L1. Introduction.pdf

PR5214 Advances in Solid Pharmaceutical Formulations L1. Introduction and Fundementals DUN JIANGNAN, Ph.D. AY24/25.S1 13-AUG-2024 Learning Outcomes Familiar with tablets dosage form and its typical components; Understand the critical quality of tablets; Familiar with vario...

PR5214 Advances in Solid Pharmaceutical Formulations L1. Introduction and Fundementals DUN JIANGNAN, Ph.D. AY24/25.S1 13-AUG-2024 Learning Outcomes Familiar with tablets dosage form and its typical components; Understand the critical quality of tablets; Familiar with various of tablets manufacturing technologies; Criticize the old philosophy in tablets formulation development; Appreciate how a good understanding of pharmaceutical material science and engineering can help in tablets formulation development. Preferred Background Knowledge Pharmaceutics (undergraduate level) Material Sciences and Engineering Basic mathematics and data visualization skills Textbooks (optional) Martin's Physical Pharmacy and Pharmaceutical Sciences (2016) Pharmaceutical Powder Compaction Technology (1995) by Patrick J. Sinko PhD RPh Edited By Goran Alderborn, Christer Nystrom Resources Drug Product Development Drug Discovery ? (Medicinal Chemistry) Generic Postmarket Phase 0 Phase I Phase II Phase III Surveillance 505 2(b) Manufacturability, Stability (Physical and chemical), Dissolution Formulation Criteria Basic Tablet Formulation Active Pharmaceutical Ingredients (API) Colorant Coating agents Diluent/ ller Binder Glidant Flavor Disintegrant Lubricant Sweetener fi Special Pharmaceutical Tablets Sustained-released Tablets Multi-layers Tablets Multi-pellets system Why tablets containing 100% API is rarely seen on the market? Diluent/Fillers To provide the bulk volume required to make a tablet Allow API to distribute in it uniformly (Good content uniformity) To have acceptable tabletability Microcrystalline Cellulose Dupont Pharma Binders To provide su cient tablet mechanical strength (low friability) For granulation process: to facilitate granulation and prevent segregation 1. Dry binder: MCC, Lactose, Mannitol, etc. (Usually, llers can serve as dry binders) 2. Wet Binder: polymers such as PVP ffi fi Lubricant To reduce friction and adhesion between the powder and equipment surfaces (especially tooling) To reduce heat (millions of tablets are compressed by each punch) More uniform stress distribution during compaction Magnesium Stearate (MgSt)  Basic Process Criteria Effective Robust High Quality Drug Products Simple Economical Direct compression, dry granulation, wet granulation, melt granulation, uid bed granulation fl Direct Compression (DC) Simplest manufacturing technology for tablet. Mixing Compression Raw materials Blend Tablet product Pros Cons Simple Sensitive to material properties Economical Risky for high drug loading Dry Granulation (DG) DG is a size enlargement process that transform powder particle into granules. Raw materials Mixing Roller compaction (Intragranular Blend Ribbons phase) Milling Compaction Mixing Tablet Final Blend Ganules Extragranular phase Pros Cons Low segregation Good owability Lower tablet strength Higher Drug Loading Fine generation Additonal process steps fl Dry Granulation (DG)  Wet Granulation (WG) WG is also a size enlargement process, but with the addition of liquid components. Raw materials Mixing Wet granulation (Intragranular Blend Wet Granules phase) Drying Compaction Mixing Tablet Final Blend Dry Ganules Extragranular phase Pros Cons Low segregation Good owability Complex and Costly Overgranulation Higher Drug Loading Chemical/Physical stability Di cult to scale up ffi fl Wet Granulation (WG) High Shear Wet granulation Melt Granulation Mixing Binder Raw materials Blend Granules Mixed at an Elevated T Cooling and milling Compaction Mixing Tablet Final Blend Dry Ganules Lubrication Pros Cons Improved owability/Tabletability Require a temp. controlled granulator Low segregation Very High Drug Loading Chemical/Physical stability No high T drying required Limited selection of binder fl Fluidization of Powder Types of Fluid Beds Fluid Bed Granulation Methods Top Spray Bottom Spray Tangential Spray Granulation Coating, Drug layering Rotary, side air entry Critical Process Parameters Key Material Attributes What do you know about water content? A Decision Tree Should be used for reference only, why?  Traditional Formulation Development Received an API Empiricism Develop a formulation Trial-and-error that works Experience Scale-up Data heavy Submit it to FDA Li le process understanding t t Reality: A Complex Problem! Direct Compression (DC) Dry granulation (DG) Wet granulation (WG) Other Factors to Consider Company history Preference/experience of key managers Preference/experience of formulator Project timeline Availability of equipment (research lab & manufacturing plant) Inventory of excipients in research lab Marketing considerations (shape, size, convenience, frequency) Patient population The FDA Old Philosophy Let’s develop something that works and never change it again! We do not know exactly what is going on during product development Three batches to validate a process Avoid any change in each step of the processes Analysis nal product to ensure product quality Materials Processes Drug Products (API, Excipients) Variable Locked Variable fi The Tablet Formulation Development Traditional approach: Trial-and-error Excipients 1 Characterizations API Blend 1 Excipients 2 Characterizations API Blend 2 …… Excipients n Characterizations API Blend n Expensive and time/labor consuming 2000 Drug products were recalled in 2020 $10M Financial Loss for each recall 80% Financial loss on each product Duerecall to Manufacturing/Testing Process Analytical Technology (PAT) In-line On-line At-line Materials Processes Drug Products (API, Excipients) Variable Dynamic Constant Blending, wet granulation, roller compaction, crystallization, drying, compaction, etc. Challenges: 1) Which property to monitor? 2) Is there any tool available? Future Formulation Development Quality by Design Mechanistic understanding of materials and processes The Tablet Formulation Development Scienti c approach: The Material Science Tetrahedron (MST) Process Engineering Fundamental understanding of materials and processes Data Science (Machine learning) Performance Material Sciences Structure Property Must be applied at multiple scales (from molecular level to bulk products level)! fi  Future Tablet Formulation Development Bulk powder properties: Flowability Particle size distribution … Manufacturability: Unknown Crystal Mechanical Tabletability Computer-aided API structures properties Compressibility composition selection Single crystal PXRD Compactability Crystal structure analysis … Energy framework study Content uniformity Process parameters: Dissolution Compaction speed Stability … Frability … 36