The following is a list of the abstracts for papers which will be presented in SECOND INTERNATIONAL SYMPOSIUM ON SURFACE SCIENCE ASPECTS OF PHARMACEUTICAL SCIENCE, PHARMACOLOGY, COSMETICS AND BIOTECHNOLOGY, To be held November 7-9,2012 at the Hampton Inn, Mid Hudson Valley, New York, USA.. The listing is alphabetical by presenting author. This list is updated continually to add abstracts as they become available and make appropriate corrections. This list may be conveniently searched by using the editor provided with most popular browsers (e.g. Microsoft Explorer, Netscape, Firefox ... etc.)

INDEX BY AUTHOR (CLICK ON AUTHOR NAME TO GO TO FULL ABSTRACT)	INDEX BY TITLE
Kevin B. Biggs	Pore Networks and Polymer Rearrangement on a Drug-Eluting Stent Revealed by Correlated Confocal Raman and Atomic Force Microscopy
Daniel J. Burnett	Measuring Surface Energy Heterogeneity of Pharmaceutical Materials
Anna Maria Coclite	Engineering Functional and Responsive Surfaces by Chemical Vapor Deposition for Biotechnology
Saswati Datta	Plasma Surface Modification for Controlled Release of Pharmaceutical Powders
Jaroslaw Drelich	Pull-off Forces Measured between Fine Pharmaceutical Particles and Polymeric Coatings using Atomic Force Microscopy
Frank M. Etzler	Tablet Tensile Strength: An Adhesion Science Perspective
David Fairhurst	NMR as an Analytical tool to Characterize Nanoparticulate Suspensions
A.J. Hickey	A Performance Based Analytical Method for Prediction of Aerosol Delivery from Pharmaceutical Dry Powder Inhalers
J. H. Kindt	Guiding Pharmaceutical Formulation development through Surface Material Characterization, using recent Scanning Probe Methods
Heidi M. Mansour	Relevance of Particle Surface Chemistry and Particle-Particle Interactions on Aerosolization

Sid Mujumdar	Relevance of Particle Surface Chemistry and Mechanical Properties to Tablet Manufacture
R. Nair	Nano and Micro- Indentation of Pharmaceutical Compacts. Comparison of Results Obtained Using a Compaction Simulator
Robert O’Brien	Quantitative Surface Defect Analysis of Drug-eluting Coronary Stents by Scanning Electron Microscopy: Coating Integrity of the CYPHER^® Sirolimus-eluting Coronary Stent
Rodolfo Pinal	The Connection Between Surface Energy and the Functionality of Powders
Santosh Rohit Yerrabolu	Tissue Friction Considerations for Percutaneous Endoscopic Gastrostomy Feeding Tubes

Kevin B. Biggs; Cordis, a Johnson & Johnson company Welsh & McKean Roads, P. O. Box 776, Spring House, PA 19477-0776

Pore Networks and Polymer Rearrangement on a Drug-Eluting Stent Revealed by Correlated Confocal Raman and Atomic Force Microscopy

Coronary artery disease (CAD), characterized by a narrowing of the luminal artery wall, is the leading cause of death worldwide. The use of the drug-eluting stent to treat CAD in humans was first published in 2001 using a sirolimus-eluting stent (SES). Drug release from and coating morphology on a CYPHER Sirolimus-eluting Coronary Stent during in vitro elution was studied by correlated confocal Raman and atomic force microscopy (CRM and AFM respectively). Chemical surface and subsurface maps of the SES were generated in the same region of interest by CRM and correlated with surface topography measured by AFM at different elution times. For the first time, a direct correlation between drug-rich regions and coating morphology was made on a drug-eluting medical device, linking drug release with pore formation, pore throats, and pore networks. The poly(n-butyl methacrylate) and poly(ethylene-co-vinyl acetate) multicomponent carrier matrix of this SES was also found to rearrange post elution, as confluence of the carrier polymer matrix reconstituted the voids created by drug release. The relevance of these studies to actual in vivo and in vitro testing will be discussed.

