COURSES
3rd Annual Meeting on FORMULATION & PROCESS DEVELOPMENT FOR ORAL DOSAGE FORMS "A 5-Day Modular and Case Study Oriented Training Program" April 23 - 28, 2006, Nassau Inn, Princeton, New Jersey Historical Location, Reputable Speakers & Innovative Program
PROGRAM	SPEAKERS	ABSTRACTS	COURSE EVALUATION	MISCELLANEOUS	REGISTRATION
ABSTRACTS
Day 1 Module 1 -Crystal Form of APIs Module 2 - Preformulation   Day 2:  Module 3 - General Formulation & Process Development Module 4 - Milling, Mixing and Flow			Day 3:  Module 5 - Granulation Module 6 - Tableting/Compaction Day 4:  Module 7 - Film Coating Module 8 - Technology Transfer   Day 5:  Module 9 - Stability
DAY 1.  Monday,  April 25, 2005
Module 1: Crystal Form of APIs Issues: Solubility; Polymorphism; Processibility; Stability Presenters:  Prof. David J.W. Grant  & Dr. Harry Brittain              Theory and Thermodynamics of Polymorphism David J.W. Grant Many drugs exhibit polymorphism, which is commonly defined as the ability of a substance to exist in two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Polymorphs may be enantiotropes, each of which has its own range of stability, or monotropes, one of which is unstable at all temperatures under normal (atmospheric) pressures. Burger, Ramburger and others have developed thermodynamic rules to determine whether polymorphs are enantiotropes or monotropes. In solid pharmaceutical formulations, the polymorph with the lowest thermodynamic activity, if bioavailable, is usually preferred because of its greater stability. The ability of a particular polymorph to crystallize is usually determined by both kinetic and thermodynamic factors, which are discussed. Ostwald’s rule of stages recognizes the common dominance of kinetic factors that often yield a metastable polymorph. Etter and coworkers have suggested that a supersaturated solution contains a variety of molecular aggregates, each of which is an embryo for a particular polymorph and competes for solute molecules. The nature of these aggregates is an emerging research area. The relative tendencies of the competing aggregates to grow to the size of a critical nucleus and subsequently to form a crystal are determined by competing thermodynamic and kinetic factors. The appearance of new polymorphs and the apparent disappearance of existing polymorphs are discussed in terms of these competing factors. The presentation will discuss the following topics: Crystal structures of polymorphs Thermodynamics of polymorphs Enantiotropes and monotropes Stability of polymorphs Nucleation and crystal growth of polymorphs Kinetics of polymorphic transitions Ostwald’s rule of stages New and disappearing polymorphs Nucleation and Crystal Growth of Polymorphs Relevant to Screening David J.W. Grant and Chong-Hui Gu Discovering the various polymorphs of a compound is an essential step in preformulation. Usually, the most stable polymorph is preferred in the marketed product. Solvent-mediated polymorphic transformation is an efficient technique for polymorph screening and for obtaining the most stable polymorph. However, solvents and impurities profoundly influence the rate of polymorphic transformation. This talk describes the influence of solvents and impurities on the rate of solution-mediated polymorphic transformation (I to II) of sulfamerazine (SMZ), and explores the underlying mechanism and molecular interactions. The nucleation rate of the more stable polymorph, II, determines the transformation rate at 24ºC in various solvents or solvent mixtures. The transformation rate is negligible in solvents giving low solubility (< 8 mmol/L) and increases and then decreases with increasing solubility. Transformation is slowed in solvents with strong hydrogen bond acceptor propensities. The balance of solubility and strength of hydrogen bonding between solute and solvent determines the transformation rate. Also, the structurally related additives, N4-acetylsulfamerazine (NSMZ), sulfadiazine (SD) or sulfamethazine (SM), in acetonitrile at 24ºC slow down the rate of solution-mediated transformation (I to II). The rank order of inhibitory effects on the rates of nucleation and crystal growth (NSMZ >> SD > SM) parallels the rank order of binding energy of the impurity molecules to the surface of the SMZ crystal. The presentation will discuss the following topics: Nucleation and crystal growth Rates of polymorphic transformation Effects of solvents and impurities Screening of polymorphs Mechanistic understanding Case study Chiral Drugs, Racemates and Polymorphism David J.W. Grant, Geoff G.Z. Zhang, Sophia Y.L. Paspal and Raj Suryanarayanan Chiral drugs are becoming increasingly common. Preformulation studies often require a fairly detailed understanding of the physical properties of each chiral drug, both alone and when mixed with its opposite enantiomer,. This presentation will examine and compare the various solid phases, in which chiral drugs may exist. Most of the talk will describe a special variant of polymorphism between a racemic conglomerate and two racemic compounds, taking sodium ibuprofen as an example. Finally, the physico-chemical implications of chiral purity will be discussed. Facts about chiral drugs Chirality, discussion of various types Enantiomer and various types of racemic species Conglomerate, racemic compound, pseudoracemate (solid solution) Phase diagrams of enantiomers and the corresponding racemic species Transitions between conglomerate and racemic compounds Example of sodium ibuprofen Enantiomeric purity and its physico-chemical implications Module 2: Preformulation Issues: Physico-chemical & mechanical properties of API s & Excipients Presenters: Dr. Navnit H. Shahl & Dr. Dukchoi Soon   Physicochemical Properties of API and Excipients:  Impact on Formulation Development Navnit H. Shah and Dukchoi Soon Part 1. Preformulation studies during discovery and development phase and its impact on clinical candidate selection and formulation development for clinical and market dosage form. Preformulation in discovery phase Impact of physicochemical properties in lead optimization, clinical candidate selection, and formulation development Impact of Physicochemical properties on bioavailability and stability Salt screening and its impact on bioavailability. Preformulation in the development phase Impact of solid state properties in formulation development and process development Chemical and physical properties of the API. Impact on processability Part 2. Crystal form and its impact on the bioavailability, stability and manufacturing Effect of physical form on bioavailability Crystallinity Solvates (Hydrates) Amorphous materials Examples - Case History Part 3. Physicochemical properties of excipients and Dosage form development Chemical properties of excipients. Effect on dosage form development Drug-excipient compatibility studies Excipients and their impact on stability Physical properties of excipients. Effect on dosage form development Particle size and morphology; Impact on content uniformity and compaction. Effect of excipients on compaction Effect of excipients on granulation density Excipients and bioavailability Lipid formulations Amorphous formulations. Stabilization by polymers Effect of excipients on dissolution
DAY 2.  Tuesday,  April 26, 2005
Module 3: General Formulation & Process Development Strategies Formulation Development Strategies: Excipients and Functionality Considerations A. Waseem Malick The presentation will address current formulation development strategies particularly focusing on the choice of excipients in pharmaceutical dosage form design. The emphasis will be on excipients and their functionality in formulations. The presentation will address drug-excipient and excipient-excipient interactions and the effect on product attributes in terms of, bioavailability, PK, stability, and manufacturability. The impact of excipient variability on functionality and consequently product performance will also be addressed  The Rationale Choice of Excipients Metin Çelik One of the most important aspects of tablet product design and development has undoubtedly been the selection of suitable excipients. Early formulators selected mainly either traditionally known excipients or the ones that they were experienced with. The success of the selected material was sometimes just a coincidence. Neither the number of new excipients nor the number of scientists who took the challenge of trying the new excipients was satisfactory. This was partly due to their lack of knowledge about the physico--mechanical properties of the pharmaceutical powders. Since the Physical, chemical and mechanical particulate properties dictate how formulations will behave during tablet processing and ultimately perform as a drug delivery system. Therefore, formulators of today do and must consider the physical, chemical and mechanical properties of the pharmaceutical materials.  In addition, the functional properties of the excipients as well as SUPAC guidelines and other regulatory issues must be integrated to the excipient selection process. Since the number of tableting excipients is limited (although it may be a large number), it is highly feasible to establish an electronic interactive preformulation database by generating information on the above properties of the excipients and the most commonly used drug substances. Also, the information contained in such a database can then form the foundation of a formulation and process expert system. In this presentation, the following issues will be addressed as related to the selection of excipients: Functionality considerations of the excipients SUPAC Guidelines Utilization of an electronic (excipient) preformulation/formulation database (A case study will be presented to show the batch-to-batch, grade-to-grade, and supplier-to-supplier variations of some commonly used excipient) Utilization of artificial intelligence (A brief demonstration of an expert system will be presented to show how artificial intelligence can be utilized the in formulation and process development of immediate and controlled release drug delivery system. Case study will be based on a new drug delivery technology) Module 4: Milling, Mixing and Flow   Issues: Material, Process, Scale-Up, Trouble Shooting, SUPAC and Validation Related Issues Presenters:  Mr. Benjamin K. Murugesu  & James K. Prescott     Size Reduction Benjamin K. Murugesu/Patrick Arthur This presentation will provide an overview of the process of milling as it relates to the size reduction of pharmaceutical materials.  Conical milling technology will be specifically described, but in general terms, the benefits of both wet and dry milling will be discussed.   Factors that influence the size reduction process will be reviewed in detail, especially as they relate to particle size distribution and granulometry.  Finally, scaling up the milling process, and GMP concerns, will be addressed. Powder Flow, Blending and Segregation: Tying it all together James K. Prescott Outline of  the presentation: Common flow, segregation and blending problems Evaluating formulations with respect to flow and segregation potential Formulation development and equipment solutions to flow and segregation problems Validation of blend and content uniformity Diagnosing root causes of uniformity problems
