Stephen R. Byrn
PhD Organic and Physical Chemistry, University of Illinois, Urbana, 1970
Post-doctoral, University of California, Los Angeles, Physical Chemistry, 1970-1972
Byrn Lab - May 2015 (l to r): Curtis Hajec, Ruba Alajlouni, Dr. Daniel Smith, Dr. Stephen Byrn, Haichen Nie, & Yang Song
Solid State Chemistry of Drugs/Pharmaceutical Solids
Investigators: S. Byrn, Amrinder Singh, Chris King
The overall goal of our research is to develop the field of Solid State Chemistry of Drugs so that all of the principles and factors governing solid-state chemistry are understood. This knowledge is then used to predict and analyze all behaviors of solids observed during the drug development process and in formulations. Thus, the solid-state chemistry of drugs is being studied to improve knowledge of the factors that affect this chemistry and to develop new methods of studying these reactions. At present, our group is focusing solid-state acid base reactions and stability. We are also interested solid-state desolvation reactions, solid state decarboxylation reactions, solid-solid reactions, and solid-state rearrangements. These studies are important in that they will lead to better understanding of the mechanism of drug degradation and eventually to new approaches to stabilizing drugs. By carrying out research on the solid-state chemistry of drugs, it is hoped that new approaches and ideas for drug analysis including solid-state NMR spectroscopy and X-ray diffraction will be developed. In addition, this research is aimed at providing new insight into drug stability and at developing methods for predicting drug stability. Furthermore, approaches to the production via crystallization of the desired drug form are an important component of these studies.
Processing, Formulation, and Manufacturing of Pharmaceuticals
Investigators: S. Byrn, Amrinder Singh, Chris King
Approaches to understanding the molecular basis of pharmaceutical formulation and manufacturing are being developed. These approaches which include Raman mapping and EDS can in favorable cases provide information on the spatial location of all components in tablets and capsules. The effect of processing on the solid state chemistry of drugs and the stability of formulations is also being investigated. Particular emphasis is placed on the wet granulation and coating. Continuous manufacturing and manufacturing design are also being investigated especially for protease inhibitors and fixed dose combination drugs. The regulatory aspects of processing and manufacturing are also being emphasized.
X-ray Structural Analysis of Amorphous Pharmaceuticals
Investigators: S. Byrn, Amrinder Singh, Chris King
The structure of amorphous pharmaceuticals is not known and poorly understood. Pair distribution functions derived from X-ray powder diffraction measurements made at Argonne National Laboratories Synchrotron as well as solid state NMR measurements along with more conventional studies can provide phase diagrams and information on the functional groups and atom-atom distances involved in drug-drug and drug –polymer interactions present in amorphous materials. These methods will lead to the establishment of a rational design method for amorphous compositions. This bottom-up design approach focuses on amorphous protease inhibitors since these are the most bioavailable compositions. This new method will determine structural details of amorphous compositions by providing atom-atom distances and other structural parameters. We will use the atomic distances, and other parameters determined, to predict properties of these compositions including stability (failure to crystallize), dissolution rate, and bioavailability. This method is particularly important since amorphous drugs are now being used to cure HCV and as potential treatments for a range of other viral diseases besides HIV and are being investigated as cures for Zika infections.
Abuse Deterrent Formulations of Opioids
Investigators: Dan Smith
The goal of the abuser is to alter the opioid dosage from such that it provides a plasma concentration that is sufficient to induce euphoria. The abuse-deterrent dosage form is designed to minimize the feeling of euphoria when taken as prescribed by a patient, i.e. when using the medication as intended. However, a prescription drug abuser would try to modify the dosage form in a manner to increase the plasma concentration to a level that would induce euphoria. They can achieve this by increasing the rate of drug uptake. For example, they could crush a controlled release tablet, which would induce dose dumping when swallowed. They could change the route of administration. For example the abuser could crush a tablet and then try and inject or snort the contents of the crushed tablet. Thus, abuse deterrent formulations are investigated to identify the failure modes. This knowledge will lead to second-generation formulations that are even more difficult to abuse than those currently on the market.
