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

Drug Discovery Delivery Manufacture 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 The success of a drug product involves three main aspects: Discovery of the molecule that has the right therapeutic effect. Delivery of the API. Manufacturing the drug in a consistent and reliable way. Delivery in a most efficient manner. In order to avoid drug degradation and target efficiently the agent, it is required that the API’s delivery vehicle is properly designed. For example drugs can be easily degraded in the stomach due to low pH (about 1). http://www.sciencebase.com/images/epothilone_anticancer_compound.jpg http://www.medgadget.com/archives/img/benephit.jpg

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. FDA regulations – major driving force in today’s drug industry. What is the FDA’s role as governmental agency? GMP – what is it? Major part of making drugs-documenting every step of the way. FDA-trying to monitor the quality of the product. How quality is being monitored – samples are tested. http://www.fda.gov/ www.fda.gov/cder/reports/rtn99-3.htm

Growth of Pharmaceutical Industry in USA US Sales Why are we interested in pharmaceutical industry? The ascending multibillion sales, makes the pharmaceutical industry one of the most important pillars of the economy. What can we do better as chemical engineers. Engineers are the link between making things and making things better. There is a big potential for optimization and doing things differently in the pharmaceutical industry. www.research.ibm.com/journal/sj/441/cortada.html

World Pharmaceutical Market The fact that USA captures 57% of the world drug market, is a powerful reason to take the lead on pharmaceutical engineering. There is a high potential for chemical engineers in the US. http://www4.dr-rath-foundation.org/PHARMACEUTICAL_BUSINESS/pharmaceutical_industry.htm

Comparison of Annual Sales Per Person ANNUAL SALES PER PERSON OF PHARMACEUTICALS (2004, £ ) Enormous market for drugs in the US. Health is major concern. http://www.abpi.org.uk/publications/publication_details/annualReview2005/ar2005_leader.asp

Growth of Pharmaceutical R&D Expenditure The amount of money invested in R&D is increasing, but what about manufacturing? Optimization can lead to a reduction of cost in manufacturing and improve quality. http://www.pharmafocusasia.com/knowledge_bank/articles/images/graph1.gif

Comparison of Pharmaceutical R&D WORLD VOLUME OF PHARMACEUTICAL R&D (2004 £m) Initiative on R&D can come from the US. http://www.abpi.org.uk/publications/publication_details/annualReview2005/ar2005_leader.asp

Employment by Establishments Total: 291000 employees in USA Pharmaceutical and medicine manufacturing provided 291,000 wage and salary jobs in 2004. Pharmaceutical and medicine manufacturing establishments typically employ many workers. Nearly 60 percent of this industry's jobs in 2004 were in establishments that employed more than 500 workers. Most jobs are in California, Illinois, Texas, Indiana, New Jersey, New York, North Carolina, and Pennsylvania. www.bls.gov/oco/cg/images/cgc009_1.gif

Pharmaceutical Employment by Position Level Occupation Employment, 2004 Number Percent   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 4.4 Others 5 2 www.bls.gov/oco/cg/cgs009.htm

New Drug Discovery Pipeline-indication of the company’s potential for profit. Usual period for putting drugs on the market is 14 years. The development of drugs starts with identifying the illness the company wants to invest in-usually chronic. Phase I – tox studies. Phase II – clinical trials on small population of patients. Phase III - clinical trials on large population of patients. Phase IV – voluntarily, continuing study on the drug to see what other effects it might have. http://www.nature.com/nbt/journal/v22/n10/thumbs/nbt1004-1215-F1.jpg http://www.syagen.com/images/drug_discovery.jpg

Dosage Forms Tablets/Capsules Injectables Inhalants Transdermal products and implants Drug Skin Different dosage forms – most desirable is pills and least desirable is injections. When it come to tablets one dose per day is preferable. http://www.indiamart.com/cscpharma/gifs/injectable.jpg http://www.bath.ac.uk/pr/releases/images/vectura-inhale.gif http://www.life-tech.com/pm/nb1app3.jpg http://www.avmed.com/images/c_rx-capsule.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 • Effervescent tablets • Hypodermic tablets Advantages • convenience of consumptiom • shelf-life (stability) • economics of manufacturing • patient acceptance Advantage of tablets. Important characteristics of the tablets are their high shelf life and stability.

