Project A-3: Drop Formation and Layering
Thrust A: Material Formation and Characterization
Making designer building blocks for structured composites
Thrust Leader: Rajesh N. Davé (NJIT)
Project Leaders: Somnath Mitra (NJIT), Paul Takhistov (Rutgers), Osman Basaran (Purdue), Rodolfo Pinal (Purdue), Ken Morris (Hawaii), Steve Beaudoin (Purdue)
A. Thrust Objective and Goals#Top
The main objective of this thrust is to develop the scientific foundation for forming materials with desired properties (size and size distribution, shape, stability, surface properties, crystal form, constitutive behavior, purity, homogeneity, degree of agglomeration, solubility) required as building blocks for products based on structured organic particulate systems. In order to achieve the desired properties, the thrust will also focus on determining and characterizing the properties crucial for achieving a desired function. The main objectives are:
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Form materials with desired properties: Develop science-based methodologies, processes, and formulations for forming materials engineered to have desired properties required for achieving ideal active substance delivery.
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Determination and characterization of crucial properties: Determine critical material attributes that influence the properties of the materials required for forming structured composite products with desired performance. Adapt or develop state-of-the-art techniques for characterization of these properties.
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Functionalization: Develop methods for material functionalization and surface modification for optimizing and controlling physicochemical properties of materials that impact composite particle system performance.
Figure 2P-5: The main goal of Thrust A is to develop the scientific foundation for forming materials with desired properties required as building blocks for products based on structured organic composites. The projects in this thrust are connected via a single major goal of developing predictive technologies for formation of materials with critical properties to achieve desired functionality. Thus they involve development of methodologies, including the selection of materials and processes for formation of particles, drops, suspensions, and films. The projects are also concerned with the development of techniques for identification, characterization, modification and control of critical properties of these materials that impact the final composite particle system performance. The overall objectives and activities of this thrust are depicted in Figure 2P-5.
B. Technical scientific barriers/grand challenges for Thrust A
There is a lack of the predictive understanding of the materials to be used as building blocks in the structuring of organic composites and related processes suitable for manufacturing pharmaceutical products. Further, there is lack of sufficient understanding of property inter-dependence at constituent and size scales. This is true for products involving particulate materials in general and in particular, those involving small organic molecules as in pharmaceutical and food industries in particular, due to the lack of models and theories for such materials. For example, although determining some properties of a material that are critical to behavior/function can sometimes be “simple”, such as the relationship between particle size and dissolution, most relevant properties cannot currently be unambiguously determined (example, hydrophobicity of a blend) and so their potential criticality is not observable. Specific barriers addressed by Thrust A are listed below, and through well-planned projects, Thrust A will develop the knowledge base to help in improving the overall quality of pharmaceutical manufacturing, based on fundamental science-based understanding of structure-function-performance, incorporating molecular level information.
- Lack of predictive, reliable processes for forming micron size or smaller API particles, drops, and their stable suspensions or spatially controlled structures, designed for achieving specific function. Lack of fundamental understanding of these processes, required for process control and scale-up.
- Lack of systematic approaches for functionalization and material property modification and their precise characterization.
- Poor understanding of the link between the material properties and the processing operations on the properties and performance of the final composite structure.
- Determining which properties and what constitutes significant differences in these properties of a material are critical to behavior/function for organic particles is largely unknown.
- There is lack of methods to predict and measure properties of a material that are critical to its behavior/function.
C. Strategic Plan and Thrust Connectivity for Thrust A
The strategic plan of Thrust A is based on the major research objective of the Center: To develop a scientific foundation, based on a predictive understanding of structure-function-performance relationships, for the optimal design of structured organic particulate systems with advanced functionality. Accordingly, the research activities of Thrust A focus on developing the predictive understanding of formation of the materials, based on their property characterization, to be used as building blocks in the structuring of organic particulate systems. Thus major activities of thrusts A and C cover the overall Strategic Plan depicted in Figure 2P-6. The projects in this Thrust connect with the projects in thrusts B and C; the connection to Thrust B is through providing starting materials along with their properties, as well as providing materials with modified properties. There is also a close connection to Thrust C via multi-scale models, structure characterization and properties at the particle and intermediate scales. All formation processes utilized in Thrust A will be integrated via informatics and model-based manufacturing methodology developed in Thrust D, and in addition, models required in thrust D will be provided.
