Test Bed 1

Test Bed 1 Plan: Continuous Manufacturing of Tablets

Faculty: Marianthi Ierapetritou (leader), Fernando Muzzio, Carl Wassgren, Carlos Velázquez, James Litster, Rodolfo Pinal, Alberto Cuitino, Bo Michniak, Venkat Venkatsubriamanian, Gintaras Reklaitis, Rodolfo Romanach, Rajesh Dave

Postdoctoral Fellows: Atul Dubey, Zhenya Jia, Athanas Koynov, Rafael Méndez, Ajit Mujumdar, Kalyana Pingali, Patricia Portillo, Mingli Ye, Arun Giridhar

Graduate Students: Avik Sarkar, Aditya Vanarese, Yijie Gao, William Engisch, Ryan John McCann, Lauren Beach, Lakxmi Gurumurthy, Tripura Mulukutla, Xi Han, Alisa Vasilenko, Intan Munirah Hamdan, Chaffee, others TBD

Mentors: Mayur Lodaya

TEST BED PLAN

Note: Goals, Scope, and Challenges of the test bed plan have been already described in Section 2.2.4 of this report, but are reproduced here for completeness of presentation.

A. Goals

The major goals of Test Bed 1 are (1) the development and integration of technologies for integrated continuous manufacturing of solids dosage forms under automatic control, and (2) the development, integration, and optimization of models and in-line strategies for process control. This platform will be a test bed for the development of the models and in-line strategies for process control, to demonstrate new equipment designs and design modifications, and to test new design models for their ability to predict performance during continuous operation.

B. Scope

This test bed focuses on the development and demonstration of feasibility of continuous technology for sequentially blending, dry-granulating, lubricating, and tableting of dry powders and granules. By focusing on continuous manufacturing methods, this test bed will facilitate the development of predictive models for single process components as well as the integration of these models into hybrid platforms to be used for process control, and the development of real time process management strategies to support long term operation. The objective is to effectively mitigate the three most common problems affecting the quality of finished products made by batch processing, namely, segregation, agglomeration, and compact quality, while simultaneously improving process controllability and robustness. Additional advantages include facilitation of process scale-up and reduction in the size and thus capital cost of equipment.

The approach is based on the use of highly efficient, small-scale (2 Kg) continuous mixers that are continuously loaded using loss in weight feeders. The mixed material stream is then discharged into the feed chute of the roller compaction system, followed by milling. This dry granulation approach, which avoids contact with water and heat, reducing stability problems, residual moisture, changes in crystalline form, etc., will be explored in detail to determine the limits of its applicability. The granulated active is then blended continuously with compression aids and lubricants and turned into finished product in a tablet press. Besides the Active Pharmaceutical Ingredient (API), the lubricant is the single ingredient responsible for the largest number of processing problems (loss of hardness, hindered dissolution, variances in flow behavior, large tablet weight variation and poor content uniformity), and therefore we will examine in detail multiple modes of addition of the lubricant in order to develop strategies for minimizing such problems. The equipment employed is well established in the industry, but its use for continuous processing has not yet been demonstrated, an integrated control platform for all the relevant steps is as of yet unavailable, and predictive design models to set processing conditions for new products are generally not available.

The mechanical properties of the compacted ribbon and tablets are the key to dosage form manufacture and performance and are the focus of advanced modeling activities. While the dry granulation method is ideal for high dose tablets, it is very sensitive to raw material variability. The gaps in modeling/understanding the process prevent process design that is robust with respect to raw material variability. For example, for high drug content blends, the mechanical properties of the drug substance control the compaction behavior, and therefore, poor deformation properties (and poor understanding of how to modify them) limit our ability to compress high drug content blends.

C. Challenges

In order to manufacture tablets continuously under closed-loop control, multiple ingredients must be accurately fed into a continuous mixing system, and the blended stream, which might also be passed through a roller compactor/mill, is then fed to a tablet press. Materials must be selected, and material properties need to be controlled, so that undesired effects detrimental to product quality (segregation, electrostatic buildup, inconsistent flow, non-uniform die filling) are prevented. Properties of intermediate products and finished product need to be monitored, and this information must be used to take corrective actions to keep the process under optimal or near-optimal control. This requires the development of models that predict the effect of material properties and processing conditions (shear, humidity) on the properties of finished products, and the implementation of adequate sensors and data handling algorithms. Soft-sensor inferential approaches must be developed for control of difficult to measure properties. Sensor data must be compared to model predictions for both model validation and as the basis of feedback control of the overall process. To maintain product quality over long periods in the face of occasional major disturbances, higher level real time process management strategies such as Exceptional Events Management are required. Efficient implementation of all this also necessitates an ontological informatics framework for storing, accessing, and manipulating data and knowledge.