Daniel J. Burnett¹; Armando R. Garcia¹, Jiyi Khoo², Majid Naderi², and Manaswini Acharya²

1) Surface Measurement Systems Limited, 2125 28^th Street SW, Suite 1, Allentown, PA 18103, USA

2) Surface Measurement Systems Limited, 5 Wharfside, Rosemont Road, Alperton, London, UK

Most pharmaceutical solids are energetically heterogeneous. This heterogeneity could be due to different crystal faces, co-crystals, impurities, defect sites, amorphous regions, or co-processed mixtures of materials. Therefore, it is often difficult or even misleading to characterize the surface energy of these materials with a single value. Recent advances in Inverse Gas Chromatography (IGC) theory and applications have developed new methods for determining surface energy distributions for powders using IGC.^1,2 This approach allows for the determination of dispersive and acid-base surface energy values at defined specific surface coverages and determination of surface energy profiles. These measurements more accurately represent the anisotropic nature of ‘real-world’ pharmaceutical solids.

This presentation will discuss several pharmaceutically relevant studies where surface energy distributions have been determined. For instance, the affects of processing route on the surface properties of partially amorphous drugs has been investigated. Studies on quench-cooled, milled, and crystalline Indomethacin indicate that different processing routes produce materials with different surface energy profiles. Further, surface energy studies on model materials like paracetamol and mannitol show that both geometric factors (i.e. aspect ratio) and thermodynamic factors (i.e. lowest attachment energy) play a role in determining which planes will preferentially cleave during milling.

1. Thielmann, F., Burnett, D.J., and Heng, J.Y.Y., Drug Development and Industrial Pharmacy, 33 (2007) 1240-1253.

2. Ylä-Mäihänemi, P.P., Heng, J.Y.Y., Thielmann, F., and Williams, D.R., Langmuir, 24 (2008) 9551-9557.

Anna Maria Coclite, Department of Chemical Engineering, 77 Massachusetts Avenue, Building 66, room 419, Cambridge MA

Engineering Functional and Responsive Surfaces by Chemical Vapor Deposition for Biotechnology

Well-adhered, conformal, ultrathin (<100 nm) coatings obtained by Chemical Vapor Deposition (CVD) augment the capabilities of traditional surface modification techniques for biotechnological applications. Functional polymeric materials can be applied to virtually any substrate at room temperature by CVD methods, organic, inorganic, rigid, flexible, planar, three-dimensional, dense, or porous. In CVD polymerization, the monomer(s) are delivered to the surface through the vapor phase and then undergo simultaneous polymerization and thin film formation. By eliminating the need to dissolve macromolecules, CVD enables insoluble polymers to be coated and prevents solvent damage to the substrate. CVD film growth proceeds from the substrate up, allowing for interfacial engineering, real-time monitoring, and thickness control. initiated-CVD has shown successful results in terms of chemical rationally designed micro- and nano-engineered materials to control molecular and cellular interactions at material surfaces, surface adsorption of biomolecules such as DNA and proteins. Control on the interfacial interactions between materials bearing adsorbed biomolecules, such as cell-adhesive proteins, and cellular entities such as mammalian cells and bacteria have been also achieved. The creation of smart biointerfaces made of switchable coatings that employ stimuli such as temperature, pH and ionic strength to control protein adsorption/desorption and cell attachment/detachment will also be demonstrated.

Pankaj Patil, Mike Gazda, Ashraf Traboulsi and Saswati Datta; Procter and Gamble, Miami Valley Innovation Center, 11810 East Miami River Road, Cincinnati OH 45252

Jaroslaw Drelich; Michigan Technological University, Department of Metallurgical and Materials Engineer, Houghton,, MI 49931

Pull-off Forces Measured between Fine Pharmaceutical Particles and Polymeric Coatings using Atomic Force Microscopy

