Material Formation &
Characterization

Thurst lead:        Rajesh Davé, NJIT
# of faculty:         18
Disciplines:        Chemistry, Chemical Engineering,
                                Food Science, Mechanical
                                Engineering, Pharmacy

THRUST A

2D Raman imaging of the hard gelatin capsules: empty, 0mL (a), 1mL (b) and filled 3mL (c)

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Effects of sonication on the initial mean particle size for 50:50 mixtures of acetone and co-solvents with 1% fenofibrate, 0.025% PF 127 (wrt solution) and 0.5% HPMC-E3 (wrt solution)

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Smart dissolution system to measure drug release during dissolution

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2D Raman imaging of the hard gelatin capsules: empty, 0mL (a), 1mL (b) and filled 3mL (c)

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Current Thrust A projects
A1
Stable Suspensions of Crystalline & Amorphous Active Particles
A8
Formation of Nano-micro API Composite Particles
Summary

While there are numerous publications dealing with the problems faced in industrial crystallization, forming nano particles, and creating amorphous forms through spray drying, there is a lack of the systematic approaches to form the materials to be used as building blocks for SOPS, particularly those exploiting nano-materials. Most of the approaches to date for handling poorly water-soluble APIs are non-predictive and do not fully exploit the potential of nano-structured APIs to help solve the problems faced with oral dosages. Thrust A team is addressing all these and more by identifying the key barriers and responding to those via well-coordinated, comprehensive research effort. 


Thrust A makes significant contributions to test-bed 2 and in addition, the projects emphasize:

 

  • Poor bioavailability drugs, including, dry forms, i.e., films and nano-structured powders. 

  • API-additive interactions on API-suspension stability and its impact on evolution of subsequent nano and micro-structure and API size stability as well as re-dispersibility and dissolution behavior. 

  • Providing fundamental understanding of cohesion controlled particles. The connection to Thrust B is by providing functionalized materials along with their properties. A close connection to Thrust C is via multi-scale models, structure characterization and properties at the molecular and particle scales.

Goals

The main goal of Thrust A is 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. Thus it deals with the scientific foundation for forming materials with desired properties required as building blocks for SOPS. The main objectives are:

  1. Formation of materials: Develop science-based methodologies, processes and formulations to form intermediate SOPS products engineered for desired properties.  

  2. Determination and characterization of crucial properties: Identify/assess critical material attributes influencing the properties of the intermediates and dosage forms. 

  3. Functionalization: Develop methods for material functionalization and surface modification for optimizing physicochemical properties that impact performance.

Key Accomplishments

Major advances during previous six years resulted in over 100 journal papers from Thrust A. Key accomplishments are listed below:

 

  • Know-how related to forming stable colloidal suspensions of poorly water-soluble drugs is generated for multiple methods, including liquid anti-solvent precipitation (LASP), wet-stirred media milling (WSMM), and melt emulsion (ME) methods. In all cases, influence of different stabilizers, physico-chemical material properties of drugs, and process parameters were examined in order to produce stable colloidal suspensions. 

  • Confounding effects of stabilizers on particle breakage and stabilization such as viscous dampening and Rehbinder effects during WSMM have been uncovered. 

  • A WSMM process was optimized at intensified processing conditions (highest rotor speed, bead loading, and suspension flow rate) using small beads. Due to the enhancement of the breakage kinetics, the process intensification enabled ~75% reduction in milling cycle time to attain 100 nm particles, while resulting in 28% energy saving with low bead contamination despite increased power consumption.

  • A multi-scale DEM–PBM (discrete element method-population balance modeling) approach connecting individual particle–ensemble–process scales was applied to particle bed impact tests, elucidating the origin of elusive non-linear breakage behavior in dense-phase dry milling processes for the first time.  

  • Ultrafine and colloidal superdisintegrant particles can be produced by WSMM either alone or along with poorly water-soluble drugs. Colloidal anionic superdisintegrants enhanced the stability of drug suspensions, which can be used for making nanocomposite particles with enhanced redispersibility and fast drug dissolution.

  • A theoretical explanation of the formation of beads-on-a-string (BOAS) morphologies in viscoelastic fluids applicable to personalized drug printing was provided. The regime was identified describing the initial dynamics of coalescence, which has been previously missed.

  • Electrodeless electrohydrodynamic printing of personalized medicines was developed.  

  • A PXRD compression stage for real-time assessment of molecular level deformation in single crystals was designed/implemented for determining the anisotropic stress-strain relationship of single crystals and changes in d-spacing was established.

  • Computational methods were developed in Material Studio for analysis of anisotropic Young’s Modulus of single crystals independent of the direction, allowing gaining insight into poorly compressible crystalline powders.

  • A web-based simulator to describe effects of particle shape, size, roughness and composition on particle adhesion force behaviors was developed and validated. A corresponding experimental approach was developed allowing for measuring Hamaker constants via simulated centrifuge-based adhesion experiments.

