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1 Particle Processing and Modeling in the Pharmaceutical Industry B. J. Glasser Department of Chemical and Biochemical Engineering Rutgers University Piscataway, New Jersey 08854 Slide 2 2 Drug A drug product consists of therapeutics and excipients combined in a delivery system. A drug products success lies in its ability to deliver the drug at a certain rate in a certain environment in the body. DiscoveryDeliveryManufacture http://www.sciencebase.com /images/epothilone_anticanc er_compound.jpg http://www.medgadget.com/archives/img /benephit.jpg Slide 3 3 Regulations FDAs 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 Slide 4 4 Growth of Pharmaceutical Industry in USA www.research.ibm.com/journal/sj/441/cortada.html US Sales Slide 5 5 World Pharmaceutical Market http://www4.dr-rath-foundation.org/PHARMACEUTICAL_BUSINESS/pharmaceutical_industry.htm Slide 6 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 Slide 7 7 Growth of Pharmaceutical R&D Expenditure http://www.pharmafocusasia.com/knowledge_bank/articles/images/graph1.gif Slide 8 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 Slide 9 9 www.bls.gov/oco/cg/images/cgc009_1.gif Employment by Establishments Total: 291000 employees in USA Slide 10 10 Pharmaceutical Employment by Position Level www.bls.gov/oco/cg/cgs009.htm Occupation Employment, 2004 Num berPercent Total, all occupations 291 100 Management, business, and financial occupations 53 18.2 Professional and related occupations 85 29.3 Office and administrative support occupations 34 11.6 Production occupations 79 27 Sales and related occupations 9 3 Installation, maintenance, and repair occupations 13 4.5 Transportation and material moving occupations 13 4.4 Others 5 2 Slide 11 11 New Drug Discovery http://www.syagen.com/images/drug_di scovery.jpg http://www.nature.com/nbt/journal/v22/n10/t humbs/nbt1004-1215-F1.jpg Slide 12 12 Dosage Forms Tablets/Capsules http://www.avmed.com/im ages/c_rx-capsule.jpg Injectables http://www.indiamart.com/cscpharma/gifs /injectable.jpg Inhalants http://www.bath.ac.uk /pr/releases/images/v ectura-inhale.gif http://www.life- tech.com/pm/nb1app3. jpg Transdermal products and implants Skin Drug Slide 13 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 Slide 14 14 Product/Process Development Paradigm Adjusted particle properties Preliminary process (unknown manufacturability) Drug is converted into Particles (sub-optimal delivery properties) Drug Synthesis Raw Chemicals Formulation Process Development & Scale up Adjusted process (unknownscalability ) Manufacturing Product Slide 15 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). Slide 16 16 Flow Sheet for Tablet Manufacture Source: F. Muzzio Slide 17 17 Synthesis Improvement in organic synthesis allow us to make larger and larger molecules. http://www.u-tokyo.ac.jp/coe/images/pic_list03_004.JPG http://www.chemsoc.org/chembytes/ezine/images/1999/persp_apr99_2.jpg Slide 18 18 Crystallization http://aiche.confex.com/aiche/2005/techprogram/images/21810-0.jpg Spheres Needles Cubes Slide 19 19 Agitated Drying of Crystals Crystal Size Distribution: Attrition decreases the size. Agglomeration increases the size. Lekhal et al. Powder Technology (2003) Drying Parameters: Drying Temperature Agitation Speed Drying time Vacuum Slide 20 20 Drying Freeze Drying Spray Drying solvent evaporation http://www.malvern.com/ProcessEng/images/processes/spray_drying_overview1.gif 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 Slide 21 21 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 Reductions in dust Improve appearance Decrease ingredient segregation Can improve dissolution (surfactant effects) Three Main Granulation Mechanisms Slide 22 22 Milling/Granulation Equipment 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 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 Slide 23 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 Slide 24 24 Powder Blenders Source: F. Muzzio Slide 25 25 Problems in Mixing - Segregation Segregation occurs if particles differ in size, density, shape, or other characteristics. Source: F. Muzzio Slide 26 26 Fluidized Bed Drying * Kunii and Levenspiel, 1991 V o : fluid velocity u t : particle terminal velocity V Om : minimum fluidization velocity Slide 27 27 Blending Drying Spray-drying Granulation Coating Pelletizing Adsorption High mass and heat transfer Billions of dollars on fluidized bed processes each year Application of FBs in Pharmaceutical Industry http://www.uic.edu/depts/chme/UnitOps/Fluidized%20Beds.jpg Slide 28 28 Classification of Gas-Fluidized Beds Slide 29 29 Problems in Fluidized Bed Processing Bubbling Uniform expansion Clustering Streamer Packed bed Increasing Gas Flows Different Flow Regimes Flow Instability Voidage Waves Drying or Reaction Rate Selectivity Product Yield Safety Environmental Impact Slide 30 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 Slide 31 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 Slide 32 32 Problems in Tableting Slide 33 33 Coating http://www1.istockphoto.com/file_thumbview_approve/344351/2/istockphoto_344351_multi_macro.jpg 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 Slide 34 34 Coating Equipment http://www.sono-tek.com/images/_biomedical/medicoat_header.jpg http://www.medicaldesign.com/ 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, and offers stage wise quality tests at drug coating stage, sub-coating stage and enteric coating stage http://www.pharmaceutical- technology.com/contractor_images/ta lwar/3.jpg Slide 35 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 Random Mixtures (Normal Distributions) Unperturbed Sampling (no thief error) Unchanging Mixtures (no segregation) Stratified Sampling Three Assumptions Source: F. Muzzio Slide 36 36 Sampling Machines Cavities can be filled with solid dies Only lower cavity used Globe-Pharma Sampler Slide 37 37 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 Source: F. Muzzio 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 Slide 38 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 Slide 39 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 Slide 40 40 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 al Chem Eng. Prog., 1994 FDC, The Gold Sheet, 2002 Wall Street Journal, 2003 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 Slide 41 41 Granular Materials Not Yet Understood Extreme behavioral regimes Makse et al, Nature 1995 Umbanhowar et al, Nature 1996 Jenike and Johanssen, 2004 GEA Buck, Inc., 2004 Curious phenomena Scale-gap between particle-level and macroscopic models Michaels, Powhder Tech., 2003 Slide 42 42 Inhomogeneity in Granular Flows 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 Jaworski, Dyakowski, Powder Tech. 2002 Pipe Flows Liss, Conway, Glasser, Phys. Fluids, 2002 Channel Flows Goldfarb, Shinbrot, Glasser, Nature, 2002 Forterre and Pouliquen, Phys. Rev. Lett., 2001 Slide 43 43 Segregation in Granular Materials Treated as unpredictable, inevitable Dominated by rules-of- thumb Breau et al, Phys. Rev. Lett., 2003 Alexander, Muzzio, Shinbrot, Chem. Eng Sci 2003 Broad application hampered: Numerous qualitative mechanisms Little agreement, eg. Brazil nut effect Slide 44 44 Granular Flows in Different Geometries Goldfarb, Glasser and Shinbrot, Nature, (2002) Conway, Shinbrot and Glasser, Nature, (2004) Conway, Lekhal, Glasser, Khinast AIChE J. (2006) Liss, Conway, Zega, and Glasser, Pharmaceutical Technology, (2004) Dry Solids Wet Solids Lekhal, Conway, Glasser, Khinast Chem. Eng. Sci. (2006) Slide 45 45 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. http://www.brighamandwomens.org/publicaffairs/Images/nanoparticles%20attack%20prostate%20cancer %20cells.jpg Slide 46 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. Slide 47 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 Slide 48 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. Slide 49 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 Slide 50 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. Slide 51 51 Cond.. Importance of Nanoparticle Surface (Gupta et.al, 2006) 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, S g, is Slide 52 52 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