Controlling the particle morphology of spray dried Eudragit L100 polymer Kim Shepard, PhD Lonza Bend Lonza Pharma & Biotech | Kim Shepard | 30 October 2018
Amorphous dispersions address growing need for solubility enhancement Increasing Solubility II I Increasing Permeability • Marketed Products – 30% • Marketed Products – 35% • Candidates – 60-70% • Candidates – 5-10% IV III • Marketed Products – 25% • Candidates – 5-10% • Marketed Products – 10% • Candidates – 10-20% Reference 1 – Rene Holm (Lundbeck) 2010 Improving Solubility Reference 2 – Pharma A – Internal Data; 2004 – 2008 Reference 3 – M.E. Brewster 3 rd Annual Congress on Strategies to Enhance Solubility and Drug Absorption 2008 Reference 4 – Pharma B – Internal Data; Oncology and Anti-Infectives Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 2
Amorphous solubility enhancement is enabling The amo amorphous state is s thermodynamic ically un unstable • Given time, most 100% amorphous drugs will Amorphous Drug crystallize to lower energy state • Amorphous dispersions stabilize the system with Solubility crystallization-inhibiting polymers • HPMCAS (substituted cellulosic) High Energy Polymorph • PVPVA (vinyl pyrrolidone/vinyl acetate) • Eudragit L100 (methacrylate copolymer) Low Energy Polymorph Free Energy • Methods to manufacture amorphous dispersions • Spray drying • Hot melt extrusion Amorphous formulations have higher solubility • Milling due to the increased free energy in the • Spray layered dispersions (fluid bed) disordered state Supersaturated relative to crystalline state Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 3
Amorphous solid dispersions ▪ Known in the literature for over 40 years ▪ ~20 products on market ▪ Lonza Bend experience: • >1000 compounds advanced through pre-clinical studies • >100 compounds advanced through clinical studies • 3 Commercial manufacturing awards Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 4
Spray Drying: Scalable manufacture of amorphous dispersions 100mg to metric ton scale processes, reduced to practice The Product: Spray Dried Dispersion (SDD) The Process: Spray Drying DSC Analysis Nozzle RESULTING FORMULATION DRYING GAS FEED SOLUTION • Reversing Heat Flow (W/g) Minimal exposure to Rapid cooling and solvent loss high temperature due to SDD Drug is dissolved traps drug in the amorphous evaporative cooling with polymer in a state common organic • Homogeneous, stable, Physical mixture solvent. amorphous dispersion Polymer only DRYING CHAMBER Solvent rapidly Amorphous drug BIOAVAILABILITY ENHANCED evaporates from • atomized droplets to Dissolves rapidly in intestine Temperature ( ° C) form amorphous powder • Solubility increased particles • Maintains super- saturation in PXRD Analysis intestine 900 900 900 SDD Intensity (counts) Intensity (counts) Intensity (counts) MULITPLE ORAL DOSAGE 800 800 800 Amorphous SDD Amorphous SDD 700 700 700 FORMS 600 600 600 • Tablets 500 500 500 • 400 400 400 Capsules POWDER COLLECTION 300 300 300 • Sachets Bulk drug The resulting SDD powder is 200 200 200 Bulk Drug Bulk Drug • separated from the gas stream Powder in bottle 100 100 100 0 0 0 using a cyclone and collected • CR dosage forms 4 4 4 10 10 10 20 20 20 30 30 30 2-Theta - Scale 2-Theta - Scale 2-Theta - Scale 30 microns oom oom oom - Ste - Ste - Ste Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 5
Characteristics of a successful SDD formulation St Stability Manufacturability Performance Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 6
Eudragit L100 is excellent for performance and stability Methacrylate dispersion polymer has high T g and dissolves rapidly at intestinal pH Eudragit it L1 L100 Manufacturer Evonik M w 125kg/mol (by viscosity) 125 190 ° C T g Drug + Eudragit L100 SDD Composit Com ition 50:50 methyl methacrylate: 100 Glass Transition Temperature, °C methacrylic acid 75 Co Co-Polymer Random Drug + HPMCAS SDD Aqueous solu solubilit ity Enteric, dissolves at pH > 6 50 Organic Or ic solu solubili lity Methanol, ethanol, IPA, 25 acetone with >3% water, THF with >3% water, DCM 0 with >15% methanol 0 20 40 60 80 %RH Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 7
Initial manufacturing issues with Eudragit L100 Typical SDD Morphology Initial Eudragit L100 sprays Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 8
Mechanism of “string” formation during spray drying Strings form when gelling occurs before droplet break up Lefebvre model for atomization Obser erved in instabilit itie ies with ith λ = = 5-10 µm in in SEMs Sheets Filaments Droplets Why do we see this for Eudragit L100? • High MW • High T g • Gelling occurs at a lower concentration than typical spray drying polymers Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 9
Strings form when t skinning < t breakup Within our model, two characteristic times: Droplet Droplet skinning time break-up time Droplet break-up time Droplet skinning time Solution Atomization t breakup concentration pressure Drying gas Nozzle temperature geometry Solvent Solution Volatility viscosity t skinning Solution Temperature Recycle Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 10
Hotter drying produces more string structures Increasing inlet temperature (Small scale dryer) Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 11
Dilute solutions form fewer string structures Increasing solution concentration (Large scale dryer) Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 12
Example Map for Eudragit L100 spray drying Red = significant strings present Green = insignificant strings present 180 Polymer degrades 175 Low 170 Inlet Temperature, °C through- 165 put 160 155 150 145 Insufficient Drying 140 2 4 6 8 10 12 Solids Loading, wt% Constant parameters: PSD-1, Methanol, 1850 g/min gas, SK80-16 nozzle, 400psi, single-pass Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 13
A dimensionless parameter to assess string formation risk Dimensionless Solvent Parameter (empirical) Strong Inle In let temperature 𝑈𝑗𝑜𝑚𝑓𝑢−𝑈𝑐𝑝𝑗𝑚 effect 𝑈𝑐𝑝𝑗𝑚 So Solut lutio ion concentratio ion 𝐸𝑇𝑄 = 1.25 ∆𝐼𝑤𝑏𝑞 .75 𝐷𝑡𝑙𝑗𝑜−𝐷𝑡𝑝𝑚𝑜 𝐷𝑡𝑙𝑗𝑜 540 Solvent volatility T inlet is the inlet temperature of the drying gas, in ° C Drying gas flow rate T boil is the boiling point of the solvent, in ° C Recycle (wet) drying gas C ski kin is the concentration of the Eudragit L100 solution, in wt%, at which skinning occurs (~15% for Atomization pressure (pressure swirl) most solvents) C soln is the concentration of the feed solution, in wt% Solution temperature ΔH vap is the standard enthalpy of vaporization, in J/g. Atomization pressure (2-fluid)* It is normalized by 540 to bring its order of Weak effect magnitude close to 1 and standardize its *Depends on dryer scale contribution to the other terms in the equation. Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 14
Conclusions: Manufacturability of Eudragit L100 dispersions • Spray drying high- aspect ratio “string” particles is possible for all spray drying particles • To prevent string formation during spray drying, increase the time to polymer gelling, or decrease the time to droplet break up • Dimensionless solvent parameter predicts effect of dominant process parameters on string formation Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 15
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