Particle Processing and Modeling in the Pharmaceutical Industry

1. Particle Processing and Modeling in the Pharmaceutical Industry B. J. Glasser Department of Chemical and Biochemical Engineering Rutgers University Piscataway, New Jersey 08854

2. Drug A drug product consists of therapeutics and excipients combined in a delivery system. A drug product’s success lies in its ability to deliver the drug at a certain rate in a certain environment in the body. Discovery Delivery Manufacture http://www.sciencebase.com/images/epothilone_anticancer_compound.jpg http://www.medgadget.com/archives/img/benephit.jpg

3. Regulations “FDA’s responsibility is to protect the American public. In terms of products that are developed by a technology--whether it's a new technology or a conventional technology--our role is to ensure that the products are safe. Our role is not really to make a judgment about whether they should be placed in the marketplace or not. . . . We are here as the gatekeeper to close the gate if a product is not going to be safe for consumers. . . . “ GMP regulations address issues including record keeping, personnel qualifications, sanitation, cleanliness, equipment verification, process validation, and complaint handling. http://www.fda.gov/ www.fda.gov/cder/reports/rtn99-3.htm

4. Growth of Pharmaceutical Industry in USA US Sales www.research.ibm.com/journal/sj/441/cortada.html

5. World Pharmaceutical Market http://www4.dr-rath-foundation.org/PHARMACEUTICAL_BUSINESS/pharmaceutical_industry.htm

6. Comparison of Annual Sales Per Person ANNUAL SALES PER PERSON OF PHARMACEUTICALS (2004, £ ) http://www.abpi.org.uk/publications/publication_details/annualReview2005/ar2005_leader.asp

7. Growth of Pharmaceutical R&D Expenditure http://www.pharmafocusasia.com/knowledge_bank/articles/images/graph1.gif

8. Comparison of Pharmaceutical R&D WORLD VOLUME OF PHARMACEUTICAL R&D (2004 £m) http://www.abpi.org.uk/publications/publication_details/annualReview2005/ar2005_leader.asp

9. Employment by Establishments Total: 291000 employees in USA www.bls.gov/oco/cg/images/cgc009_1.gif

10. Pharmaceutical Employment by Position Level www.bls.gov/oco/cg/cgs009.htm

11. New Drug Discovery http://www.nature.com/nbt/journal/v22/n10/thumbs/nbt1004-1215-F1.jpg http://www.syagen.com/images/drug_discovery.jpg

12. Dosage Forms Transdermal products and implants Inhalants Tablets/Capsules Injectables Drug Skin http://www.bath.ac.uk/pr/releases/images/vectura-inhale.gif http://www.indiamart.com/cscpharma/gifs/injectable.jpg http://www.life-tech.com/pm/nb1app3.jpg http://www.avmed.com/images/c_rx-capsule.jpg

13. Types of Tablets (>80% of Total Products) • Compressed tablets – Multiple compressed tablets • Sugar - Coated tablets • Film - Coated tablets – Enteric coated tablets • Buccal or sublingual tablets • Chewable tablets • Effervescent tablets • Hypodermic tablets Advantages • convenience of consumptiom • shelf-life (stability) • economics of manufacturing • patient acceptance

14. Raw Chemicals Drug Synthesis Drug is converted into Particles (sub-optimal delivery properties) Formulation Adjusted particle properties Preliminary process (unknown manufacturability) Process Development & Scale up Adjusted process ) (unknown scalability Manufacturing Product/Process Development Paradigm Product

15. Pharmaceutical Engineering • Around 15 years to bring a new drug to market • Blockbuster drug - $1B annual sales • Product development and scale-up • Hiring of chemical engineers • Muzzio, Shinbrot, & Glasser, “Powder Technology in the Pharmaceutical Industry: The Need to Catch Up Fast”, Powder Tech., 124,1-7, (2002). • Glasser, Cole & Muzzio, “Pharmaceutical Engineering Training”, Pharmaceutical Technology, 25:12, 34-36, (2001).