The research activities conducted under Thrust A will ultimately contribute an essential materials science component to the product based testbeds, in particular, test-bed 2, and thus helping improve the overall quality of pharmaceutical manufacturing through the use of fundamental physics-based understanding of structure-function-performance in product design.
D. Key Scientific Deliverables
- Development of scalable processes for formation of materials for Structured organic particulate systems including the basic building blocks such as particles, drops and suspensions; which is based on fundamental understanding of the thermodynamics of crystallization, nucleation and growth for small organic molecules (SOMs); colloids and interfacial science as well as inter-particle interaction; and physics of drop-formation, drop impact and layering.
- Development of materials based understanding of stable formulations in form of suspensions, thick slurries or pastes and films, all loaded with micro-structured active pharmaceutical ingredients.
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Process level, predictive understanding of operations for particle formation, drop formation, and suspension stabilization.
- Identification of several critical material attributes that influence, (a) the mechanical properties of the crystals of APIs, (b) size and morphology of the particles formed via anti-solvent crystallization, (c) stability of API suspensions and heavy slurries, (d) properties of API particle loaded films, (e) particle-particle interactions, and (f) drop formation, drop-substrate interaction and layering.
- Development of material level understanding of the properties listed above, done in concert with the thrusts B and C.
- Development of methods to characterize critical material properties and functionality of the building blocks, which form the intermediate SOPS based products.
 In addition to these scientific deliverables, there are Thrust-level integrating deliverables that bring together scientific accomplishments from the projects. Examples are: Formation of API suspension having a desired dissolution property and stability; and a solid oral dosage form based on micron and nano sized API particles stabilized in a matrix form (e.g., a strip film) having a set of desired properties such as dissolution and stability.
Individual projects’ scientific focus is designed to help establish the knowledge base of the thrust, hence, this thrust makes strong contributions to the bottom and middle planes of the 3-plane chart as shown in Figure 2P-7. However, the project deliverables also serve to support specific test bed (shown in the top plane in Figure 2P-7) needs in addition to the thrust level goals. The ten year milestones for the Thrust A are shown in Figure 2P-8, where scientific as well as current test-bed related tasks are emphasized for the period of 5-8 years.
Major milestones for Thrust A, addressing scientific and technological deliverables are listed below and milestones shown in Figure 2P-8.
T-A-1. Formation of micron or smaller API particles with narrow size distribution
T-A-2. Predictive formation of stable aqueous suspensions of micron or smaller API particles
T-A-3. Formation of stable slurries of edible polymers with well-dispersed fine API particles
T-A-4. Formation of films of edible polymers with well-dispersed, stable fine API particles
T-A-5. Dynamics of formation of drops of complex fluids from few to 100s of microns
T-A-6. Understanding of drop impact and substrate interactions
T-A-7. Methodology for property modification through surface modification or dry coating
T-A-8. Identification and characterization of crucial particle and suspension properties
T-A-9. Experimental approach to validate and characterize mechanical strength of individual and ensemble of API particles
T-A-10. Methodologies for measuring and predicting surface interactions amongst particles, drops, and substrates
T-A-11. Materials science based formulations for suspensions, slurries, films, granules, and other forms, uniformly loaded with API particles having desired properties (content uniformity, stability, API crystal form, and dissolution)
T-A-12. Prediction of the single crystal elastic/plastic behavior, yield criteria, and strength tensors for small molecular organic crystals
T-A-13. Prediction of crystal properties and their potential impact on performance properties Develop models for the SOPS building blocks required for the multi-scale models for SOPS properties (e.g. compaction, flow, dissolution)
T-A-14. A scientific basis of mini-manufacturing and strip-film manufacturing systems for dosage forms having desired properties
T-A-15. A scientific basis for novel nano API delivery systems
T-A-16. Materials and process based understanding of API loaded particles, slurries, pastes and films relevant to personalized medicine formulations
E. Thrust A Projects
While the scientific challenges of the thrust are quite broad, we have identified as part of the strategic plan, six interrelated and coherent projects that will allow us to address and successfully advance the critical issues required to integrate the current and future test beds. These projects are listed below.
