الإسم : فهد جلعود سيف القحطاني رقم المنسوب : التخصص : معيد بكلية الصيدلة – قسم الصيدلانيات استخدام الحاسب لتقديم و شرح محاضرة عن طريق برنامج

Pharmaceutical Manufacturing

Stages of pharmaceutical manufacturing API Excipients Primary Packaging Secondary Packaging API Finished Product Starting Materials (Chemicals)

Drug product manufacture Dosage Form Wet granulation milling blending Fluid Bed Dryer lubrication tableting coating imprinting Process combines the drug and excipients into the dosage form Excipients API crystallization filtration oven drying Dry granulation / milling Direct compression

Solid dosage processing Dosage forms – Quality factors Excipients Particle properties Processing routes Unit operations – Size reduction (milling) – Blending – Dry granulation (roll compaction) – Wet granulation – Drying – Tablet compaction – Coating

Solid dosage forms Oral – Tablets Lozenges Chewable tablets Effervescent tablets Multi-layer tablets Modified release – Capsules Hard gelatin Soft gelatin – Powders Inhaled – Aerosol Metered dose inhalers Dry powder inhalers

Quality factors for solid dosage forms Functional quality factors - Disintegrates to desired size quickly - The constituent particle size of the dosage form should dissolve and be absorbed in the GI tract at a pre-determined rate Physical quality factors - Must not break up on processing, packaging, transportation, dispensing or handling - Surface of tablet or capsule must be free of defects - Must be stable under anticipated environmental conditions - Have the same weight and composition for each tablet or capsule Sensorial quality factors - Easy and pleasant to swallow

Models at different scales ScaleSubject Problems EnterpriseBusiness processSourcing, contract manufacturing, capacity planning PlantProcess synthesis, simulation, development Generation of process alternatives, process optimization EquipmentEquipment selection, performance, sizing, costing Mixing, classification, granulation, milling ContinuumFlow and handling of powdersGranular flow ParticleParticle attributes: composition, size distribution, density, strength, shape Interparticle forces, breakage MoleculeEnantiomers and polymorphs, material properties Polymorph prediction, prediction of physical and chemical properties

Product and process functions Product function – Product property: Content uniformity, dissolution, flowability, dust formation – Particle Properties: Particle size, particle shape, surface characteristics Process function – Process parameters: Type of unit operation, operational parameters Product property = F(particle properties, formulation) Particle properties = F(process parameters, raw material/intermediate properties)

Mean particle size and flowability

Size distributions for various powders

Powder flow and tablet weight variations

Excipients To aid in the processing of the drug delivery system during its manufacture; To protect, support, or enhance stability, bioavailability or patient acceptability; To assist in product identification; To enhance any other attribute of the overall safety, effectiveness, or delivery of the drug during storage or use. Excipients are substances, other than the active drug substance, or finished dosage form, that have been appropriately evaluated for safety and are included in drug delivery systems:

Excipient functions ComponentFunction Examples FillersIncrease size and weight of final dosage form Microcrystalline cellulose, sucrose BindersPromote particle aggregationPregelatinized starch, hydroxypropyl methylcellulose DisintegrantsPromote break down of aggregatesSodium starch glycolate Flow AidsReduce interaction between particlesTalc LubricantsReduce interactions between particles and surfaces of processing equipment Magnesium stearate SurfactantsPromotes wettingSodium lauryl sulfate, Polysorbate Modified Release Agents Influences the release of activeHydroxypropyl methylcellulose, Surelease,

Most popular excipients Magnesium stearate (lubricant) Lactose (compression aid) Microcrystalline cellulose (compression aid) Starch (corn) (compression aid) Silicon dioxide (glidant) Stearic acid (lubricant) Sodium starch glycollate (disintegrant) Gelatin (binder) Talc (film coating adjuvant, glidant) Sucrose (sweetener, coating) Calcium stearate (lubricant) Povidone (binder) Pre-gelatinized starch (binder) Hydroxypropylmethylcellulose (film coating, binder) OPA products (film coats and dyes) Crosscarmelose sodium (disintegrant) Hydroxypropylcellulose (binder, film coating) Ethylcellulose (enteric coating) Dibasic calcium phosphate (compression aid) Crospovidone (disintegrant) Shellac and Glaze (coating agent)

Processing routes Fill die Coating, Packaging etc.. Compress Tablet Direct Compression Drug Diluent Glidant Disintegrant Lubricant Mixing Dry Granulation Disintegrant Glidant Lubricant Drug Diluent Lubricant Mixing Compression Comminution Screening Mixing Wetting Granulation Drying Screening Mixing Drug Diluent Binder Solvent Disintegrant Glidant Lubricant Wet Granulation Other Routes Fluidized bed granulation Extrusion / rotary granulation Tablet Compression

Unit operations Process function – Process parameters: Type of unit operation, operational parameters Type of unit operation – Size reduction (Milling) – Blending – Dry granulation (Roll compaction) – Wet granulation – Drying – Tablet compression – Coating Particle properties = F(process parameters, feed/intermediate properties)

Unit operations Size reduction (milling) – Advantages and disadvantages – Forces in milling – Milling equipment (dry milling) – Media mills (wet milling) – Mill selection – Energy requirements