16. Flow Sheet for Tablet Manufacture Source: F. Muzzio

17. Synthesis http://www.u-tokyo.ac.jp/coe/images/pic_list03_004.JPG http://www.chemsoc.org/chembytes/ezine/images/1999/persp_apr99_2.jpg Improvement in organic synthesis allow us to make larger and larger molecules.

18. Crystallization Spheres Needles Cubes http://aiche.confex.com/aiche/2005/techprogram/images/21810-0.jpg

19. Agitated Drying of Crystals Drying Parameters: Drying Temperature Agitation Speed Drying time Vacuum Crystal Size Distribution: Attrition decreases the size. Agglomeration increases the size. Lekhal et al. Powder Technology (2003)

20. Drying • Freeze Drying • Spray Drying Spray drying consists of the following unit operations: Pre-concentration of liquid Atomization (creation of droplets) Drying in stream of hot, dry gas (usually air) Separation of powder from moist gas Cooling Packaging of product solvent evaporation http://www.malvern.com/ProcessEng/images/processes/spray_drying_overview1.gif

21. Milling and Granulation Three Main Granulation Mechanisms Create a desired particle size Improve flow and handling Increase flow rate Increase uniformity in finished product Increase density -reduce volume required for processing and storage -Increase batch size Reductions in dust Improve appearance Decrease ingredient segregation Can improve dissolution (surfactant effects)

22. Milling/Granulation Equipment High shear granulators use both an impeller to provide vigorous mechanical agitation and a chopper to break large agglomerates and promote the growth of small ones. Typically, they produce hard granules less than 2 mm in size. http://www.tollcompaction.com/POWDER.jpg A Pulva mill is used for fine grinding of dry or wet materials ranging from 180 microns (80 U.S mesh) to 45 microns (200 U.S. mesh). http://www.tollcompaction.com/POWDER.jpg

23. Blending Three main mechanisms for mixing (J.C. Williams) Convection •Driven by bulk flow •Fast macromixing •Easy to scale up •Limited by segregated flow structures (incomplete mixing) Dispersion •Driven by individual particle motion •Always slow •Leads to complete macroscopic homogeneity •Scale-up criteria unknown Shear •Caused by velocity gradients •Required for micromixingof cohesive systems •Scale-up criteria unknown

24. Powder Blenders Source: F. Muzzio

25. Problems in Mixing - Segregation Segregation occurs if particles differ in size, density, shape, or other characteristics. Source: F. Muzzio

26. Fluidized Bed Drying Vo: fluid velocity ut: particle terminal velocity VOm: minimum fluidization velocity * Kunii and Levenspiel, 1991

27. Application of FBs in Pharmaceutical Industry •Blending •Drying •Spray-drying •Granulation •Coating •Pelletizing •Adsorption • High mass and heat transfer • Billions of dollars on fluidized bed processes each year http://www.uic.edu/depts/chme/UnitOps/Fluidized%20Beds.jpg

28. Classification of Gas-Fluidized Beds

29. Problems in Fluidized Bed Processing • Different Flow Regimes • Flow Instability • Voidage Waves Uniform expansion Packed bed • Drying or Reaction Rate • Selectivity • Product Yield • Safety • Environmental Impact Bubbling Clustering Increasing Gas Flows Streamer

30. Tableting Compaction Mechanism • Particle re-arrangement (low pressure densification). Particles move into closer packing, air leaves the powder plug. Spherical particles move less than irregularly shaped particles • Deformation occurs as pressure is increased, enlarging the area of contact between particles • Fragmentation, which gives high yield stress, occurs next as pressure increases. New surfaces and bonding points are created • Bond formation then takes place between previously existing and newly created surfaces http://www.sripharmacare.com/gifs/tablet-capsule1.jpg

31. Tableting Machines Four main stages for tableting : Die fill, weight adjustment, compression, and ejection Rotary tablet presses http://www.capsule-filling-machine.com/rimages/131/tablet-h01.jpg