The presentation will address the issue of particle-surface adhesion in respiratory drug delivery devices by measuring the pull-off (adhesion) forces between a single drug particle (beclomethasone dipropionate, insulin, and lactose) and rough polymeric surfaces using the atomic force microscope (AFM). Two variables including surface roughness and the effect of relative humidity level have been examined in this work. It will be demonstrated that surface roughness of the polymer surfaces used for storage containers has a strong effect on the pull-off forces due to its influence on the area of contact of adhering particle to the polymer surface. Reduced adhesion of 10 to 14 micron diameter lactose and insulin particles to the polypropylene coatings with a RMS roughness of 194 nm was found in this study. Similar pull-off force versus roughness relationships were also obtained for the model spherical particles, silanized glass particle with a size of 10 microns and polystyrene particle with a diameter of 9 microns, in contact with polypropylene coatings of varying roughness characteristics. The pull-off force results were analyzed using a theoretical model proposed by Rabinovich et al. and a correlation between theoretical and experimental pull-off forces will be presented. Additionally, the results of the AFM pull-off force measurements indicate that the relative humidity level inside drug particle storage containers should be maintained less than 55-65% to reduce the effect of capillary forces on drug particle-polymer hold-up.

Frank M. Etzler; School of Pharmacy, Lake Erie College of Osteopathic Medicine, 1858 W. Grandview Blvd., Erie, PA 16509

Tablets are the most common dosage form employed by the pharmaceutical industry. They are both inexpensive to produce and convenient to patients. Active pharmaceutical ingredients, particularly those incorporated into innovator company products, are new chemical substances whose chemical and physical properties are incompletely known and are sometimes present in large amounts in the manufactured products. Excipients present in the formulation can, at least partially, offset undesirable properties of active ingredient. Successful tablet formulations must, in addition to having desirable medicinal properties, must be manufacturable. In order to be manufacturable tablets must have sufficient tensile strength to survive handling, processing and packaging. In this paper the tensile strength of common pharmaceutical excipients mixed with sodium dodecyl sulfate is investigated. Sodium dodecyl sulfate, if incorporated into formulations, usually has an undesirable effect on tensile strength. A model, based on adhesion science principles is proposed that allows the tensile strength of candidate formulations to be calculated from the Ryshkewitch-Duckworth parameters of the component materials. Both the model and the Ryshkewitch-Duckworth equation suggest that tablet porosity is the principal measure of the outcome of the tableting process. Complications related to surface chemical changes induced during wet granulation are also discussed.

Characterization of nanoparticles is often difficult due not only to their active nature but also because of limitations and requirements of available techniques.

There is currently much effort underway in producing nanoparticulate suspensions of drug materials since reducing the API particle size is seen to result in increased bioavailability. Importantly, however, reducing the particle size will significantly increase the specific surface area-to-volume ratio and dramatically increase the rate of dissolution of the drug in the gut milieu, thereby increasing the efficacy and reducing the potential toxicity (because less drug substance is needed). Thus, the dispersed (or wetted) surface area can be a critical metrix of drug product performance. Further, poorly water-soluble API need to be correctly dispersed and stabilized or the subsequent suspensions may suffer from an inadequate, or highly variable, rate and/or extent of drug adsorption.

NMR relaxation can be used to directly measure the surface area of particles dispersed in a liquid. Suspensions can be measured non-invasively and without dilution. The technique is based on the fact that liquid in contact with, or ‘bound” to, the particle surface behaves differently than the bulk or “free” liquid. The NMR relaxation time of bound versus bulk liquid is markedly different: the relaxation time of the latter is much longer. There are no assumptions made about the particle size (distribution) or shape in the determination of the surface area. Further, if a moiety adsorbs at an interface it will result in a change in the relaxation time. One important consequence of this is that competitive adsorption and/or displacement of polyelectrolytes, macromolecules and surfactants at interfaces can be followed.

The theory underpinning these new approaches to suspension characterization will be described and the factors affecting reduction to practical implementation will be discussed. In addition, there is a synergy between NMR diffraction and both small angle light scattering (SALS) and ultra-small angle neutron scattering (USANS). This aspect will also be briefly reviewed.