D. Integration with Thrusts and Project Interdependencies

The fishbone diagram for this test bed is shown in Figure 2R-46 in section 2.2 of this report and it is not repeated here. This test bed, which at the present time represents the largest technology development effort in the ERC, draws heavily from all four planned Thrusts of the center, taking significant inputs from 15 projects (out of 21). Table 2P-1 succinctly presents the main role played by each project on the test bed.

However the integration of the Thrusts also occurs at a higher level. In fact Test Bed 1 represents the most advanced attempt by the ERC to link and connect the four Thrusts along the schematic depicted in Figure 2P-20. Each Thrust plays its major role as intended: Thrust A provides knowledge about raw material properties, and develops strategies for modifying those properties (i.e., via dry coating) if necessary. Thrust B focuses on understanding, modeling, and designing the major processing steps. Thrust C examines the structure and properties of resulting structured materials as a function of composition and processing history, providing essential information to Thrust D to perform the integrated design, optimization, and control of the entire operation

Table 2P-2: Major Inputs to TB 1 from projects within each Thrust

E. Planned Research Activities

A plan for achieving test goals has been formulated following an engineering paradigm of providing an end-to-end integrated manufacturing solution which is rooted in robust operation of individual process components. A finer degree of granularity of timed deliverables is outlined next. Activities spanning three broad domains are discussed: (1) Materials Characterization activities, (2) Characterization and modeling of individual structuring steps, and (3) Integration activities

(1)Materials Characterization Activities.

Solid dose manufacturing is essentially a structuring process wherein particles of multiple organic (and sometimes inorganic) materials are organized into larger systems having a microstructure that controls the final product performance. In order to understand and control this structuring process, it is necessary to characterize the relevant material properties as materials enter the process and are gradually transformed by it. Understanding of these transformations and developing accurate measurement approaches of material properties that contain the relevant information is essential not only to proper design of the process, but also to develop sensing methods and control strategies that allow effective operation of the system.

Tasks required to achieve the necessary characterization of material properties ranging from incoming materials to finished tablets include input from projects (A5, A6, C2, C3, C4, and C5). Timed deliverables from these projects are discussed next.

A5. Crystal Morphology and Strength

The scope of this project relevant to the test bed is to develop the methodology to identify mechanical properties of organic particles. Key technological objectives relevant to TB1 include:

·    Determine the stress-strain relationship of single crystals of materials relevant to the test bed

·    Relate this through modeling to the strength of the crystals as a function of application of stress, size,

   and other properties relevant to the needs of the thrust and test beds

·    Generate a knowledge base for related materials

A6 Surface Interactions and Surface Modification

Key technological objectives relevant to TB1 include:

· Develop validated methodology for systematic tuning of particle properties by tuning of particle coating processes

· Develop and validate meta-level framework for predicting powder behaviors based on particle coating properties and key measured properties

· Generate a knowledge base for related materials

C2. Granular Rheology/Powder Flow/Effects of Processing

Technological objectives relevant to the test bed include:

· Select, install, and qualify existing equipment for powder testing. This includes shear cell(s), rheometers (GDR and FT4), Flodex and Hosokawa Powder Tester.

· Select powder blends based on test-bed 1 requirements, in low (1-5%), moderate (20-40%) and high drug (>80%) concentrations. Evaluate the powder properties with and without the presence of flow-aids and lubricants.

· Prepare blends with pre-treated APIs (nano-coated, or surface modified, done after input from industry mentors) and evaluate their properties. It is expected that the amount of flow-aids required will be less for pre-treated APIs in contrast to blends.

· Develop and/or modify powder testing apparatus suitable for characterizing blends containing pre-treated cohesive powders; e.g., FT4, Sevilla Powder Tester, Vibrated Packed Density tester, etc.

· Employ and/or develop methods for quantifying properties such as surface energy, hydrophobicity and electrostatic properties of the blend constituents.

· Examine the feasibility of drawing from the DEM work to correlate the powder properties with processing conditions for blending operation.