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 (unknown scalability ) Manufacturing Production of successful drug product involves discovering the right API and developing an adequate delivery unit. Process control plays an important role along the way. Product

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 Big potential for engineers in the pharmaceutical industry. Where they can best fit – product development and scale-up. 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).

Flow Sheet for Tablet Manufacture Typical scheme for making drugs – tablets are delivery units only for chemical API. When we can not make chemical API then we make biological API. Usually very large molecules are made using biological routs. Amorphous APIs have high solubility. Source: F. Muzzio

Synthesis http://www.u-tokyo.ac.jp/coe/images/pic_list03_004.JPG Trends in today's pharmaceutical industry are towards producing bigger and bigger molecules. Today larger molecules are discovered at an increasing rate due to the development of combinatorial chemistry, and organic synthesis is getting better. Nevertheless, large molecules have less solubility. http://www.chemsoc.org/chembytes/ezine/images/1999/persp_apr99_2.jpg Improvement in organic synthesis allow us to make larger and larger molecules.

Crystallization Spheres Needles Cubes Crystallization is better understood operation. The morphology of the crystals can be controlled. Spheres and cubes are preferred over needles due to the difficulty in filtration and friability of the particles. http://aiche.confex.com/aiche/2005/techprogram/images/21810-0.jpg

Agitated Drying of Crystals Drying Parameters: Drying Temperature Agitation Speed Drying time Vacuum Less studied unit operation than crystallization. Still many opportunities for chemical engineers. Common practice to avoid agglomeration is to use antisolvent during the washing step. Crystal Size Distribution: Attrition decreases the size. Agglomeration increases the size. Lekhal et al. Powder Technology (2003)

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 Freeze drying is used mainly during the production of injectables. solvent evaporation http://www.malvern.com/ProcessEng/images/processes/spray_drying_overview1.gif

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) Milling and granulation – an important unit operation.

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. The Pulva mill operates with a set of hammers on a rotor assembly that rotates at very high speeds. A screen is placed under the hammers to help control the particle size distribution. 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 harder granules less than 2 mm in size. They are particularly well-suited to handle viscous binder formulations and fine, cohesive powders. While may designs are available, there is little scientific evidence regarding the advantages of any particular designParameters: Agitator speed (typically 100-1000 rpm), chopper (1500-2000 rpm), solids lot size, rate and amount of binder 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

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 Blending is used when pills are the preferred way of delivery. Segregation of the API and excipients is a problem of major concern. Dispersion during blending is associated with diffusion.

Powder Blenders Source: F. Muzzio

Problems in Mixing - Segregation As much as we mix we segregate. Mixing and segregation go hand in hand. Fighting segregation is difficult when particles do not move in the same way. Segregation occurs if particles differ in size, density, shape, or other characteristics. Source: F. Muzzio

Fluidized Bed Drying Vo: fluid velocity ut: particle terminal velocity Poor drying compromises the stability of the drug. The idea is to dry as much as possible to fight degradation. Mechanical integrity of the particles is compromised when they are wet. Challenging area for chemical engineers. Vo: fluid velocity ut: particle terminal velocity VOm: minimum fluidization velocity * Kunii and Levenspiel, 1991

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

Classification of Gas-Fluidized Beds Flow in solids is not uniform. Different flow regimes affect the heat and mass transfer. Drying rates are greatly affected.

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

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 After compaction will nano-particles remain as such? There are still many major challenges for making nano-particles. http://www.sripharmacare.com/gifs/tablet-capsule1.jpg

Tableting Machines Four main stages for tableting : Die fill, weight adjustment, compression, and ejection There are four distinct stages in tableting. Enormous amount of difficulties. Rotary tablet presses http://www.capsule-filling-machine.com/rimages/131/tablet-h01.jpg

Problems in Tableting If adequate dryness is not achieved quality problems arise. A common practice to find the drying operation parameters is by trial and error.

