Particle Processing and Modeling in the Pharmaceutical Industry

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

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 http: //www. sciencebase. com /images/epothilone_anticanc er_compound. jpg Delivery Manufacture http: //www. medgadget. com/archives/img /benephit. jpg 2

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/ 3 www. fda. gov/cder/reports/rtn 99 -3. htm

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

World Pharmaceutical Market http: //www 4. dr-rath-foundation. org/PHARMACEUTICAL_BUSINESS/pharmaceutical_industry. htm 5

Comparison of Annual Sales Person ANNUAL SALES PERSON OF PHARMACEUTICALS (2004, £ ) http: //www. abpi. org. uk/publications/publication_details/annual. Review 2005/ar 2005_leader. asp 6

Growth of Pharmaceutical R&D Expenditure http: //www. pharmafocusasia. com/knowledge_bank/articles/images/graph 1. gif 7

Comparison of Pharmaceutical R&D WORLD VOLUME OF PHARMACEUTICAL R&D (2004 £m) http: //www. abpi. org. uk/publications/publication_details/annual. Review 2005/ar 2005_leader. asp 8

Employment by Establishments Total: 291000 employees in USA www. bls. gov/oco/cg/images/cgc 009_1. gif 9

Pharmaceutical Employment by Position Level Employment, 2004 Occupation Percent Office and administrative support occupations Production occupations Sales and related occupations Installation, maintenance, and repair occupations Transportation and material moving occupations 53 18. 2 85 29. 3 34 11. 6 27 9 3 13 4. 5 13 4. 4 5 Professional and related occupations 100 79 Management, business, and financial occupations 291 Total, all occupations Others Num ber 2 www. bls. gov/oco/cg/cgs 009. htm 10

New Drug Discovery http: //www. nature. com/nbt/journal/v 22/n 10/t humbs/nbt 1004 -1215 -F 1. jpg http: //www. syagen. com/images/drug_di scovery. jpg 11

Dosage Forms Tablets/Capsules Injectables Inhalants Transdermal products and implants Drug Skin http: //www. avmed. com/i mages/c_rx-capsule. jpg http: //www. indiamart. com/cscpharma/gifs/ injectable. jpg http: //www. bath. ac. uk /pr/releases/images/v ectura-inhale. gif http: //www. lifetech. com/pm/nb 1 app 3. 12 jpg

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 Advantages • convenience of consumptiom • shelf-life (stability) • economics of manufacturing • patient acceptance • Effervescent tablets • Hypodermic tablets 13

Product/Process Development Paradigm 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 14 Product

Pharmaceutical Engineering • • Around 15 years to bring a new drug to market Blockbuster drug - $1 B 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). 15

Flow Sheet for Tablet Manufacture Source: F. Muzzio 16

Synthesis http: //www. u-tokyo. ac. jp/coe/images/pic_list 03_004. JPG http: //www. chemsoc. org/chembytes/ezine/images/1999/persp_apr 99_2. jpg Improvement in organic synthesis allow us to make larger and larger molecules. 17

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

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

Drying • Freeze Drying • Spray Drying solvent evaporation 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 20 http: //www. malvern. com/Process. Eng/images/processes/spray_drying_overview 1. gif

Milling and Granulation 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 Three Main Granulation Mechanisms Reductions in dust Improve appearance Decrease ingredient segregation Can improve dissolution (surfactant effects) 21

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). 22 http: //www. tollcompaction. com/POWDER. jpg

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 23

Powder Blenders 24 Source: F. Muzzio

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

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

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/Unit. Ops/Fluidized%20 Beds. jpg 27

Classification of Gas-Fluidized Beds 28

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

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 30 http: //www. sripharmacare. com/gifs/tablet-capsule 1. jpg surfaces

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-h 01. jpg 31

Problems in Tableting 32

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: The number of layers Layer thickness Viscosity Solids content Accuracy Solvent systems Surface treatment and so on 33 http: //www 1. istockphoto. com/file_thumbview_approve/344351/2/istockphoto_344351_multi_macro. jpg

Coating Equipment http: //www. medicaldesign. com/ http: //www. sono-tek. com/images/_biomedical/medicoat_header. jpg Talwar Pharma manufactures a wide range of pellet products, mainly omeprazole and lansoprazole pellets, and offers stage wise quality tests at drug coating stage, sub-coating stage and enteric coating stage The surface profile of a drugeluting 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 http: //www. pharmaceuticaltechnology. com/contractor_images/t 34 alwar/3. jpg

Sampling • Accurate sampling is a key technical need for quality control and process characterization Stratified Sampling • 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 Three Assumptions Source: F. Muzzio • Random Mixtures (Normal Distributions) • Unperturbed Sampling (no thief error) 35 • Unchanging Mixtures (no segregation)

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

Challenges in Pharmaceutical Industry • 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” • 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 37 Source: F. Muzzio

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 38 Source: F. Muzzio

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 ØMature ØPortable ØHighly reliable (2. 5 s 6 s) 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 39 – Scalable, flexible Source: F. Muzzio

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

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

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

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

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

Introduction to Nanoparticles • 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. 45 http: //www. brighamandwomens. org/publicaffairs/Images/nanoparticles%20 attack%20 prostate%20 cancer %20 cells. jpg

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. 46

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, 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 47

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

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 49

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

Cond. . Importance of Nanoparticle Surface • Small size nanoparticles are suitable for variety of drug delivery applications. • As the particle size decreases, number of molecules present on particle surface increases. • Increased contact area can increase adhesion • For spherical solid particle of diameter d, surface area per unit mass, Sg, is (Gupta et. al, 2006) 51

Nanoparticle Flow for Drug Delivery • Nanoparticle flow can be facilitated by – Convective flow induced by the flow of blood, lymph or interstitial fluid – Influence of the interaction of nanoparticles with themselves or with biological components – Diffusion and particle movement of particle suspensions in interstitial tissue • Advantages of nanoparticle flow – Small dimension allows them to interact more effectively with cells – Can be safely injected – Diffuse further into tissues – Diffuse through individual cells • Larger particles are vulnerable to detachment by shear forces 52