· Coordinate experimental plans and blend compositions between related projects, and thus prepare powder blends for downstream projects, so that influence of powder flow and structure is understood on compaction, tablet and dissolution properties. This also includes evaluation of feeder and mixer performance as a function of powder flow properties.

· Develop a knowledge base and correlations between results from various powder testers, processing conditions, and blend constituent properties. Based on this and input from other projects, develop guidelines for achieving API blends that flow better and have less stickiness (triboelectric charging, etc.) and hence less problems in subsequent processing, while avoiding adverse effects on tablet and dissolution properties.

C3. Structural Characterization of Composite Solids

Technological objectives relevant to the test bed include:

· Establishing methodologies for measuring relevant microstructural attributes of compacted solids

· assessment of the material response as a function of its structure

· verification and validation of the models based on multiscale materials structure and performance

· (long term) inform the development of online, at line, and inline methods for extracting microstructural information and using it for control purposes

C4. Bonding of Granular Solids

The technological objectives relevant to TB1 include

· Provide spatially resolved characterization of the compact, which will be use to identify and quantify

the severity of defects.

· Identification of the dominant mechanisms responsible for bonding (development of strength) during consolidation of compaction of granular systems

· Development of multiscale modeling and simulation strategies to account for powder related properties (size distribution, shape, surface characteristics, etc) and processing conditions

· Development of 3D mechanistic continuum models for confined granular systems describing both tensile and compressive regime under different degree of confinement

· Design and implementation of experimental test to verify and validate the models, including biaxial and tri-axial testing.

C5. Drug Release from Complex Solids

The scientific and technological objectives of this project relevant to the test bed include:

· Perform dissolution testing of tablets manufactured under variable composition and processing conditions

· Correlate matrix characteristics with drug release parameters

· Examine the distribution of actives and excipients using chemical imaging and relate to processing conditions and dissolution characteristics (in conjunction with Project C-3)

· Develop mechanistic models to explain dissolution properties of tablets

· Develop and implement level-set models to simulate coupled drug dissolution and surface erosion

· Determine and calibrate constitutive parameters for level-set dissolution model

· Develop new approaches to measurement of dissolution /drug release that relate more closely to drug release and bioavailability in the body. Initially this will involve the use of new equipment from TNO (The Netherlands) that is a gastrointestinal in vitro model for drug release.

(2)Local-level (unit operation) monitoring, modeling and control.

Each of the unit operations must be equipped with a suitable local process control strategy. For many unit operations such a localized strategy exists but these control solutions are mostly based on empirical correlations and/or vendor installed pid control loops. The standard control designs will be tested and further enhanced by incorporatinge the scientific understanding provided by Center's projects. Once these strategies for control have been deemed as robust, they will be transferred to the integrated platform.

Tasks performed at the local-level, which include input from projects (B1, B2, B4, and B5, which are respectively concerned with feeders, mixers, roller compaction, and tabletting. Timed deliverables from these projects are discussed next.

B1. Feeders

The technological deliverables that have been established for this project are as follows:

· Select, install, and qualify feeder and feed frame equipment

· Characterize equipment performance for parametric space for loss in weight feeders (powder cohesiveness, flow rate, feeder size, screw speed, screw design, screen, agitator design) and feed frame (excipient and API particle size, flow rate, feed frame design, feed frame rotation rate, tablet size and tableting speed)

· Develop set of recommended operating conditions for the loss-in-weight feeders and feed frame

· Develop statistical (response surface) model of feed rate variability and dynamical (transfer function) model of feeders and feed frame as a function of powder properties and processing parameters suitable for process design and control (shared with 4.5)

· Examine effect of feed frame design (size, paddle design, number of chambers)

B2. Mixing

The test bed relevant objectives established by project B2 are:

· Select, install, and qualify equipment for API and lubricant blending

· Characterize equipment performance for parametric space (raw material properties, speed, angle of inclination, weir position, blade pattern, fill level, residence time) for API and lubricant blending.

· Develop set of recommended operating conditions for API blending low (1-5%), moderate (20-40%) and high drug (>80%) concentrations.

· Develop a set of recommended operating conditions for lubricant blending

· Develop effective sampling protocol for continuous blending,

· Develop online sensing method for monitoring the concentration of the blend

· Develop a DEM model that allows effective characterization of mixing mechanisms as a function of design parameters

· Develop reduced order (response surface) model suitable for process control

B4. Roller Compaction

The technological objectives for this processing operation are:

· Validate the design model and establishment of the full design space for roll compaction using the test bed 1 pilot plant.