  • New continuous and batch approaches are developed for dry coating based surface modification to produce powders with modified particle surface properties. It is shown that dry coating alleviates adverse impact of the intrinsic poor API flow properties, which can be done in a design-predictive manner using a material sparing approach that employs particle contact models. Adhesion and friction forces were shown to be dependent on nanoparticle surface area coverage. In addition, it is shown that surface energy measurements of pharmaceutical particles along with the physical contact models qualitatively correlate with the adhesion models to describe the particle-scale adhesion and its relation to bulk-scale behavior.

  • A two-property phase map (flow index versus bulk density) for pharmaceutical blends is proposed to make manufacturability decisions for direct compression, dry granulation or wet granulation based tableting. It is shown that dry coating of fine drug particles always leads to improved properties sufficient to transition from original WG to DG or even DC, and likewise, from DG to DC.   

  • Nanocomposite microparticles (NCMPs) containing poorly water-soluble drugs were prepared by fluid-bed (FB) drying process, exhibiting enhanced drug recovery and dissolution. 

  • Drug particle suspensions from WSMM, LASP, and ME processes have been integrated into film formation process as part of C-SOPS test-bed 2 to achieve robust film formulations. In contrast to prevalent solvent based casting, engineered drug particles in nano- and micro- sizes may be incorporated through slurry casting for achieving high quality films that have excellent drug content uniformity and lead to very fast immediate release of even poorly water-soluble drugs.

  • A simple, novel approach to forming stable amorphous dispersions with high drug loading was developed. 

Impact

Thrust A has been the major contributor to C-SOPS efforts in not just particle engineering but also in establishing numerous fundamentally based approaches that will have a lasting impact on pharmaceutical industry for years to come. Examples of major impacts are:

 

  • Prolific scholarly output of over 100 journal papers with high industry relevance: at least 30 papers have been cited 10 or more times, of which over dozen cited over 25 times, for a total of at least 800 times (as per Scopus). Particularly noteworthy papers are: beads-on-a-string (BOAS) morphologies paper (Basaran – 77 times), controlling drug particle size in LASP (Dave – 52 times), strip-film formation (Dave – 47 times), WSSM for stable drug suspensions (Bilgili – 42 times), modeling and validation of van der Waals forces (Beaudoin – 34 times), and flow improvement of simultaneous dry coated and milled drug micro powders (Dave – 32 times). 

  • Thrust A work has uncovered underlying principles in not only stabilizing poorly water soluble drugs in form of nano and micro suspensions, but also in avoiding particle agglomeration or growth while achieving full recovery of high surface area after storage, processing and drying to form nano-composites. This work has a major impact on bio-availability enhancements of poorly water soluble drugs formulated in form of crystalline drug-excipient composites with high drug loading.  As specific example is the work in thin-films in C-SOPS testbed 2, where we have a leadership position.

  • C-SOPS work in dry coating for improving powder flow and packing is not only well-cited, but very well received by industry. This work in conjunction with modeling at particle scale has led to fundamental understanding of cohesion-controlled particles. Our industry partners have been either utilizing this approach or considering this in enhancing the flow of typically cohesive drug powders. Its major impact will be seen in coming years as C-SOPS and its industry partners move towards cost efficient continuous tablet manufacturing employing direct compression. C-SOPS work shows that adding one step of dry coating eliminates uncertainties in powder feeding and greatly expands the range of APIs and drug loadings possible using direct compression instead of more cost-intensive dry or wet granulation approaches. 

  • An associated C-SOPS project funded by Catalent Pharma Solutions has led to two patents and a commercial license for a novel non-C-SOPS technology for solventless coating for taste-masking. This work is expected to have high impact as Catalent is working on commercialization of this technology.

Future Plans

Future C-SOPS thrust A work will continue to focus on bioavailability enhancements as well as measuring, improving and predicting powder material and their blend properties. 

 

  • Thrust A activities associated with addressing poorly water soluble drugs will be consolidated in to three major activities include: (1) HME for amorphous materials, solid dispersions, as well as development of novel nano and micro composite materials through melt or wet granulation techniques, (2) Stripfilm based processing to develop unique products and their characterization, and. (3) Preparing engineered nano-composites, including suspensions that are sterile filterable.

  • Thrust A will address aspects of continuous manufacturing of tablets, including design, prediction, and optimization of formulation platforms based on materials property characterization and modification. It includes establishing relationship between key material properties of powder blends and “tablettaibility” of the blend and means to expand regimes of feasibility for direct compression (DC) as well as dry granulation (DG). Powder agglomeration, sticking and prevention/mitigation thereof will be also addressed with respect to CM platforms (both DC and DG). Expanded database of associated properties, including cohesion, flow, packing density, and compactaibility will be generated and continually updated on pharmaHUB.