استخدام الحاسب لتقديم و شرح محاضرة عن طريق برنامج

1. الإسم :فهد جلعود سيف القحطانيرقم المنسوب :4350182التخصص : معيد بكلية الصيدلة – قسم الصيدلانيات استخدام الحاسب لتقديم و شرح محاضرة عن طريق برنامج Power Point

2. Pharmaceutical Manufacturing

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

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

5. 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

6. 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

7. Quality factors for solid dosage forms

8. Models at different scales

9. 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)

10. Mean particle size and flowability

11. Size distributions for various powders

12. Powder flow and tablet weight variations

13. Excipients 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: • 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.

14. Excipient functions

15. 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)

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

17. 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(processparameters, feed/intermediate properties)

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

19. Particle size reduction Benefits • 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 Disadvantages

20. 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

21. 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

22. 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

23. Milling equipment – impact mills • Significant wear on surfaces • Hammer mills • Medium to coarse size reduction • Peripheral speed 20-50 m/sec • Pin mills • Peripheral speed up to 200 m/sec • Capable of fine grinding • Can be used to mill sticky materials

24. 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)

25. 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

26. Mill selection

27. 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

28. Unit operations • Blending • Blending equipment • Impact of size difference • Radial vs axial mixing

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

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

31. 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

32. 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

33. Effect of entrained air on feeding and discharging

34. 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

35. Chopper Blade Mixer Blade Discharge Bowl 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

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

37. Outlet Temperature Outlet Filter Damper Air Flow Filter Bag From Granulator Drying Zone Air Flow Product Temperature Air Flow Retaining Screein Inlet Temperature Condensor Steam Damper Inlet Filter To Mill Fluid bed drying

38. Unit operations • Tablet compaction • Relative density and compaction pressure • Coating • Objectives • Critical parameters

39. Rotary tablet press

40. Relative density changes in manufacture of tablets

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

42. 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, 7th Ed., McGraw Hill (1997).