· Develop models and validation experiments to investigate how particle properties and applied stresses result in a compact’s microstructure

· Investigate feed region dynamics (stress distribution, pressure fluctuations at the upstream of nip region, particle segregation in the feed region and trapped air dynamics) and their influence on the ribbon properties and develop new feed region designs to dramatically improve ribbon uniformity.

· Develop and/or validate on-line measurement techniques for ribbon density distribution.

· Validate closed loop control strategies including model predictive control (MPC)

· Validate Exceptional Events Management (EEM) strategies for high level real time process management

B5. Tabletting

To achieve the main objective of the Test Bed of enabling continuous manufacturing of tablets under robust closed-loop control, an integrated package must be developed for controlling the tablet press which includes the monitoring of the properties of the incoming blend, communication with the press sensors, integration with the predictive models and automatic adjustment of the press operation. Two important operational scenarios must be addressed: (1) avoiding conditions of process failure which can disrupt the entire continuous manufacturing line, and (2) correcting processing conditions in order to produce tablets within the specification window. These overall objectives require the accomplishment of the following activities:

· Characterize equipment performance for parametric space (powder properties, pre-compression force, compression force, tablet speed, dwell time) for API/excipient/lubricant formulations.

· Develop set of recommended operating conditions for a relevant set of formulation from low (1-5%), moderate (20-40%) and high drug (>80%) concentrations.

· Develop online sensing method for monitoring the powder feeds and tablet properties

· Develop a FEM model that allows effective press operation as a function of design parameters

· Develop reduced order (response surface) model suitable for process control

(3)Integrated-level monitoring, modeling and control.

Integration of knowledge, models, and measuring methods for the projects discussed in the previous two sections is a formidable task. Material properties must be understood, and measuring techniques must be translated into robust sensing systems, in order fo r this information to be usable for control purposes. Unit operation models and local control strategies when they exist, are mostly based on empirical correlations. Incorporating these measurement methods and local models into an integrated platform for design, optimization, and control is the focus of projects D1-D5,and working group 2. Rather than describing integration activities project by project, we now go to a higher level of discussion and provide an integrated description of the integrated effort.

Integration Milestones:

Integrated mixing-lubrication-feeding-compaction platform. This setup will continuously manufacture tablets from two different blends of granular materials: low (1-5%) and moderate (20-40%) drug concentration. This setup will serve to identify and resolve connectivity/coherency issues among different equipment and processes. In addition, it will allow determining conditions of operability and failure regimes. Finally, it will provide the environment for the development and implementation of the sensory equipment and control modules. – This is stage is now complete.

Monitored/Integrated mixing-lubrication-feeding-compaction platform. It will incorporate to the previous setup the necessary inline devices for assessing critical material properties. As previously pointed out, the identification of techniques that will provide critical property measurements is a central goal of several Center project.

Moreover, identifying which are the critical properties to monitor and measure is a research issue on itself. From the view point of integration, we will however utilize the best technologies currently available. New techniques will be incorporated as they become available. – This stage is under development.

Controlled/Monitored/Integrated mixing-lubrication-feeding-compaction platform. The modeling strategies developed for each individual unit operation will be integrated in this platform. Models will need to interact within the integrated informatics environment. – Control schemes have been developed.

Controlled/Monitored/Integrated mixing-granulation-lubrication-feeding-compaction platform (Embodiment 2). An additional operation will be incorporated to the manufacturing platform to assess the flexibility of the framework to robustly incorporate alterations to the manufacturing protocol. – Plan for the first phase of this stage is reported in the following section.

Embodiment 1: The manipulated and controlled variables are summarized as follows:

	Manipulated variables	Controlled variables
Feeder	Rotation rate	Flow rate
Blender	Impeller Rotation Rate	Concentration
Tablet press	Lower punch position Upper punch position	Tablet weight Tablet thickness

Control strategies

The basic control strategy starts from establishing a setpoint for the number of tablets per time, which can be taken care of by the current algorithm in the tablet press. The other setpoint is the tablet weight. The total mass flow of powders can be derived from those two setpoints. Other parameters required are the concentration of each component, which can be used to compute the flow of each component, and those values will become the set point for each feeder.

· The feeders will provide the desired powder flow using the existing integrated control algorithm.