Project A-1 Particle Formation and Formation of Dilute Phase Slurries #Top
Faculty: Somnath Mitra (Lead)(NJIT), Rajesh Dave (NJIT), SylvinaTomassone (Rutgers)
Consultants: Paul Takhistov (Rutgers), Rodolfo Pinal (Purdue), Boris Khusid (NJIT)
Mentors: Rennan Pan (GSK), Luis Eduardo Alvarez (Pfizer), David Harris (Schering Plough), Markus Wolkenhauer (Boehringer Ingelheim), Peter Given, Yuan Fang (Pepsi), Kostas Saranteas (Sepracor)
Graduate Students: Christian Beck (NJIT), Anagha Bhakay (NJIT), Azad Mohamad (NJIT), Maxx Capece (NJIT), Xinagxin Meng (NJIT)
Goals:
· Develop particle formation methods effective at the manufacturing scale to produce particles with micron or smaller sizes having narrow size distribution.
· Develop model-guided methodology to form stable aqueous suspensions of micron or smaller API particles.
Deliverables:
· An understanding of basic mechanism of particle stability and its experimental validation for predictive process performance for several classes of APIs.
· An understanding of what properties of the molecule are critical to their particle formation performance for a given process (material properties and process suitability/selection).
· Advanced knowledge base through molecular dynamic simulations and other modeling tools for predictive particle stability and selection of API and process conditions.
· An understanding of suspension and particle stability issues during solvent removal from aqueous suspensions of micron and smaller sized particles, in presence of surfactants and polymers.
· Experimental knowledge base on the influence of materials and process conditions on polymorphs and crystal defects via XRD and Raman Spectroscopy.
· Development of strategies for producing suspensions having high particle concentrations, free of organic solvents, and having sufficient stability.
· Methodology to understand the particle and suspension dissolution properties, done in conjunction with projects in Thrust C.
· Integration of particle formation and suspensions stabilization processes into Test Bed 2.
Project A-2: Formation and Stabilization of Dispersions of API in Polymer Solutions and Gels #Top
Faculty: Paul Takhistov (Lead)(Rutgers), Aldo Acevedo (UPRM), Madeline Torres (UPRM)
Consultants: Somnath Mitra (NJIT), Boris Khusid (NJIT), Rodolfo Pinal (Purdue), Bo Michniak-Kohn (Rutgers)
Mentors: Yu Li (GSK), Denise Rivkees (Pfizer), Siddharthya Mujumdar (Boehringer Ingelheim)
Graduate Students: Xiangxin Meng (NJIT), Vivian Florian (UPRM), Karen Court (UPRM)
Goals:
· Develop materials and model-based formulations for stable, edible polymer based dense phase slurries of micron and smaller sub-micron (nano) API particles, starting from stable, dilute phase API suspensions.
· Develop formation methods effective at the manufacturing scale to produce dense phase slurries loaded with stabilized micron or smaller sizes dispersed uniformly without irreversible agglomeration.
Deliverables:
· An experimentally validated, advanced knowledge base obtained via multiscale simulations and other modeling tools for understanding of the basic mechanism of particle stability during formation of multi-component dense phase slurries.
· Knowledge base of rheological properties of multi-component slurries loaded with API particles.
· In concert with the output from project A1 and input needs of the project A4, develop scalable, predictive processes for forming dense phase slurries containing several classes of API particles. This would include mixing strategies for API loaded slurries and evaluation of mixing efficacy.