Particle size reduction Mixing is more uniform if ingredients are roughly the same size Milling of wet granules can promote uniform and efficient drying Increased surface area can improve dissolution rate and bioavailablity Improved content uniformity of dosage units Excessive heat generation can lead to degradation, change in polymorphic form Increase in surface energy can lead to agglomeration May result in excessive production of fines or overly broad particle size distribution Benefits Disadvantages

Forces in milling Shear (cutting forces) Compression (crushing forces) Impact (high velocity collision) Griffith theory T = Tensile stress Y = Young’s modulus ε = Surface energy c = fault length

Milling equipment – screen mills Critical parameters for a conical screen mill – Screen Hole Size/Shape – Impeller Type – Impeller Clearance – Speed Evaluate impact on aspirin granulation – Particle size reduction – Milling time and energy requirements – Overall milling performance Milling Work Index = Size reduction / Milling work Milling Time Index = Size reduction / Milling time

Milling equipment – screen mills Screen hole size has largest impact on particle size reduction, milling time and energy requirements Milling work index significantly lower for smaller screen hole sizes Impeller type has largest effect on overall milling performance Impeller clearance not significant at small clearances Milling work index lower at higher mill speeds – Deflection of material away from screens Milling work index= Particle size reduction / Milling work

Milling equipment – impact mills Significant wear on surfaces Hammer mills – Medium to coarse size reduction – Peripheral speed m/sec Pin mills – Peripheral speed up to 200 m/sec – Capable of fine grinding – Can be used to mill sticky materials

Milling equipment – jet mill Superfine to colloid size reduction Can be used for heat sensitive products Different configurations – Pancake (spiral) jet mill Fines exit from center – Loop/oval jet mill Fines exit from top – Opposing jet mills Particles impact each other in opposing jets – Fluidized bed jet mill Particles are jetted towards center (low wear on equipment) – Fixed/moving target jet mills Particles impact on surface of target (wear can be significant)

Milling equipment – stirred media mill Critical parameters – Agitator speed – Feed rate – Size of beads – Bead charge – Density of beads – Design of blades – Mill chamber – Residence time

Mill selection

Energy based analysis – ball mill Macroscale energy-size relationships (Chen et al., 2004) – Calculate specific energy for a given size reduction – Functional form derived from theoretical considerations – Rittinger’s model Energy required for particle size reduction is proportional to the area of new surface created – Kick’s model Energy required to break a particle is proportional to the ratio of the particle volume before reduction to the volume after reduction

Unit operations Blending – Blending equipment – Impact of size difference – Radial vs axial mixing

Blending – diffusion mixing Critical parameters – Blender load – Blender speed – Blending time V-Blender Cross Flow Blender Bin Blender Double Cone Blender

Blending – convective mixing Ribbon Blenders Orbiting Screw Blenders Planetary Blenders Horizontal Double Arm Blenders Forberg Blenders Vertical High Intensity Mixers Horizontal High Intensity Mixers Diffusion Mixers with Intensifier/Agitator

Unit operations Dry granulation (roll compaction) – Critical parameters – Johanson’s theory – Feed system – Impact of granulation on flow properties Wet granulation – Monitoring liquid addition Drying – Fluidised bed dryer

Roll compaction Critical parameters – Roll speed and pressure – Horizontal and vertical feed speed, deaeration – Roll diameter and surface Advantages – Improve powder flow – Reduce segregation potential – No moisture addition, drying

Effect of entrained air on feeding and discharging

Characterization of flowability Hausner ratio = tapped density / bulk density – Excellent 1.05–1.10 – Good 1.11–1.15 – Fair 1.15–1.20 – Passable 1.21–1.25 – Poor 1.26–1.31 – Very Poor 1.32–1.37 – Extremely Poor 1.38–1.45

High shear wet granulation Advantages – Improve flow – Improve uniformity – Increase bulk density – Enhance resistance to segregation Critical parameters – Amount of binder – Rate of addition – Time of granulation – Speed Mixer Blade Bowl Chopper Blade Discharge

Wet granulation – monitoring liquid addition (A)0.24 ml/g (1 min) SEM of α–Lactose Monohydrate/MCC granules (C) 0.47 ml/g (2 min) agglomeration (B) 0.36 ml/g (1.5 min) nucleation (D) 0.53 ml/g (2.25 min) agglomerate growth bar = 500 μm

Fluid bed drying

Unit operations Tablet compaction – Relative density and compaction pressure Coating – Objectives – Critical parameters

Rotary tablet press

Relative density changes in manufacture of tablets

Pan coating Benefits – Mask taste – Chemical barrier – Controlled release – Appearance Critical Parameters – Air flow – Spray – Drum dynamics Rotational speed Fill fraction Air+Moisture Dry Air Rotation Baffle Spray Nozzle Air Flow Inlet Filter Steam Inlet Temperature Inlet Air Outlet Air Outlet Filter Outlet Temperature

References Theory and Practice of Industrial Pharmacy, L. Lachman et al. (eds) (1986). Handbook of Pharmaceutical Granulation Technology, D. M. Parikh (ed), Marcel Dekker (1997). Pharmaceutical Dosage Forms: Tablets, vol 2, Marcel Dekker (1990). Encyclopedia of Pharmaceutical Technology, Marcel Dekker (2003). Perry’s Chemical Engineers Handbook, 7 th Ed., McGraw Hill (1997).