conditions Erosion type can be o Uniform o Density based o Fluid-Shear influenced Simple depiction of solvent penetration over defined grid Pharmahub input gui for tablet dissolution

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