· In the mixer the output concentration is the control variable. An NIR will be installed at the exit of the continuous mixer to estimate the outlet powder concentration. The value of the NIR will be compared to the setpoint of concentration to adjust the impeller speed of the mixer.

· The tablet weight will be also controlled using a PID loop adjusting the position of the lower punch. Separately, the set point for the compression force (tablet thickness) must be entered and compared to the actual compression force (tablet thickness setpoint) provided by the sensor available in the tablet press, so as to adjust the upper punch position. In this loop, a dead band must be implemented to avoid chattering of the upper punch.

Sensors

· Scales on the feeders

· NIR – powder concentration on the continuous mixer

· Custom made sensor for tablet weight

· Custom made sensor for tablet height

Hardware integration

The most critical step of integration is to ensure that DeltaV can communicate with the individual process units using some suitable protocols. Therefore it is important to pick a set of protocols that the DeltaV cards can all use at once, so that each process unit can talk at least one of those protocols using one of those hardware connectors. Once the protocols are fixed, reading the data from the equipment is relatively straightforward.

Embodiment 2: In addition to the control loops for individual units and sensors presented above for embodiment 1, the dry granulation testbed is being installed at Purdue. The manipulated and controlled variables of roller compactor are summarized as follows:

Manipulated variables

Controlled variables

Roller Compactor

Ribbon density

Feed screw speed

Roll pressure

Control strategies

The planned control strategy for the feeder/blender/roller compactor is a cascade control design focusing on the feeder group and the roller compactor.

· The planned control strategy is to use MPC on the roller compactor, based on the work already done as part of Project D4 by Hsu et al. The aim is to simultaneously control ribbon density and roll gap by simultaneously manipulating the feed screw speed and the hydraulic pressure. Currently the roller compactor is being run in open loop for the ribbon characterization experiments. The roller compactor also has in-built PID control to maintain roll gap which has been used for ribbon characterization.

· The ratios of the API and excipient feed rates will be controlled by a local master-slave control system. The feeders have in-built control systems for manipulating the feed screw speed for a set feed rate. The ratio control will vary the setpoint on one feeder to keep it within a constant ratio of the feed rate of another feeder, should the feed rate vary for any reason.

· The blender will have only minimal control, focusing only on the rpm. Other aspects of the blender are essentially open loop, with feedback achieved by the overall control cascade.

Sensors

· Scales on the feeders

· NIR – powder concentration on the continuous mixer

· NIR – ribbon density on the roller compactor. Offline measurements indicate good correlation between NIR spectrum slope and the ribbon density. The online NIR monitoring is under development.

· Characterization of ribbon properties in the middle API loading region: The ribbon densities and tensile strength have been characterized under different formulations and different operating conditions to suggest the appropriate operating region for continuous ribbon manufacturing. Feeder and blender selection and installation: Schenck AccuRate feeders are selected as the feeding system to be consistent with Embodiment 1. The feeders have been calibrated and verified to convey excipient and API at the different flowrate setpoints. The motor and controller have been selected to be compatible with the body donated by Gericke. The installation of blender is undergoing and will be complete at the end of February. Hardware integration: Set up communication between DeltaV control system and individual equipment. The Alexanderwerk roller compactor has been integrated with DeltaV through Ethernet IP. The Schenck AccuRate feeders had been integrated using Ethernet IP as well, however communication proved problematic due to incompatible master/slave settings on the feeder cards and the VIM card used by DeltaV. It was therefore decided to switch the protocol to Profibus, which eliminates the master/slave problem. The cards have been replaced, and commisioning is in progress. The blender motor controller was selected to use Profibus as well to synergize with the feeders.

F. Timed Deliverables

For the period 1/1/2009 – 6/30/2009, activities on Embodiment 1 will concentrate on installing and linking DeltaV and the sensors, and setting up the PAT software. Development of Embodiment 2 will focus on interconnecting the main hardware components in order to assemble the integrated line, and expanding the integration with DeltaV, Pope, and the ABB PAT software. The timed deliverables for TB 1 for this six-month period, which were presented in Section 2.2.4, include the following:

· Phase I of embodiment 2 system (feeders, blender, roller compactor) to be completed 4/2/2009.