DAY 3.  Wednesday,  April 27, 2005
Module 5: Granulation   Issues: Material, Process, Scale-Up, Trouble Shooting, SUPAC and Validation Related Issues Presenters:  Mr. David M. Jones, Mr. Dilip M. Parikh & Mr. Gary Bubb   Overview of the Fluid Bed Granulation Process David M. Jones Granulations used in pharmaceutical processing are made using a variety of techniques.  Two commonly used methods involve either wet massing (using low or high shear vertical or horizontal processors), or fluidized bed spray granulation.  Universal goals of granulation include improved flow and compression properties (hardness, friability and disintegration) and uniform distribution of the ingredients in the mixture.  The technique chosen will likely play a significant role in the physical properties of the resultant granulation.   In general, granules produced in the fluidized bed are more porous and lower in density than those produced by wet massing.  For some products this is an advantage, for others a shortcoming.  While the majority of granulation in the fluidized bed takes place in the conventional top spray configuration, the rotor tangential spray and Wurster are used commercially for this task.  The basic configurations of these techniques will be reviewed, as will process parameters.   The advantages and limitations with respect to product applications will also be discussed. Granulation Techniques Dilip M. Parikh  Granulation of powders to produce pharmaceutical solid-dosage form is an essential unit operation. The dry and wet granulation processes have been used in the industry to achieve the free flowing granulation. The advent of changing pharmaceutical market place and the emergence of potent compound processing has created needs for enhancing the older processes and exploring the innovations that the technology is now providing.  The selection of a process sometimes depends on the physico-chemical characteristics of the drug substance, and final dosage form requirements.  This presentation will discuss various wet granulation methods pertaining to high and low shear granulation techniques, their application in the pharmaceutical dosage form development and equipment used. Processing variables, binder distribution and its impact on the quality of granulation produced will be discussed. Current thinking on process controls, end point determination methods, and scale up approaches will also be presented. Granulation End Point Determination (Optional Presentation - Maybe removed from the program) Gary Bubb Outlines of the presentation: Amps Power Power Cell Slip Angle Boots Probe Capacitance Reaction Torque Direct Torque Computed Torque Module 6: Tableting/Compaction   Issues: Material, Process, Scale-Up, Trouble Shooting, SUPAC and Validation Related Issues Presenters: Dr. Metin Çelik & Mr. Gary Bubb   Theory and Practice of Pharmaceutical Compaction Metin Çelik The phenomena and mechanisms involved during compaction of pharmaceutical powders became an increasingly important concept in the design and development of solid dosage forms. The principal physico-mechanical process involved in the compaction of particulate matter can be considered to occur as follows: i) Particle Rearrangement: At this stage, the particles flow with respect to each other, with the finer particles entering into the voids between the larger ones, resulting in a closer packing arrangement. ii) Deformation of Particles: The deformation features either one or a combination of the following: elastic, plastic, and/or fragmentation. The type of deformation depends upon the rate and magnitude of the applied force as well as the duration of the locally induced stress and physical properties of the material. iii) Bonding: Attraction between particles is inversely proportional to the distance between them and when the particles are in sufficiently close proximity they can become permanently attached to each other. The following mechanisms contribute to the strength of the bond, although they never act independently: mechanical interlocking, fusion or cold welding, inter-molecular forces (i.e., van der Waals force, hydrogen bonding, and ionic-bonding). iv) Further Deformation of the Compact Followed by Its Expansion: When a compact has been formed in the die, a further increase in the applied pressure, or application of a constant stress during dwell time, may cause further deformation of a time-dependant material as the compact consolidates by visco-elastic and plastic flow. When the applied pressure is removed during decompression, which is the final stage of a compaction event, the compact undergoes a sudden elastic expansion