Design of Solid Dosage Formulation and Process via Fundamental Understandings of Soft Matters

Jie Ren September 2018

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A tribute to Robert P. Behringer

GSOFT/FIAP Co-sponsored Focus Session Session #: GSOFT - 02.01.19 / FIAP - 22.01.03 Organizer: Jie Ren, Joshua Dijksman, (Bob Behringer) “Multiphase physics: soft matter research at the interface of industrial and academic interests” -- with a focus on physics at soft matter interfaces

What are soft matters?

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Where are soft matters?

Can we look beyond the diversity?

• Powders || Colloids || Porous Structures || Gels || Polymers || Cells || etc... • Disordered || Amorphous || Multi-particular || Multi-component || Multi-phase || etc… • Friction || Adhesion || Electro-magnetics || Sound propagation || Vapor sorption || etc…

• Research disciplines including math, physics, biology, engineering, etc. • Industrial contexts including energy, construction, pharmaceutics, food, consumer products, healthcare, etc.

• How to connect problems across academia and industry, with fundamental understandings of soft matters?

Pharmaceutical Formulation Sciences

Formulation

Performance Process

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Formulations for pharmaceuticals need to meet needs in many aspects, including but not limited to – • chemical properties that deliver desired drug release profile • physical properties that allow for robust processing (powder flow, mixing,

compression) • physical, chemical stabilities against environmental factors (temperature,

humidity) • robustness against raw material or process variations We often face compounds with great challenges – • low solubility | pH sensitivity | incompatibility with other drugs | low

compactibility | poor flow | … Each processing technology comes with unique features and challenges – • Powder compaction • Granulation • Spray drying • Extrusion • Coating • etc.

Formulation & Process – Example #1: Tablet Compression

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Image courtesy: Adam Procopio

Formulation & Process – Example #1: Tablet Compression

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Powder Feeding • powder flow / segregation • particle density, morphology, cohesion, friction, electro-staticity, air permeation

Y. Guo et al. / Chemical Engineering Science 66 (2011) 661–673

Formulation & Process – Example #1: Tablet Compression

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Powder Compression • particle movement, deformation, powder rheology • inter-particle bonding, fracture, stress distribution • air permeation

Simulation courtesy of Jerry Klinzing, MSD

Formulation & Process – Example #2: Spray Drying

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Drug amorphization • polymer selection – miscibility among drug / polymer / surfactant, Tg of

binary/ternary systems, thermodynamics • solvent selection – solubility, surface tension, heat capacity

Drug amorphization: amorphous solid dispersions

Image Courtesy: Bend Research Inc.

Dajun D. Sun, Ping I. Lee, Acta Pharmaceutica Sinica B, 2014; 4, (1): 26-36

Formulation & Process – Example #2: Spray Drying

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Drug amorphization • polymer selection – miscibility among drug / polymer / surfactant, Tg of

binary/ternary systems, thermodynamics • solvent selection – solubility, surface tension, heat capacity

Drug amorphization: amorphous solid dispersions

Image Courtesy: Kenneth Rosenberg, MSD

Vehring, R. Pharm Res (2008) 25: 999

Ideal

Realistic Dajun D. Sun, Ping I. Lee, Acta Pharmaceutica Sinica B, 2014; 4, (1): 26-36

Formulation & Process – Example #2: Spray Drying

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• mechanical behavior of the fluid – shear thinning liquid • viscosity, surface tension • droplet size, plume angle, vertical velocity – related to nozzle design

Atomization & droplet formation

Image Courtesy: Bend Research Inc.

Formulation & Process – Example #2: Spray Drying

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• Random droplet trajectory, particle/gas interaction • Complex drying dynamics within extremely short timescale • Evaporation, particle movement, bubble formation, pore permeation, elasto-plasticity, moisture propagation • Thermal quenching of glass state

Droplet drying

Image Courtesy: Kristin Ploeger Ali et al., chemical engineering research and design 92 (2014) 826–841

Saleh, World Academy of Science, Engineering and Technology 62 (2010)

Formulation & Process – Example #2: Spray Drying

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Downstream handling • low density • poor flow • high surface area

Huang et al., Acta Pharmaceutica Sinica B 2014;4(1):18–25

Image Courtesy: Bend Research Inc.

Image Courtesy: Kenneth Rosenberg, MSD

Physical stability • phase separation • re-crystallization • moisture / temperature effect

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Performance – Example #3: drug release through porous structure

Implant drug delivery systems • Provide controlled delivery of long period of time

• Improved compliance (hence efficacy) • Avoids high peak and trough concentrations (minimize side effect)

• Biodegradable or Non-biodegradable • Manufactured via Compression / Molding / Extrusion • Performance depends sensitively on microstructure • Activation can be modulated, delivery rate can be programmed • But – needs long time to collect experimental data on drug delivery…

• Imaging and modeling becomes very important

Image Courtesy: Bindiya Patel Relevant Problems:

• Visualization of the porous structure • Modeling and simulation of drug wetting and diffusion • Wetting, deformation & degradation of the pore structure

Image Courtesy: DigiM

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Performance – Example #3: drug release through porous structure

Controlled-release tablets • Water ingress, polymer swelling, drug dissolution

Chen et al., Mol. Pharmaceutics 2014, 11, 630−637

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GSOFT/FIAP Co-sponsored Focus Session Session #: GSOFT - 02.01.19 / FIAP - 22.01.03 Organizer: Jie Ren, Joshua Dijksman, (Bob Behringer) “Multiphase physics: soft matter research at the interface of industrial and academic interests” -- with a focus on physics at soft matter interfaces

Conclusion

Hopefully I have covered so far: • A few examples on the challenges and opportunities of

pharmaceutical formulations and processes as complex soft matter systems

Through which I have found a somewhat recurring theme: • Interactions at the interfaces, on top of many-body

frameworks (either multi-particular or porous), are at the center of a very diverse set of soft-matter problems that cross the boundaries among industries and between industry/academia.

• There is then a common ground of interest that is worth pursuing together!

Design of Solid Dosage Formulation and Process via Fundamental Understandings of Soft MattersSlide Number 2What are soft matters?Pharmaceutical Formulation SciencesFormulation & Process – Example #1: Tablet CompressionFormulation & Process – Example #1: Tablet CompressionFormulation & Process – Example #1: Tablet CompressionFormulation & Process – Example #2: Spray DryingFormulation & Process – Example #2: Spray DryingFormulation & Process – Example #2: Spray DryingFormulation & Process – Example #2: Spray DryingFormulation & Process – Example #2: Spray DryingSlide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Slide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Mechanistic understanding of formulations as complex soft mattersThank youFormulation & Process – Example #1: Powder Compression