· DeltaV control system at Rutgers installed and operational by 4/2/2009 (project 1.2)

· ABB multichannel analyzer, NIR and Raman sensors selected, installed, and interfaced by 6/1/2009 (project 1.1)

· ABB PAT software installed and interfaced by 6/1/2009 (project 1.2)

· Interface POPE/MPC system with roller compactor system by 3/30/2009 (project 1.3),

· Test RTO & EEM for TB1 simulations by 3/30/2009 and integrate process control for embodiment 2 (including startup/shutdown) by 6/30/2009 (project 1.4)

· Reduced order model for integrated operation of feeders and mixer completed by 6/30/2009 (project 1.5)

· Characterization of effects of feed frame operational parameters on particle size distribution and hydrophobicity of blends completed for the current case study by 6/30/2009 (project 2.1).

· Dynamic behavior of the mixer characterized for the present case study (project 2.2) finalized by 6/30/2009

· Major effects of composition, shear rate, strain, compression force, and compression speed on tablet content uniformity, hardness, and dissolution characterized for the current case study by 6/30/2009 (project 2.3).

· Measurement and modeling of particle adhesion to surfaces, specifally accounting for particle nonuniformities and roughness, as well as substrate roughness (project 3.1).

· Preliminary measurements and models of effect of relative humidity on particle adhesion (project 3.1).

If the proposed research program reorganization is approved, deliverables after 7/1/2009 refer to the new project line-up. Major components of research activities planned for the next three years include:

· The main focus will fall on the closed loop operation of both continuous lines. This includes the full implementation and integration of sensing and control systems (projects D1, D2 and D4) ) and implementation of exceptional events management and real time optimization on both lines.

· NIR sensing seems the most promising component for blend homogeneity and density. The working hypothesis is that the response surface is of low dimensionality and that these variables will provide sufficient control of the process. If this Hypothesis proves to be incorrect, additional sensing method will be implemented. Negotiations are underway with multiple companies, including ABB and VTT for the supply of sensors (project D1).

· Efforts will continue in the characterization and understanding of the multivariate relationship between inputs (raw materials properties, powder composition, shear/strain, compression force, compression speed), intermediate material properties (blend homogeneity, cohesion, density, blend and tablet hydrophobicity), and “finished product” responses (tablet weight variability, hardness, dissolution, drug content uniformity). A large study already under way will be continued (project D5).

· The informatics framework developed in Project D3 will be customized and expanded in order to provide an integrated modeling platform for the Test Bed.

· Commissioning of the integrated embodiment 2 line will be completed. The line will be operated in open and closed loop with extreme events to collect data for the validating extreme events management system ) and implementation of exceptional events management and real time optimization on both lines.

· The emphasis of dynamic experiments for validation of process control, EEM and RTO strategies will move from changes in process parameters to feed formulation changes eg. variability in excipient properties.

· The development and improvement of both detailed physics-based models and coarse models for the design and scaling of each process involved in the continuous tablet manufacturing will continue. Steady state experiments using test bed 1 will play a major role in validating and continuously improving these models. These models will further the understanding of the phenomena underlying the relationships between material mechanical and micromeritic properties, operating conditions and product characteristics as well as facilitate the system control (projects B1, B2, B4, and B5).

· Activities in project C2 will continue to expand the database of powder flow properties as a function of composition and strain. Characterizations of feeders and feed frames will continue in project B1, expanding available information regarding the operation of powder feeding equipment.

· Project B2 will complete the basic characterization of mixing performance in the “Niro 2” and the Gericke mixer using experiments, DEM and statistical models, and PEPT experiments that will be performed in the UK in collaboration with Professor Jonathan Seville.

· Projects B4, C3 and C4 will expand efforts in modeling of the compression process, focusing on understanding the effect of blend properties and compression parameters on tablet microstructure and performance.

· Test bed 1 will also provide the platform for testing modified equipment designs that result from the fundamental understanding and modeling that is occurring in thrust B (B1, B2, B4, B5).

· An extension to test bed 1 to include continuous wet granulation in the final year of this period will be considered.

For the period 7/1/2009 – 6/30/2010, activities at Rutgers will concentrate primarily on exploring the performance space for low drug concentration (1-5 %), examining the effect of API (APAP and others TBD), lubricant (MgSt), SIO₂, and excipient grades (Avicels 101, 102, 200, Lactose Fast flow, milled lactose), examining product structure, determining dissolution performance. At Purdue, the focus will be on exploring the performance space for the largest drug concentration (60-100%). A key material issue to be explored in detail is the joint size/density/composition distribution of the dry-granulated material and its impact on product performance. Timed deliverables for this period include:

· Methods for modifying flow properties and achieve effective continuous feeding of APIs will be implemented (projects B1 and C2)

· Mixing performance and effects of strain for minor ingredients (lubricant, and SiO₂) characterized (project B2)

· Reduced order model of integrated feeders and mixer for all ingredients available (Project D5)

· Powder compaction models including inter-particle deformation and bonding experimentally validated and calibrated (Projects B4, B5, C4).