followed by a much slower visco-elastic recovery as the compact is ejected. It is well known that it is the elastic expansion that are main cause of some tableting problems such as capping and lamination. Such problems can be minimized by altering the formulation and/or process conditions since the magnitudes of both elastic and visco-elastic recoveries depend on both the time-dependant properties of that material as well as machine characteristics, such as the speed of compaction and the geometry of punch travel guide. In the compaction studies, the equipment used (instrumented single-station and multi-station presses, universal testing machines, and Integrated Compaction Research Systems) and the parameters monitored (the forces on and displacements of the upper and lower punches, axial to radial load transmission, die wall friction, ejection force, temperature changes, and other miscellaneous parameters) vary widely. The number of compaction equations proposed to characterize the compressional process approximates to the number of workers in this field. However, many of the equations have applicability over only a limited range of applied force and for only a few types of materials. Certainly no universal relationship has yet emerged and is unlikely to do so, since a comprehensive analysis of the mechanisms involved is difficult due to the complexity of the systems being compacted. The data analysis methods can be classified in three groups as thods that utilize the data obtained from the measurements of: i- applied pressure and punch displacements; ii- transmitted pressure; and iii- miscellaneous parameters. In this presentation, the phenomena and mechanisms involved during compaction of a particulate system will be dealt. The equipment used in compaction studies and the techniques that have been utilized to evaluate the compaction data will also be discussed utilizing an interactive software developed by the presenter. Tablet Press Instrumentation Gary Bubb Outlines of the presentation: 1.       Pre-Formulation Force Displacement Porosity Heckel 2.       R&D ·Compaction Profiles 3.       Scale up or Pilot Plant Strain Rate Studies Compression roll diameters Tangential Velocity for different rotary presses. 4.       Production Feed Back and Control Systems  5.      Calibration 6.     Validation and CFR-21 Part 11
DAY 4.  Thursday,  April 28, 2005
Module 7: Film Coating   Issues: Material, Process, Scale-Up, Trouble Shooting, SUPAC and Validation Related Issues Presenters:  Prof. Michael E. Aulton & Dr. Stuart C. Porter    Introduction to Pharmaceutical Coating Esay Okutgen Outlines of the presentation: reasons for coating types of coating coating formulations [outline only] coating processes [outline only] ideal coat properties coat defects roughness film formation Assessment of Film-Coat Quality Esay Okutgen Outlines of the presentation: uniformity of thickness mechanical properties colour quality surface roughness, gloss dissolution characteristics  Film Coating Processing & Scale Up Stuart C. Porter In terms of examining the factors that can influence the quality of the final product, the film-coating process is potentially one of the most complex unit operations performed in the pharmaceutical industry today. This complexity increases when critical variables associated with the formulation of the core and the applied coating are also considered. This presentation will provide a brief overview of the basic types of processing equipment that may be used, and will then discuss in more detail the critical parameters that must be considered if a quality product is to be produced. During this discussion, the prime focus will be on the aqueous film coating of tablets with non-release-modifying coatings, although relevant reference will also be made to the coating of other types of products (such as multiparticulates) with modified-release coatings where the issues may differ from those involved in more conventional processes. Key issues to be discussed will include gaining an understanding of: The impact of the coating process on film-coat quality. The influence of process parameters on uniformity of distribution of the coating. The importance of the spray parameters chosen, and how these may be greatly influenced by the spray equipment chosen, and, ultimately, how the characteristics of the atomized liquid can affect product quality Attention will also be paid to those issues that are critical to success when scaling up the coating process, including consideration of changes that may have to be considered post product approval (that is, key SUPAC issues).   