32. Problems in Tableting

33. Coating There are several types of coating method that are divided into two main categories: the single layer and the multi-layer coating methods. The first category is most commonly used for the pharmaceutical patches Some of the main variables involved in the selection of the appropriate method are: http://www1.istockphoto.com/file_thumbview_approve/344351/2/istockphoto_344351_multi_macro.jpg

34. Coating Equipment http://www.medicaldesign.com/ http://www.sono-tek.com/images/_biomedical/medicoat_header.jpg The surface profile of a drug-eluting coating on a stent examined with an optical interferometer reveals some waviness in the coating, along with a lower region in the middle of the area examined Talwar Pharma manufactures a wide range of pellet products, mainly omeprazole and lansoprazole pellets, andoffers stage wise quality tests at drug coating stage, sub-coating stage and enteric coating stage http://www.pharmaceutical-technology.com/contractor_images/talwar/3.jpg

35. Sampling • Accurate sampling is a key technical need for quality control and process characterization • In pharmaceutical manufacturing, batch sampling is increasingly becoming a regulatory expectation • Standard tools (thief probes) are extremely unreliable, often resulting in samples of uncertain size and composition Stratified Sampling Three Assumptions • Random Mixtures (Normal Distributions) • Unperturbed Sampling (no thief error) • Unchanging Mixtures (no segregation) Source: F. Muzzio

36. Sampling Machines •Cavities can be filled with solid dies •Only lower cavity used Globe-Pharma Sampler

37. Development cost is rising – 50% increase in five years • Why is this happening? • New drugs are harder to formulate • Products are increasing in complexity • “Regulation is inefficient” Challenges in Pharmaceutical Industry • Health care cost is rising rapidly • Uninsured, underinsured, and third world populations cannot afford many new drugs • Many drugs do not get developed because the economic incentive is not there • Number of new drugs has decreased 50% in 10 years Source: F. Muzzio

38. The Barriers – and the Opportunity • Three inter-related barriers • Lack of synergy between fundamental science and domain knowledge • Lack of predictive models • Lack of the properly trained human resource • A major opportunity • Develop the predictive science • Create inter-disciplinary training programs • Provide a forum for science-based regulation Source: F. Muzzio

39. 2016 – Imagine if …… • Product development only took six months • Cost of development and manufacturing could be cut in half • Products and processes could be designed in the computer (like airplanes, microchips) • Regulation promoted continuous improvement • Pharmaceutical manufacturing was • Mature • Portable • Highly reliable (2.5s  6s) Could manufacture finished pharmaceuticals in a compact device, such as a modified ink-jet printer? • Greatly reduced facilities cost • Reduced batch size and stock • Personalized dosage based on weight • Scalable, flexible Source: F. Muzzio

40. Acute for pharmaceutical industry • 80% of drug products are capsules, pills or tablets • 18% FDA recalls for “potency/content uniformity” • Uncertain, rudimentary scale-up • Manufacturing efficiency lags other industries FDC, The Gold Sheet, 2002 Wall Street Journal, 2003 Significance of Particle Processes • Essential for 60% of manufactured products • Numerous, recurring industrial problems • 40-50% operations below design specifications • Commissioning delays & productivity delays • No strong theoretical design basis • Design strategies are usually empirical  Erratic flow and inhomogeneity Bridgwater, Gran. Matt., 2002 Knowlton, et alChem Eng. Prog., 1994

41. Makse et al, Nature 1995 Umbanhowar et al, Nature 1996 Granular Materials Not Yet Understood • Extreme behavioral regimes GEA Buck, Inc., 2004 Jenike and Johanssen, 2004 • Curious phenomena • Scale-gap between particle-level and macroscopic models Michaels, Powhder Tech., 2003

42. Uniform flows often desirable, but “cluster” spontaneously Mesoscale structures Interstitial fluid negligible Determines performance Segregation potential? Examination of instabilities illuminates: Underlying physics Flow transitions, onset of chaos? Fluid analogies exploited Inhomogeneity in Granular Flows Pipe Flows Liss, Conway, Glasser, Phys. Fluids, 2002 Jaworski, Dyakowski, Powder Tech. 2002 Channel Flows Forterre and Pouliquen, Phys. Rev. Lett., 2001 Goldfarb, Shinbrot, Glasser, Nature, 2002