A.J. Hickey and Z. Xu; Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7360

A Performance Based Analytical Method for Prediction of Aerosol Delivery from Pharmaceutical Dry Powder Inhalers

J. H. Kindt⁽³⁾, M. E. Lauer ^(1*,2), O. Grassmann ⁽¹⁾, M. Siam⁽¹⁾

(1) F. Hoffmann-La Roche Ltd., Discovery Technologies, CH-4070 Basel, SWITZERLAND

(2) Center for Cellular Imaging and Nanoanalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH 4006 Basel, SWITZERLAND

Guiding Pharmaceutical Formulation development through Surface Material Characterization, using recent Scanning Probe Methods

Many experiments in the field of drug discovery and during formulation development require screening and analyzing of bigger sample sets in an automated manner. The development of an amorphous formulation, which is an option to enhance the bioavailability of an in principle poorly water soluble compound, requires to identify the polymers’ and/or surfactants’ potential to form a stable solid dispersion. We will present an Atomic Force Microscopy (AFM)-based assay allowing us to do this efficiently.

We will also review recent results confirming the scalability of these results to production scale material.

Finally, we will share some further new data examples that highlight the potential of scanning probe methods for surface material characterization in industrial Pharmaceutical applications, including time resolved powder surface phase changes, after milling.

Figure 1: Images were collected on two different drug-polymer mixtures. Both mixtures were stressed for 2 hr. at room humidity of 75%, and temperature of 40°C. The evolved patterns indicate a surface-directed spinodal decomposition, theleft mixture already contains nanometers-sized nuclei , the z-scale is 20 nm.

1. M. E. Lauer; O. Grassmann; M. Siam; J. Tardio; L. Jacob; S. Page; J. H. Kindt; A. Engel; J.

Rodolfo Pinal; Dane O. Kildsig Center for Pharmaceutical Processing Research, Heine Pharmacy Building, 575 Stadium Mall Drive, West Lafayette, IN 47907-2091

Santosh Rohit Yerrabolu, Joseph C. Mollendorf, Robert E. Baier and Michael G. Caty; Mechanical and Aerospace Engineering (MAE) + Industry/University Center for Biosurfaces (IUCB) + Kenneth A. Krackow Orthopaedic Research Laboratory (ORL), NYS University at Buffal, New York 14214-3000

Tissue Friction Considerations for Percutaneous Endoscopic Gastrostomy Feeding Tubes

Some individuals have insufficient nutritional intake and lower quality of life because they are unable to chew or swallow food. These are generally nutritionally supported by means of injecting or infusing food directly into their stomachs or small intestines via feeding tubes (Gastrostomy tubes and Percutaneous Endoscopic Gastrostomy (PEG) tubes) inserted via an incision through the abdominal wall. This investigation examined conceptual alternative PEG tube designs along with the materials to be used for their construction, selected from commercial catheters and polymers. Tissue-catheter-friction testing and surface chemistry characterization (Infrared spectroscopy and Critical Surface Tension approximation) were addressed to minimize slipping/dislodgement of gastrostomy tube/seal, to reduce peristomal leakage, and to attain size variability of PEG tubes while maintaining a low profile. Scanning Electron Microscope- Energy Dispersive X-ray Spectroscopy was employed to further determine the influence of filler materials in the samples. Nylon coated with fatty ester and filled with barium sulphate emerged as best candidate material for the construction of the tube part of the feeding tubes to reduce slipping/dislodgment of gastrostomy tube/seal and to minimize peristomal leakage. Rapid prototyping techniques are suitable for manufacturing of the product and Radio Frequency Glow Discharge Treatment is the proposed combined sterilizing and sample preparation technique.

Heidi M. Mansour; UK Center of Membrane Sciences, UK College of Pharmacy, Dept of Pharmaceutical Sciences-Drug Development, 789 South Limestone St., Office 331 , Lexington, Kentucky 40536-0596

Relevance of Particle Surface Chemistry and Particle-Particle Interactions on Aerosolization

Siddharthya Mujumdar, Dabing Chen, Anne Borsavage, Doris Chiappetta and Mayur Dudhedia; Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd, Ridgefield, CT 06877

Impact of Pharmaceutical Processing on Drug Product Quality Attributes – Case Studies in Granulation and Film Coating

In this talk, we discuss two “real life” examples where material properties of the formulation components and changes occurring therein during pharmaceutical processing significantly impacted final drug product quality attributes. In the first case study, the impact of high shear wet granulation on compaction behavior of final blends is presented. Applicability of the Ryskewitch-Duckworth model for multicomponent formulation manufactured using dry blending and high shear wet granulation is discussed. In the second case study, we show an example where “pimple formation” occurred on tablet surfaces during film coating. Root cause investigations to identify the key contributors to the pimple formation and steps taken to ultimately mitigate this problem and prevent its recurrence during drug product manufacturing and storage are also presented. In conclusion, a good understanding of material properties of the formulation components and changes they may undergo during pharmaceutical processing is vital to ensure that the quality target product profile are consistently met during drug product development.