Troubleshooting the Film Coating Process Stuart C. Porter In terms of examining the factors that can influence the quality of the final product, film coating process is potentially an extremely complex process, especially when considered in terms of all the critical process parameters, as well as those associated with the formulation of the core and the applied coating, that can ultimately affect product quality. Troubleshooting is, in essence, a difficult subject to address, since it reflects a condition that requires change in an environment (that is, post product approval) where significant change is all but impossible to contemplate. The need to embrace troubleshooting activities is often considered an admission of failure, where activities that should have taken place during product and process development are not completed to the level where a robust product and process can successfully be transferred into the production setting. Formulations and processes that are essentially "knife edge" are unable to tolerate the natural variation (that occurs with raw materials form batch-to-batch, and routinely with process conditions, especially with processes that are transferred to remote geographical locations where equipment differences may be greater than anticipated) that will always occur with such a complex process. Accepting that troubleshooting activities can be a routine part of film-coating operations, this presentation will seek to review many of the common problems that are likely to be encountered, and provide insight into how these problems may be managed. Examples of classes of problems to be discussed include those associated with: Loss of logo definition. Tablet erosion Tablet breakage Poor color uniformity Film cracking Film peeling Excessive film roughness Adherence between coated products Unacceptable dissolution behavior The application of modern tools (such as application of statistical design of experiments techniques, and use of expert systems) will be also briefly reviewed. Module 8: Technology Transfer   Issues: Material, Process, Scale-Up, Trouble Shooting, SUPAC and Validation Related Issues Presenters: Dr. Russell Somma & Dr. Hashim Ahmed     Technology Transfer or Knowledge Transfer of Product Formulations and Manufacturing Processes: Which Expedites the Process More? Russell Somma    The goal of all pharmaceutical companies is to reduce the amount of time to reach peak sales. The concept of reduced time to market is out of date when one considers the volatility of the market we are serving. This faster approach to peak sales requires that strategies and policies be streamlined and globally based to attain a commercial success. To achieve this success, rapid commercialization of a process into a production environment is mandatory. The technology transfer aspect of this commercialization process requires a close partnership with manufacturing leading finally to product and process ownership by the production unit. One cannot discuss technology transfer without thinking about the objectives which are the essence of the undertaking and that is to deliver a product and process, which is validated. Validation must deliver a good return on investment. With this in mind, the validation objectives are easily broken down into three areas: to demonstrate control, to ensure compliance and to generate knowledge. Knowledge of the product and the related process are the primary focus of this discussion and it will be demonstrated that the transfer of product knowledge is the area of greatest benefit to our business. If we take process introduction as the starting point on our journey to business efficiency then the validation segment may be looked upon as part of the continuous improvement continuum for the product. A well-planned technology transfer will bring the company up the learning curve faster to 100% efficiency. The conduit for this transfer is the existing interface between research and development and manufacturing. It will be shown that critical analysis and a team approach by R & D and manufacturing combined with product knowledge will yield the best path for commercial success. It is only with a shared knowledge base that a seamless introduction may be achieved.    Pharmaceutical Product Development for Successful Technology Transfer Hashim Ahmed The presentation will define Technology Transfer as the formal transfer of product development, process and analytical methodology information from laboratory R&D to production. Recently Technology Transfer has received greater attention because of several factors including speed to market, issues from the generic drug scandal, globalization, and good business practices (cGMP etc.). Technology transfer teams, their formation and composition together with their functions will be discussed in this presentation. The route for a successful technology transfer will be shown using case studies and examples. Points of possible failures and their trouble-shooting will be discussed and practical examples will be given in the presentation. Scale-up challenges, SUPAC and validation related issues will also be addressed.
DAY 5.  Friday,  April 29, 2005
Module 9: Stability   Issues: Establishing an appropriate stability program; Identifying stability issues; Designing formulations to maximize stability; Dealing with stability problems Presenters:  Prof. Lynne S. Taylor and A Speaker to be determined.     Water-Solid Interactions - Relevance to Stability Lynne S. Taylor Mechanisms of water-solid interactions Adsorption Absorption Hydrate formation Capillary condensation Deliquescence Sources of water during pharmaceutical processing and storage Solvent Hygroscopic excipients Atmosphere Transfer from packaging Effect of processing operations on solid state properties and subsequent solid-water interactions e.g. Milling Wet granulation Drying Coating Impact of residual water on chemical and physical stability Disordered regions Molecular mobility Salts Phase transformations Chemical reaction mechanism