· The initial focus will be on the materials for manufacturing option B, which is medium viscosity system that resembles softgel capsule formulation. That will be followed by investigation and recommendations for option C, which is amenable to extrusion type processes.
· Predictive understanding of maintaining particle stability and content uniformity in multi-component dense phase slurries at various process conditions, based on the molecular and interfacial interactions between slurry components and APIs including electrostatic, steric and bridge stabilization mechanisms.
· An understanding of what properties of the individual material and their combinations are critical to slurry formation performance for a given process (material properties and process suitability/selection).
· Methodology for characterization of API load uniformity/homogeneity and stability, developed in conjunction with projects in Thrust C.
· Methodology to understand the dissolution properties of multi-component slurries, done in conjunction with projects in Thrust C.
· Integration of slurry formation processes into Test Bed 2.
Project A-3: Drop Formation and Layering #Top
Faculty: Osman Basaran (Lead) (Purdue), Boris Khusid (NJIT), Michael Harris (Purdue)
Consultants: Paul Takhistov (Rutgers), Lynne Taylor (Purdue), Carlos Rinaldi (UPRM), Aldo Acevedo (UPRM)
Mentors: Esteban R Bornancini (GSK), Ingi Choo (Pfizer), Victor Wong (Schering Plough), Chris Burcham (Lilly), Chitra Telang (Boehringer Ingelheim)
Post Docs: Pradeep Bhat (Purdue)
Graduate Students: Santosh Appathurai (Purdue), Ezinwa Elele (NJIT)
· Investigate the dynamics of formation of drops of complex fluids containing active ingredients in solution as well as slurry forms from a drop-on-demand (DOD) ink jet nozzle as well as other types of nozzles capable of creating drops from a few to 100s of microns.
· Investigate the dynamics of drop-surface interactions and drying and layering of drops on edible surfaces, and the influence of materials and process conditions on the final printed product (micro-structure, API stability, dissolution).
· Develop materials and process based understanding of drop formation as well as deposition on edible substrates, contributing to the development of personalized medicine formulations.
Deliverables:
· Experiment, theory, and computational tools will be developed in tandem to develop predictive implementation of drop-on-demand methods in the delivery of liquid drops containing drugs onto edible substrates.
· Development of reliable processes for continuous production of the "printed" products.
· Processing and materials level understanding of the drop drying and attachment on edible surfaces.
· An understanding of the API stability abd stryctyre fir tge "printed" products.
· Methodology for charqacterization of microstructure, content uniformity and stability, developed in conjunction with project(s) in Thrust C.
· Methodology to understand the dissolution properties of printed products, done in conjunction with project(s) in Thrust C.
· Integration of all the processes into Test Bed 3.
Project A-4: Film Formulation #Top
Faculty: Rodolfo Pinal (Lead) (Purdue), Somnath Mitra (NJIT)
Consultants: Boris Khusid (NJIT), Paul Takhistov (Rutgers), Rajesh Dave (NJIT), Zafar Iqbal (NJIT), Rodolfo Romañach (UPRM)
Mentors: Fiesser (GSK), Siddharthya Mujumdar (Boehringer Ingelheim)
Graduate Students: Ryan John McCann (Purdue), Bo Zhou (Purdue), Azad Mohamad (NJIT)
Goals:
· Develop materials property based formulations for forming stable, edible polymers based films containing micron and smaller API particles, starting from stable, dilute phase, API suspensions as well as stabilized dense phase slurries or pastes.
· Develop a basic understanding of the interplay between the formulation and drying/processing conditions on the final properties of the films, such as the physical properties (thickness, strength, mechanical/lexural strength) content uniformity, stability, API crystal form, and dissolution.
· Develop the guidelines for formation methods effective at the manufacturing scale to produce films loaded with stabilized micron or smaller sizes despersed uniformly.
Deliverables:
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Specifications of the properties of the films as an oral dosage form containing micron and smaller API particles.