43. Treated as unpredictable, inevitable Dominated by rules-of-thumb Segregation in Granular Materials • Broad application hampered: • Numerous qualitative mechanisms • Little agreement, eg. Brazil nut effect Alexander, Muzzio, Shinbrot, Chem. Eng Sci 2003 Breau et al, Phys. Rev. Lett., 2003

44. Granular Flows in Different Geometries Goldfarb, Glasser and Shinbrot, Nature, (2002) Liss, Conway, Zega, and Glasser, Pharmaceutical Technology, (2004) Conway, Shinbrot and Glasser, Nature, (2004) Conway, Lekhal, Glasser, KhinastAIChE J. (2006) Lekhal,Conway, Glasser, KhinastChem. Eng. Sci. (2006) Dry Solids Wet Solids

45. Nanoparticles are ultra fine powders whose particle sizes are in the range of 1-100 nm. Applications in materials and manufacturing, health care, medicine, electronics, environment, energy, chemical and pharmaceutical biotechnology, agriculture, information technology. Nanoparticles in the range of 1-5 nm have potential applications in nanoscale electronics. Nanoparticles below 5 nm exhibit unique physical and chemical properties. Introduction to Nanoparticles http://www.brighamandwomens.org/publicaffairs/Images/nanoparticles%20attack%20prostate%20cancer%20cells.jpg

46. Contd.. Introduction to Nanoparticles • Difference in the range of structural chemistries between bulk and nanoscale particles make nanoparticles unique in vast applications. • Properties of nanoparticles vary considerably with size • Activity and selectivity can be greatly influenced by nanoparticles. • Particle size is critical in determining the properties of nanoparticles. • Synthesis of nanomaterials over a range of chemical composition and sizes has been a challenge. • An ordered geometry and structure is of interest in nanoparticles (control of shape, size and structure). • Spherical nanoparticles were of interest due to their high surface area. • Due to high surface area, metal oxide nanoparticles have wide range of applications in sensors, catalysis and electronics.

47. Drug Nanoparticles • In pharmaceutics, active ingredient is in the form of solid particles. • Application of nanotechnology for treatment, diagnosis, monitoring, and control of biological systems has been determined by NIH as nanomedicine. • Drug nanoparticles can be used with the development of nanotechnology. • For example, in 2005, FDA approved 130 nm albumin nanoparticles loaded with paclitaxel. • Several polymeric, metal nanoparticles, liposomes, micelles, quantum dots, dendrimers, microcapsules, cells, cell ghosts, lipoproteins, and many different nanoassemblies play a major role in diagnosis and therapy. • Nanoparticulate pharmaceutical carriers enhance the vivo efficiency of many drugs http://nano.cancer.gov/objects/img_resource/nanoparticles.jpg

48. Importance of Nanosize in Drug Delivery Ref: Gupta R.B, Kompella U.B, Nanoparticle Technology for Drug Delivery, Drugs and Pharmaceutical Sciences. 2006; 159: 2-3.

49. Cond.. Importance of Nanosize • Size matching is important for drug delivery. • Drug delivery aimed at influencing the biochemistry of the body. • Nanoparticles are of great interest in drug delivery due to comparable sizes to the human cells. • Biological systems are in the nanometer range • To treat the disease, one needs to use the same nanoscale. • For example correcting faulty gene, killing leprosy bacteria in the blood cells, blocking multiplication of viral genome, killing cancer cell, repair cellular metabolism etc. http://www.aist.go.jp/aist_e/museum/science/7/7_4.jpg

50. Importance of Nanoparticle Surface Ref: Gupta R.B, Kompella U.B, Nanoparticle Technology for Drug Delivery, Drugs and Pharmaceutical Sciences. 2006; 159: 3-4.