Introduction to Solid Dosage Processing

1. Introduction to Solid Dosage Processing

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

3. 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

4. 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

5. 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 Singh, Naini (2002), Dosage Forms: Non-Parenteral, Encyclopedia of Pharmaceutical Technology

6. Quality factors for solid dosage forms Fung and Ng (2003), AIChE Journal, 49(5), 1193-1215

7. Models at different scales Ng (2002), Powder Technology, 126, 205-210

8. 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)

9. Particle properties Product property = F(particleproperties, formulation) Hlinak et al, Journal of Pharmaceutical Innovation, 1 (2006)

10. Mean particle size and flowability Bodhmage, A. (2006). Correlation between physical properties and flowability indicators for fine powders. MS Thesis, Department of Chemical Engineering, University of Saskatchewan.

11. Size distributions for various powders Bodhmage, A. (2006). Correlation between physical properties and flowability indicators for fine powders. MS Thesis, Department of Chemical Engineering, University of Saskatchewan.

12. Powder flow and tablet weight variations Hancock, Bruno (2007). Dosage Form Specific Tests. Short course on Material Properties, Purdue University.

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. USP, General Information Chapter <1078>, Good Manufacturing Practices for Bulk Pharmaceutical Excipients

14. Excipient functions Hlinak (2005)

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) International pharmaceutical excipients council of the americas, http://www.ipecamericas.org/public/faqs.html

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 Rumpf (1965), Chem Ing Tech, 37(3), 187-202

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 Byers, Peck (1990), Drug Dev Ind Pharm, 16(11), 1761-1779

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 Byers, Peck (1990), Drug Dev Ind Pharm, 16(11), 1761-1779

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 Wibowo and Ng (1999), AIChE Journal 45 (8) 1629-1648

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 Chen et al. (2004), J Pharm Sci, 93(4), 113-132

28. Kick’s Law High loading Low frequency Rolling attrition Rittinger’s Law Low loading High frequency Impact fragmentation Energy based analysis – ball mill Attrition Fragmentation Size Reduction of α–Lactose Monohydrate in a Ball Mill Chen et al. (2004), J Pharm Sci, 93(4), 113-132

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

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

31. 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

32. Size difference and mixing uniformity Campbell and Bauer (1966), Chem Eng, 73, 179

33. Mixing in a bin blender – axial mixing Composition after 30 revolutions (10rpm, 60%fill, w/o baffle) Sudah et al. (2002), Powder Technology, 126, 191-200

34. Mixing in a bin blender – radial mixing Composition after 30 revolutions (10rpm, 60%fill, w/o baffle) Sudah et al. (2002), Powder Technology, 126, 191-200

35. 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

36. 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

37. Johanson’s theory Slip Region Nip Region

38. Johanson’s theory Slip region Nip region Compressibility Eff. angle of friction Wall angle of friction Yu et al. (2013), Chem Eng Sci, 86, 9-18

39. Johanson’s theory – nip angle Bindhumadhavan et al. (2005), Chem Eng Sci, 60(14), 3891-3897

40. Johanson’s theory - stress profile Bindhumadhavan et al. (2005), Chem Eng Sci, 60(14), 3891-3897

41. Eff. angle of friction and peak pressure (Johanson’s theory) Eff. Angle of Friction

42. Eff. angle of friction and nip angle (Johanson’s theory) Nip Angle Eff. Angle of Friction

43. Effect of lubrication on friction properties Yu et al. (2013), Chem Eng Sci, 86, 9-18

44. Effect of lubrication on peak roll pressure Yu et al. (2013), Chem Eng Sci, 86, 9-18

45. Effect of lubrication on nip angle Yu et al. (2013), Chem Eng Sci, 86, 9-18

46. Impact of feed and roll speed on granule properties Avicel PH 101 Compressibility Mean particle size R R H H Falzone et al. (1992), Drug Dev Ind Pharm, 18(4), 469-489

47. Impact of feed and roll speed on granule properties Hydrous Lactose R=4 R=8 Mean particle size V V H H Falzone et al. (1992), Drug Dev Ind Pharm, 18(4), 469-489

48. Effect of entrained air on feeding and discharging Johanson (1989), Powder Bulk Eng, Februay, 43-46

49. 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

50. Roll compaction and flow properties Before Compaction (poor) After Compaction (excellent) Soares et al. (2005),Dry granulation and compression of spray dried plant extracts, AAPS PharmSciTech