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Determination of which material and product properties are critical to achieve a desired product performance (content uniformity, API stability, and dissolution).
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Experimentally validated formulations for edible films (based on the material input from projects A1 as well as A2) containing APIs, and an understanding of the influence of materials and processing conditions on the final film properties. Continue film-csating investigation, and additionally, examine alternate options, beginning with the medium viscosity system that resembles softgel capsule formulation of an industry test-bed partner.
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An understanding of particle stability and content uniformity during film formation.
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Development of alternate paths for scalable film formation, carried out in conjunction with project(s) in Thrust B and C.
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Methodology for characterization of content uniformity/homogeneity and stability, developed in conjunction with projects in Thrust C.
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Methodology to understand the dissolution properties of the films, done in conjunction with projects in Thrust C.
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Integration of film formulation and film formation process recommendation processes into project B3 and Test Bed 2.
Project A-5: Crystal Morphology and Strength #Top
Consultants: Alberto Cuitiño (Rutgers), Lynne Taylor (Purdue), Rajesh Dave (NJIT)
Mentors: Lirong Liu, (Pfizer), Qun Lu (Schering Plough), Lori Hilden (Lilly), Soojin Kim (Boehringer Ingelheim), Kostas Saranteas (Sepracor)
Goals:
· Develop methodology based on ab initio and molecular mechanics for generating strength tensors for small molecular organic crystals (SMOC).
· Develop experimental approach to validate and characterize mechanical strength of individual and ensemble SMOCs.
· Develop outline of a future approach to extend the modeling to predict other properties such as surface energy,
partition coefficient, melting point, hydrophopicity, and surface charge of SMOCs.
Deliverables:
· Identification of critical materials properties of SMOC
· Development of crystal shear tester
· Develop method for predicting crystal strength; Full force field minimizatio, Coarse grain validation and Dynamic crystal graph (DCG) implementation
· Extend DCG platform and apply to predict bulk mechanical properties, correlating with single crystal strength measurements
· An outline of a future approach to extend the modeling to predict other properties and connecting with modeling efforts in thrusts A, B and C.
Project A-6: Surface Interactions and Surface Modification #Top
Faculty: Stephen Beaudoin (Lead) (Purdue), Rajesh Davé (NJIT)
Consultants: James Litster (Purdue), Ken Morris (Hawaii), Carl Wassgren (Purdue)
Mentors: Matt Mullarney (Pfizer), Qun Lu (Schering Plough), Ron Lacocca (Lilly), Frank Etzler (Boehringer Ingelheim)
Graduate Students: Dave Balachandran (Purdue), Nyah Zarate (Purdue), Michelle Cipich (Purdue), Laila Jallo (NJIT)
Goals:
· Develop methodologies for measuring and predicting surface interactions amongst particles, drops, and substrates so that material and process conditions can be related to properties at ensemble scale for structured organics particulate systems.
· Develop systematic approaches to property modification and subsequent characterization of the improvements and their impact on the powder behavior.
Deliverables:
· Methodologies and models for predicting particle adhesion properties based on material and known particle properties.
· Development and implementation of a web-based particle adhesion simulator that predicts particle-substrate adhesion forces as functions of particle and substrate shape, size, roughness and composition. This tool can be used by researchers to optimize particle and surface coating properties to control adhesion.
· Development of improved understanding of particle surface modification done by nano-coating or surface treatment, in particular, the relationship of guest particle size, shape and density distribution as well as the surface energy on flow properties of original (host) particles. This understanding, articulated in the form of experimental results and correlated with geometrical modeling, can be used by researchers to design nanoparticle coatings to control powder properties such as flow, electrostatic, etc.
· Development of practical recommendations for selecting surface modification method and materials for a variety of active ingredients in order to achieve desired properties such as improved flow, uniform dispensing from feeders, improved mixing, reduced tendency to agglomerate and sticking to surfaces of processing vessels, better die or capsule filling properties, while avoiding adverse impacts on compaction and dissolution of powder products.
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