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 Dip Coating - According to this method the film is dipped into the solution and then withdrawn. The affinity of film to the web determines the thickness. Additional adjustment of thickness can be achieved using rolls, knives and so on Rod Coating - A rotating rod removes any excess solution from the web and moves it in the opposite direction of the rod's rotation. The width of the rod and the distance between the wire crowns mainly determine the thickness Knife Coating - In this method, a stationary knife removes any excess solution from the web Blade Coating - This is similar to the system mentioned above, except instead of the perpendicular knife, a flexible rigid bevelled blade is used Air Knife Coating - This is used mainly for pigmented coatings. The speed of coating and viscosity determine the thickness Gravure Coating - This system uses an engraved cylinder that 'receives' the coating solution on the web. The thickness depends on the gravure geometry. It is a very accurate method Forward and Reverse Roll Coating - An applicator roll rotates in the same or opposite direction as the web's movement Slot and Extrusion Coating - This method presents a very interesting, accurate and 'closed' coating system. It is highly recommended for pharmaceutical coatings that are based on a similar principle, although the slot is used for lower viscosity solutions Multi-Layer Coating Methods Although multi-layer coatings are not very common for pharmaceutical patch production, the two main systems used are slide coating and curtain coating. http://www1.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 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 Operating Principle The MediCoat™ Benchtop stent coating system combines Sono•Tek’s unique microspray atomizing nozzle with low-pressure gas to produce a soft, highly focused beam of atomized spray drops. Compressed gas, typically at 1 psi, is introduced into the diffusion chamber of the air shroud, producing a uniformly distributed flow of air around the nozzle’s atomizing surface. The ultrasonically produced spray created is immediately entrained in the air stream. An adjustable focusing mechanism on the air shroud allows complete control of the spray width. http://www.pharmaceutical-technology.com/contractor_images/talwar/3.jpg

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 Sampling issues that arise. Difficulties taking representative samples. Three Assumptions • Random Mixtures (Normal Distributions) • Unperturbed Sampling (no thief error) • Unchanging Mixtures (no segregation) Source: F. Muzzio

Sampling Machines Sampling instruments affect the sample. How can we test better? •Cavities can be filled with solid dies •Only lower cavity used Globe-Pharma Sampler

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 Where the future lies? FDA and its “preventing innovation” effect. 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 Provide FDA with new information to obtain more reasonable regulations. 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 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 Design products so that they can be controlled at the nano scale. Source: F. Muzzio

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 Motivation for particle process development: Majority of final drug products are in powder form Particle handling is a poorly understood area Particle form highly affects quality of final product

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 Makse et al, Nature 1995 Umbanhowar et al, Nature 1996 There is a better understanding of liquids than solids Michaels, Powhder Tech., 2003

Inhomogeneity in Granular Flows Pipe 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 Liss, Conway, Glasser, Phys. Fluids, 2002 Jaworski, Dyakowski, Powder Tech. 2002 Channel Flows Particles system differs significantly from the well understood fluid systems. Non uniform flow is major difficulty in particles systems. In addition, particles have the tendency to form clusters. Particles with different properties move differently. Forterre and Pouliquen, Phys. Rev. Lett., 2001 Goldfarb, Shinbrot, Glasser, Nature, 2002

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

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, Khinast AIChE J. (2006) Lekhal, Conway, Glasser, Khinast Chem. Eng. Sci. (2006) Dry Solids Wet Solids

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. In the range of 1 to 5 nm, the size of the particles becomes comparable to the length of the bonds, thus quantum effects start to dominate the system. This fact brings more complexity but at the same time accounts for many of the properties that are of great interest to the pharmaceutical companies. One of the potential use of nano particles is as an efficient delivery vehicles for cancer therapies. http://www.brighamandwomens.org/publicaffairs/Images/nanoparticles%20attack%20prostate%20cancer%20cells.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. Nanostructures are very well ordered materials that can be composed of nanoparticles. It is this specific order of the nano particles that bestow attractive properties to the nanostructures.

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

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.

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

Importance of Nanoparticle Surface Ref: Gupta R.B, Kompella U.B, Nanoparticle Technology for Drug Delivery, Drugs 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)

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