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Particle property improvement by surface modification through nano-coating


Most drug powders used in the pharmaceutical industry have very poor flowability, which affects unit operations like blending, tabletting and leads to problems such as lack of content uniformity resulting in significant loss of revenue. We are developing tools to improve flow of such powders through surface modification methods, through dry coating of original poorly flowing powders with nano silica (physically altering the surface structure) or surface treatment (chemically altering the surface structure). The work also involves predicting flow improvement via particle-adhesion models and physically measuring the property improvement requiring small samples. This leads to predicting the bulk level performance based on particle and ensemble scale models and physical measurements.

IGERT trainee Lauren Beach has been making major contributions towards this research, where she has worked on several collaborative projects with researchers in US as well as abroad. Currently, her work focuses on using dry coating of various pharmaceutical active ingredients or excipients using nano-particles to alter properties such as flow, electrostatic, hydrophilicity, compressibility, packing, etc. The work is also examining the influence of surface modification via use of glidants and lubricants instead of simple addition via blending. Second major part of her work involves evaluating the extent of property improvement as well as examining the effect of coating on downstream processes. An added feature of her research is its wide-scale industrial applicability. For example, she has helped develop a novel technique for characterization of the flow improvements, for which a provisional patent has been filed.

The surface modification of acetaminophen, a model drug used in our study, is illustrated in Figure 1 where the powders are shown before and after coating of 1 % by weight nano-silica. This surface modification results in significant flow improvement, indicated via detailed property characterization (Figure 2), for example, angle of repose (A smaller angle implies better flowing powders) or vibrated packing density of a blends, showing a remarkable increase in packing density for blends containing surface modified powder. These powders were also tested in a Schulze Shear Tester at an industry partner site, and nano-coating resulted in the reduction of the Effective Angle of Internal Friction by as much as 10 degrees, indicating significant flow improvement for consolidated powders. The nano-coated powders were also examined via Positron Emission Particle Tracking (PEPT) method at University of Birmingham, indicating that their mobility under excitement was several orders of magnitude higher than uncoated powders. Another student, inspired by this work, developed simultaneous size reduction and surface modification approach, where freely dispersible powders in size range 1-5 microns were produced as shown in Figure 3. The powders that underwent size reduction without nano-coating were highly agglomerated and could not be dispersed. On the other hand, those with nano-coating were freely dispersible and non-agglomerated.

Another collaborative work involved use of near-infrared spectroscopy as a novel approach to characterize the improved flowability of APIs. Acetaminophen and ibuprofen were coated with nano-size silica at two different coating levels (0.5% and 1% wt) in dry particle coating devices. Surface modified (dry coated) APIs were then blended with excipient (Fast flo Lactose) in a V-blender by two commonly used industry methods. Flow results showed that dry particle coated acetaminophen or ibuprofen blends performed better than commonly used industry methods. In addition, it was discovered that the inverse of the signal to noise ratio of spectra could be used as an index to examine flow uniformity. This approach showed that nano-particle coated ibuprofen blends had more uniform and smooth flow.

One important contribution of this work is the inter-particle force prediction from measurement of surface energy (using Inverse Gas Chromatography) and surface roughness (using Atomic Force Microscopy), based on the model of Derjaguin-Müller-Toporov (DMT), requiring only about a gram of material. This measurement agrees well with bulk-level measurement such as the angle of repose (AOR; smaller AOR implies better flow, typically, less than 35 degrees is good flow, while over 50 degrees is poor flow), shown for various surface treated materials in Figure 4, thus pointing to a promising methodology to characterize powder materials using small samples. Another notorious problem with pharmaceutical powders is that they gain electrostatic charge upon processing and stick to all processing vessels and machines, leading to significant manufacturing problems. Our investigation shows that judicious surface modification via dry coating leads to reduction in charge generation (Figure 4), which also strongly correlates with flow improvement, indicated via lower angle of repose. Thus overall, our research demonstrates a methodology for particle property improvement and its characterization at particle-scale, correlated with bulk scales.

We have also examined the influence of nano-coating on tablet propeties. The tablets were tested for hardness and their dissolution profile. There was a slight improvement in the tablet hardness results for nano-coated powder blend versus the uncoated powder blend. Further, the nano-coated powder blend tablets dissolved slightly faster than the uncoated powder tablets and reached a 100% drug dissolution faster than the uncoated powder tablets. This is a significant result indicating that while nano-coating improves the powder properties, it does not have any adverse effect on the downstream product such as tablets.

Address Goals

Learning: This research investigation created excellent training environment for IGERT trainees and other graduate students. For example, Lauren Beach has learnt numerous advanced particle processing and characterization techniques and was exposed to opportunities for national and international collaborations. She is a model example of how the IGERT program has opened up multiple avenues of learning which has led to truly interdisciplinary research. Through IGERT funding, she was able to travel to the University of Birmingham, England, where she worked with people from the Chemical Engineering and Physics Departments to apply PEPT technique to characterize the improved mobility of nano-coated powders for the first time ever. Later, she worked with a visiting scientist from the Physics Department, University of Seville in Spain, Dr. Miguel Sanchez Quintanilla. Together, they built a novel vibrated packed density apparatus to determine the packing density of nano-coated powders, which is a unique device, that has been patented. Next, based on the industry input she started examining blends of active drugs and excipients, for improvement in flow and discharge form a hopper. She teamed up with Prof. Romanach, an expert in use of near-IR spectroscopy, at the University of Puerto Rico Mayaguez. She spent several in Puerto Rico, working with his students and contributed towards development of a simple approach to monitor flow uniformity in powder discharge. She also collaborated with mentors in industry who allowed her to use powder flow characterization instruments in their laboratories. While developing such collaborations, she also did mentoring of her own; she has mentored one high school student (female) and three undergraduate students (all underrepresented minority students), all of them are now interested in post-graduate education. She has alo mentored four beginning graduate student, all of them are females. These students and mentors from academia and industry have helped Lauren learn interdisciplinary skills and grow into an all-rounded engineering researcher.

This experience has been very rewarding for Lauren. In addition to having opportunity to attend conferences and work at various places, she has also received numerous awards. For example, she received all expense paid travel award as a result of regional poster competition to attend the Annual meeting of the International Society for Pharmaceutical Engineering. Through the NJIT Provost’s office and the Graduate Student Association, she was invited to participate in several research showcases and won one of the Poster Completion awards. She also won the Top Place Award in the Professional Presentation competition in the Chemical Engineering Department at NJIT, where she and three other IGERT students were the top four performers in the class. The department also recognized her as the Outstanding Graduate Student in the Chemical Engineering Department, and this ultimately led to her winning the 2009 Schering-Plough Science and Innovation Award, which included a $5,000 cash reward.

Discovery: Interdisciplinary, collaborative research has led to several important findings which are expected to have lasting practical value in pharmaceutical industry. The work has led to development of fundamental understanding of particle surface modification via nano-coating, which also resulted in practical benefits such as flow improvement, reduction in tribo-electric charging, methodology for simultaneous size reduction and surface modification to produce very fine dispersible powders, and development of novel powder property characterization methods including an approach where very small samples are required.