spray dried Eudragit L100 polymer Kim Shepard, PhD Lonza Bend - - PowerPoint PPT Presentation

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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

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Controlling the particle morphology of spray dried Eudragit L100 polymer

Kim Shepard, PhD Lonza Bend

Lonza Pharma & Biotech | Kim Shepard | 30 October 2018

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Amorphous dispersions address growing need for solubility enhancement

I

  • Marketed Products – 35%
  • Candidates – 5-10%

II

  • Marketed Products – 30%
  • Candidates – 60-70%

III

  • Marketed Products – 25%
  • Candidates – 5-10%

IV

  • Marketed Products – 10%
  • Candidates – 10-20%

Increasing Solubility Increasing Permeability

Reference 1 – Rene Holm (Lundbeck) 2010 Improving Solubility Reference 2 – Pharma A – Internal Data; 2004 – 2008 Reference 3 – M.E. Brewster 3rd 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

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Amorphous solubility enhancement is enabling

Solubility Free Energy

Low Energy Polymorph High Energy Polymorph Amorphous Drug

Amorphous formulations have higher solubility due to the increased free energy in the disordered state Supersaturated relative to crystalline state

The amo amorphous state is s thermodynamic ically un unstable

  • Given time, most 100% amorphous drugs will

crystallize to lower energy state

  • Amorphous dispersions stabilize the system with

crystallization-inhibiting polymers

  • HPMCAS (substituted cellulosic)
  • PVPVA (vinyl pyrrolidone/vinyl acetate)
  • Eudragit L100 (methacrylate copolymer)
  • Methods to manufacture amorphous dispersions
  • Spray drying
  • Hot melt extrusion
  • Milling
  • Spray layered dispersions (fluid bed)

Lonza Pharma & Biotech | Kim Shepard | 30 October 2018

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▪ 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

Amorphous solid dispersions

Lonza Pharma & Biotech | Kim Shepard | 30 October 2018

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5 30 microns Nozzle

The Process: Spray Drying

FEED SOLUTION Drug is dissolved with polymer in a common organic solvent. DRYING GAS Minimal exposure to high temperature due to evaporative cooling POWDER COLLECTION The resulting SDD powder is separated from the gas stream using a cyclone and collected DRYING CHAMBER Solvent rapidly evaporates from atomized droplets to form amorphous powder particles DSC Analysis

Reversing Heat Flow (W/g) Temperature (°C)

  • Ste
  • om

Intensity (counts)

100 200 300 400 500 600 700 800 900

2-Theta - Scale

4 10 20 30

Amorphous SDD Bulk Drug

  • Ste
  • om

Intensity (counts)

100 200 300 400 500 600 700 800 900

2-Theta - Scale

4 10 20 30

  • Ste
  • om

Intensity (counts)

100 200 300 400 500 600 700 800 900

2-Theta - Scale

4 10 20 30

Amorphous SDD Bulk Drug

PXRD Analysis

SDD

Bulk drug

The Product: Spray Dried Dispersion (SDD)

RESULTING FORMULATION

  • Rapid cooling and solvent loss

traps drug in the amorphous state

  • Homogeneous, stable,

amorphous dispersion BIOAVAILABILITY ENHANCED

  • Dissolves rapidly in intestine
  • Solubility increased
  • Maintains super- saturation in

intestine MULITPLE ORAL DOSAGE FORMS

  • Tablets
  • Capsules
  • Sachets
  • Powder in bottle
  • CR dosage forms

Spray Drying: Scalable manufacture of amorphous dispersions

100mg to metric ton scale processes, reduced to practice

Amorphous drug Polymer only SDD Physical mixture

Lonza Pharma & Biotech | Kim Shepard | 30 October 2018

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Characteristics of a successful SDD formulation

Performance St Stability Manufacturability

Lonza Pharma & Biotech | Kim Shepard | 30 October 2018

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Methacrylate dispersion polymer has high Tg and dissolves rapidly at intestinal pH