Nano and Micro- Indentation of Pharmaceutical Compacts. Comparison of Results Obtained Using a Compaction Simulator

The purpose of this study is to evaluate the mechanical properties of compacts by analyzing compacts using the Nano indentation tester and comparing these results with results obtained on the compaction simulator.

The excipients selected for the experiment, representing different excipient classes with varied physicomechanical properties, were: AvicelPH101; lactose monohydrate and sucrose.

Uniaxial Compaction: Compacts of target porosity were prepared by uniaxially compressing powder using a flat-faced tooling on the Stylcam 100R compaction simulator. The force-displacement data was acquired at a frequency of 2,000 Hz and at different speeds (5 and 25 rpm).

Indentation: The sucrose compacts were analyzed using a Nano-indentation tester with Berkovich geometry indenter, whereas a micro indentation tester equipped with Vickers geometry indenter was used to perform the hardness testing on lactose and Avicel PH101 samples. The plasticity index and universal hardness were determined from the force-displacement profiles.

AvicelPH101 required the highest net work of compaction as compared to lactose and sucrose. The elastic recovery for the three materials was comparable and relatively small compared to the net work of compaction. The data indicate that the net work of compaction is a more representative measure of the physicomechanical properties of these materials as compared to the plasticity index.

The force displacement curves for the micro-indenter were reproducible for AvicelPH101 and lactose. The curves for sucrose were variable, which may be attributable to the presence of fractures in the compact that were formed during tablet ejection.

AvicelPH101 demonstrates a higher net work of compaction as compared to lactose. Small differences in the net work of compaction were observed for the different compression speeds. The universal hardness for the compacts was somewhat dependent on the compaction speed for AvicelPH101 and lactose. For sucrose, the hardness results were variable mostly likely due to the fractured nature of the compact. It is evident that both techniques may be employed to differentiate the physicomechanical properties for the selected excipients. Nano/Micro-indentation represents new tools for characterizing pharmaceutical compounds, especially when limited quantities are available during early development. Further experimentation is needed to establish this novel technique for routine characterization.

Robert O’Brien, Karin M. Balss, Vladimir Veselov, Hannah Li, Eugena Akerman-Revis, MarkInderbitzen, Jorge Alvarez, Cheryl Wendel, Elaine Pottinger-Cooper, Lori A. Alquier, Maureen F.Chisholm, Silvia Garcia-Tunon, George Papandreou, and Cynthia A. Maryanoff; Cordis, a Johnson & Johnson Company, Welsh & McKean Roads, P. O. Box 776, Spring House, PA 19477-0776

Quantitative Surface Defect Analysis of Drug-eluting Coronary Stents by Scanning ElectronMicroscopy: Coating Integrity of the CYPHER^® Sirolimus-eluting Coronary Stent

A method was developed to assess the durability of drug-polymer coatings, such as those found on drug-eluting stents (DES). The method is based on scanning electron microscopy (SEM) and intensity threshold detection for converting qualitative SEM images to quantification of defects on a DES surface. Previously, a method was developed to examine fatigue of stents subjected to pulsatile loading conditions. The particles generated during fatigue testing were captured and evaluated for chemistry, size, and quantity. The amount of particulates observed from a commercially available DES product was low and on the same order of magnitude as the blanks/controls after acute and chronic simulated in vitro fatigue testing. These results are confirmed using the method developed in this work by evaluating the stent surface before and after chronic fatigue cycling. The relative change in surface defect area during the entire pulsatile fatigue testing cycle was insignificant (<3%), indicating the polymer coating maintains remarkable durability even when subjected to deployment, expansion to the maximum diameter, and repetitive fatigue cycling. Further chemical analysis by FTIR microscopy of individual particles supports the claim that the polymer coating does not shed appreciably during the testing.