Application of Fundamental Relationships and Models to Predict Spray-Dried Dispersion Particle Size John Baumann, Sr. Principal Engineer Drug Product Development and Innovation Lonza - Bend, OR Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018
Spray-drying for Bioavailability Enhancement Using Spray- Dried Dispersions Atomizati tion The Process Nozzle Drying Gas Drying Chamber The solution is spray-dried to remove the solvent Feed Solution Drug is dissolved with excipient(s) in a common solvent Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 2
Droplet Drying Process Defines SDD Particle Attributes Holl Ho llow Sp Sphere T particle > > T boil P particleSolventVapor > > P sprayD yDryer Dr Drie ied Part rticle le Droplet Dr Solv olvent Skin in Formation Evaporation Formation Solvent Solvent, Polymer Col Colla lapsed Ho Hollo llow Sp Sphere and API T particle < < T boil Solvent P particleSolventVapor < < P sprayD yDryer Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 3
Particle Size Considerations Performance Manufacturability – Spray-drying Scale-up PSD SD-1 70 140 Drug Concentration (µg/mL) Droplet D[3,2] (µm) 120 PSD SD-2 60 100 PSD SD-4 50 80 40 60 30 40 20 20 0 10 0 500 1000 1500 2000 0 Flowrate (g/min) 0 30 60 90 Time (min) Manufacturability – Powder Flow 10 y = 0.0807x + 0.9123 8 R² = 0.9214 ffc at 3kPa 6 4 2 0 0 20 40 60 80 100 D(50) [µm] Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 4
Approaches used to measure or predict droplet size Empirical Models Experimental Tools First Principles Models / CFD TSI I - PDP DPA Malv lvern - Spraytec Belhadef, et al. Pressure-swirl Atomization: Modeling and Experimental Approaches. Int J Multiphase Flow. 2012. Ashgriz, ed. Handbook of Atomization and Sprays. 2011. Increasing Complexity / Resource Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 5
Atomization and Droplet Formation Pressure Swirl Nozzles No Nozzle le Operatin ing Par arameters Solution Propertie So ies Nozzle No le Ge Geometry ry • Nozzle Pressure • Viscosity • Orifice Diameter • Solution Feed Rate • Density • Swirl Channel Diameter • Surface Tension • Number of Swirl Channels Lefebvre 0.25 ሶ 𝐸 3,2 = 2.25𝜏 0.25 𝜈 𝑀 0.25 ∆𝑄 −0.5 𝜍 𝐵 −0.25 𝑛 𝑀 𝑀 Jones 0.03 0.07 −0.13 0.21 −0.22 ሶ 𝑚 0 𝑀 𝑡 𝐵 𝑡 𝐸 𝑡 0.16 𝜈 𝐻 −0.04 𝜍 𝑀 0.315 ∆𝑄 −0.47 𝐸 50 = 2.47𝜏 0.25 𝜈 𝑀 𝑛 𝑀 𝑀 𝑒 𝑝 𝐸 𝑡 𝐸 𝑡 𝑒 𝑝 𝑒 𝑝 Arthur Lefebvre, Atomization and Sprays (1989) Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 6
Model Approach – tying droplet size to SDD particle size 0.25 ሶ 𝐸 3,2 = 2.25𝜏 0.25 𝜈 𝑀 0.25 ∆𝑄 −0.5 𝜍 𝐵 −0.25 𝑛 𝑀 𝑀 Drie Dr ied Part rticle le Skin in Formation Droplet For Dr ormation d ski skin =d SD C drop *V drop =C ski skin *V skin SDD Solvent, Polymer and API Assumptions: • Polymer properties dominate solution properties and skinning concentration • Drying rate after film formation does not significantly impact final SDD particle size (no impact of morphology) Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 7
Spray Drying Case Study – HPMCAS SDDs from Acetone BLD BLD-35 35 Var ariable Mea easurement te technique Solvent Acetone Polymer HPMCAS-M Concentration range of HPMCAS 1wt% – 9wt% Dryer Scale BLD-35, BLD-200 Solu Solution Property Mea easurement te technique Res esult lts BLD BLD-200 200 Viscosity Low shear 0.6 – 14 cP (Hydramation ReactaVisc) Surface Tension Tensiometer 23-25 mN/m (Wilhelmy plate) Skinning Concentration Thermogravimetric 21wt% Analysis Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 8
Particle Size Predictions for HPMCAS SDDs By scale / nozzle type 60 BLD-200 (Spraying Systems SK) BLD-35 (Schlick 121) 50 Actual SDD D[3,2] (µm) 40 y = 0.7562x - 1.1302 R² = 0.9773 30 20 y = 0.7498x - 5.9343 10 R² = 0.8554 0 0 10 20 30 40 50 60 Predicted SDD D[3,2] (µm) Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 9
Particle Size Predictions for HPMCAS SDDs Combined data 60 60 50 50 (µm) D[3,2] (µm 40 40 y = = 0.6 .6812x - 2.4 .4577 l SDD D[3 R² ² = = 0.8 .8374 30 30 ctual 20 20 Act 10 10 0 0 10 10 20 20 30 30 40 40 50 50 60 60 Predicted SDD D[3 D[3,2] (µm (µm) Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 10
Model Troubleshooting – viscosity value for droplet size Unrealistic values required (viscosity < pure acetone) to make predicted = actual 0.25 ሶ 𝐸 3,2 = 2.25𝜏 0.25 𝜈 𝑀 0.25 ∆𝑄 −0.5 𝜍 𝐵 −0.25 𝑛 𝑀 𝑀 10 y = 0.3666e 0.4029x Measured viscosity R² = 0.9929 Fit Viscosity y = 0.1202e 0.2959x 1 R² = 0.508 Viscosity (cP) Ace cetone Vis iscosity 0.1 0.01 0 2 4 6 8 [HPMCAS] in acetone (wt%) Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 11
Model Troubleshooting – skinning concentration Unrealistic values (>>100%) required to make predicted = actual C dr op *V drop op =C skin kin *V skin drop 900 Skinning concentration (wt%) 800 700 600 500 400 300 200 100 0 0 2 4 6 8 10 Polymer concentration (wt%) Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 12
Model Troubleshooting – Constant value for droplet size Adjusting model constant = 1.33, shows improved accuracy 0.25 ሶ −0.25 𝐸 3,2 = 2.25𝜏 0.25 𝜈 𝑀 0.25 ∆𝑄 −0.5 𝜍 𝐵 𝑛 𝑀 𝑀 60 50 Actual SDD D[3,2] (µm) 40 y = 1.149x - 2.4577 R² = 0.8374 30 20 10 0 0 10 20 30 40 50 60 Predicted SDD D[3,2] (µm) Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 13
Summary ❑ Application of empirical models and fundamental relationships can be applied for predicting SDD particle size as demonstrated by HPMCAS case study ✓ Sensitivity analysis of Lefebvre model identified gaps with viscosity value (e.g. as f(shear rate)) and constant – this was anticipated from the conditions which this model was developed ✓ Accuracy of Lefebvre droplet size prediction needs further refinement for polymeric spray solutions ✓ Skinning concentration was not found to have a large impact on the model prediction ❑ Ongoing work focuses on a range of formulation and process considerations to broaden the applicability to additional dispersion polymers Lonza Pharma & Biotech | Drug Product Development and Innovation | John Baumann | 30 Oct 2018 14
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