Eudragit L100 is excellent for performance and stability

Lonza Pharma & Biotech | Kim Shepard | 30 October 2018

Eudragit it L1 L100

Manufacturer Evonik Mw 125kg/mol (by viscosity) Tg 190°C Com Composit ition 50:50 methyl methacrylate: methacrylic acid Co Co-Polymer Random Aqueous solu solubilit ity Enteric, dissolves at pH > 6 Or Organic ic solu solubili lity Methanol, ethanol, IPA, acetone with >3% water, THF with >3% water, DCM with >15% methanol

25 50 75 100 125 20 40 60 80 Glass Transition Temperature, °C %RH

Drug + Eudragit L100 SDD Drug + HPMCAS SDD

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Initial manufacturing issues with Eudragit L100

Lonza Pharma & Biotech | Kim Shepard | 30 October 2018

Typical SDD Morphology Initial Eudragit L100 sprays

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Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 9

Strings form when gelling occurs before droplet break up

Mechanism of “string” formation during spray drying

Why do we see this for Eudragit L100?

  • High MW
  • High Tg
  • Gelling occurs at a lower concentration than typical

spray drying polymers

Lefebvre model for atomization

Sheets Filaments Droplets

Obser erved in instabilit itie ies with ith λ = = 5-10 µm in in SEMs

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Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 10

Strings form when tskinning < tbreakup

Within our model, two characteristic times:

Droplet skinning time

tskinning tbreakup

Droplet break-up time

Droplet skinning time

Solution concentration Drying gas temperature Solvent Volatility Solution Temperature Recycle

Droplet break-up time

Atomization pressure Nozzle geometry Solution viscosity

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Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 11

Hotter drying produces more string structures Increasing inlet temperature (Small scale dryer)

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Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 12

Dilute solutions form fewer string structures Increasing solution concentration (Large scale dryer)

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Example Map for Eudragit L100 spray drying

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140 145 150 155 160 165 170 175 180 2 4 6 8 10 12 Inlet Temperature, °C Solids Loading, wt%

Red = significant strings present Green = insignificant strings present Constant parameters: PSD-1, Methanol, 1850 g/min gas, SK80-16 nozzle, 400psi, single-pass Insufficient Drying Low through- put Polymer degrades

Lonza Pharma & Biotech | Kim Shepard | 30 October 2018

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Lonza Pharma & Biotech | Kim Shepard | 30 October 2018 14

A dimensionless parameter to assess string formation risk

𝐸𝑇𝑄 =

𝑈𝑗𝑜𝑚𝑓𝑢−𝑈𝑐𝑝𝑗𝑚 𝑈𝑐𝑝𝑗𝑚 𝐷𝑡𝑙𝑗𝑜−𝐷𝑡𝑝𝑚𝑜 𝐷𝑡𝑙𝑗𝑜 1.25 ∆𝐼𝑤𝑏𝑞 540 .75

Tinlet is the inlet temperature of the drying gas, in °C Tboil is the boiling point of the solvent, in °C Cski

kin is the concentration of the Eudragit L100

solution, in wt%, at which skinning occurs (~15% for most solvents) Csoln is the concentration of the feed solution, in wt% ΔHvap is the standard enthalpy of vaporization, in J/g. It is normalized by 540 to bring its order of magnitude close to 1 and standardize its contribution to the other terms in the equation.

Dimensionless Solvent Parameter (empirical)

In Inle let temperature So Solut lutio ion concentratio ion

Solvent volatility Drying gas flow rate Recycle (wet) drying gas Atomization pressure (pressure swirl)

Solution temperature Atomization pressure (2-fluid)*

*Depends on dryer scale

Strong effect Weak effect

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  • 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

Conclusions: Manufacturability of Eudragit L100 dispersions

Lonza Pharma & Biotech | Kim Shepard | 30 October 2018

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Want more information? https://pharma.lonza.com/contact

Lonza Pharma & Biotech | Kim Shepard | 30 October 2018