· Stress distributions during roll compaction measured directly on the test bed for a range of conditions to validate FEM based design model (B4)

· On line sensing of ribbon density and cross ribbon density variability installed and validated for the Purdue embodiment (B4, D1)

· Reduced order models for the integrated operation of the tablet press and roll compactor implemented (Project B5, B4).

· On-line sensing of tablet properties including tablet weight, thickness and surface composition implemented (Project D1).

· Feed frame operation characterization and investigation of operating parameters on powder flow properties (Project B1).

· Measurement, modeling and integration of effects of individual particle chemical and mechanical properties on particle-particle and particle-substrate interactions, including effects of relative humidity and inferences for powder flow and processing.

· Tablet mechanical properties and internal structure characterization and correlation to powder composition and process parameters (Projects C3, C4, C5).

· Implementation of NIR chemical imaging and development of novel Raman imaging techniques to further understand the structure of the composites under development.(July,2009)

· Initiate on-line Raman monitoring using fiber optic probes. (July, 2009)

· Methods for on-line monitoring of powder density. (July, 2009)

· Set up Raman spectrometer to study formation of polymorphs in as-received and processed drug powders in the

Tera Hertz region below 150 cm^-1. (July, 2010)

· Prepare accurate density and moisture standards and measure dielectric properties. Use X-ray tomography to measure density variations in samples. Compare reflection and transmission methods for measuring complex dielectric properties of powder density standards. Complete initial test of microwave reflection probe on fluidize bed or ribbon process to measure density. (July 2010)

· Evaluate the capability of SORS (Surface Offset Raman Spectroscopy) imaging and photon migration for measuring powder and roller compact bulk density. (July 201)0

· Complete simultaneous moisture content and density measurements by microwave reflection and transmission methods on fluidize bed and ribbon processes. (July 2010)

· Expand spectroscopic methods for porosity to assess the relationship between shear forces and porosity for multi-component compacts prepared under unrestricted geometry as in roller compaction. (2011)

· Quantitatively compare multivariate hyperspectral imaging (MHI) and CCD based micro-Raman imaging methods (2011).

· Full integration of process components, sensors, and informatics completed (project D1, D2 and D4)

· Failure modes for low API concentration identified. Control actions needed to prevent or overcome failures identified and tested (project D3).

· Substantial validation for EEM and RTO strategies on both lines (Project D4)

· Process and composition design space for low-content and high drug content scenarios determined (Project D5)

For the period 7/1/2010 – 6/30/2011, activities both at Rutgers and Purdue will concentrate primarily on exploring (a) modifications to equipment design to improve performance, and (b) the performance space for intermediate drug concentrations (20-40%). This will allow us to compare and explore relative benefits of Roller Compacted vs. Directly Compressed formulations. Most key deliverables during this period are similar to those listed above for the previous year. A few necessary additions include:

· Modification to the feed system for the roll compactor to improve cross ribbon density distribution and validation of the system using embodiment

· Mixing performance for larger API concentrations will be characterized. Feeder/mixer model will be updated (projects B1 and B2).

· Powder compaction models for larger API concentrations will be expanded to include roller-compacted materials (projects B4, B5, and C4).

· Failure modes for intermediate API concentration identified. Control actions needed to prevent or overcome failures identified and tested (project D3).

· Process and composition design space for low-content scenario determined (project D3).

· Application of designer particles with physical, mechanical, and chemical properties selected based on first principles models of relationship between particle and substrate properties and powder behavior. Validation of relationships between particle properties and population behavior.

· Scoping study for developing a expansion of test bed 1 to incorporate continuous wet granulation.

Finally, for the period 7/1/2011 and 7/1/2012, activities will focused on more advanced structured materials - blends containing nanoparticles and nanocoatings, possibly with encapsulated biomolecules. If a decision is made to expand the test bed to include wet granulation, this will be a made focus for 2011/2012. Timed deliverables for this period will be provided at a later date.