Dr. Byrn also works with the Industrial and Physical Pharmacy Services Laboratory.
Dr. Byrn is in charge of the Dosage Form Course PHAR 828 for Pharm. D. students and co-teaches PHAR 461, Drug Development II, for BSPS students.
Dr. Byrn teaches several times a year in Tanzania, Africa. The sustainable medicine program in Africa is aimed at addressing the problem of lack of access to high quality medicines in Africa. This program consists of: (1) Master’s degree in Biotechnology Innovation and Regulatory Science taught at the Kilimanjaro School of Pharmacy and jointly administered with the Kilimanjaro School of Pharmacy (Sr. Zita Ekeocha)); (2) an actual GMP-level pharmaceutical manufacturing facility at SLF/KSP, and (3) a quality medicines laboratory equipped with HPLCs. The educational programs are aimed at providing source of well-trained manufacturing scientists for pharmaceutical industry in Tanzania and Africa. The GMP-level facility is used to teach manufacturing under strict quality control. The GMP facility will serve as a model for other such facilities throughout Sub-Saharan Africa. The feasibility of establishing a sustainable medicine program in Tanzania is supported by the experience of the former Infusion Units Project in Tanzania, now known as Saint Luke Foundation (SLF). This program has manufactured and distributed infusion solutions throughout Tanzania since 1983. Additionally, the availability of trained personnel and a model facility will combat several current problems especially those related to counterfeited/poor quality medicines.
This Master’s degree in Biotechnology Innovation and Regulatory Science is supported by UNIDO (United Nations Industrial Development Organization) and Merck Foundation who provide grants to defray the cost of attendance. Recently, this program was recognized as an ANDi (African National Drug Innovation) Center for Pharmaceutical Manufacturing and Regulatory Training. This center is one of less than 50 centers in Africa.
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Honors and Credentials
Dr. Stephen R. Byrn received the 2016 AAPS Dale Wurster Award in Pharmaceutics and the 2009 AAPS David Grant Research Achievement Award in Physical Pharmacy in 2009. Special Issue (September 2010) of the Journal of Pharmaceutical Sciences was dedicated to Stephen R. Byrn, based on his contributions to the field of solid state pharmaceutics.
Stephen Byrn and coauthors, George Zografi and Xiaoming (Sean) Chen published a book entitled Solid State Propoerties of Pharmaceutical Materials. The publisher is John Wiley and Sons.
Nie, Haichen; Mo, Huaping; Byrn, Stephen R., Investigating the Physicochemical Stability of Highly Purified Darunavir Ethanolate Extracted from PREZISTA Tablets, AAPS PharmSciTech (2018), 19(5), 2407-2417.
Boyce, Heather; Smith, Dan; Byrn, Steve; Saluja, Bhawana; Qu, Wen; Gurvich, Vadim J.; Hoag, Stephen W. In Vitro Assessment of Nasal Insufflation of Comminuted Drug Products Designed as Abuse Deterrent Using the Vertical Diffusion Cell, AAPS PharmSciTech (2018), 19(4), 1744-1757.
de Araujo, Gabriel L. B.; Ferreira, Fabio Furlan; Bernardes, Carlos E. S.; Sato, Juliana A. P.; Gil, Otavio M.; de Faria, Dalva L. A.; Loebenberg, Raimar; Byrn, Stephen R. ; Ghisleni, Daniela D. M.; Bou-Chacra, Nadia A.; et al, A new thermodynamically favored flubendazole/maleic acid binary crystal form: Structure, energetics, and in silico PBPK model-based investigation, Crystal Growth & Design (2018), 18(4), 2377-2386.
Kalra, Arjun; Luner, Paul; Taylor, Lynne S.; Byrn, Stephen R.; Li, Tonglei, Gaining Thermodynamic Insight From Distinct Glass Formation Kinetics of Structurally Similar Organic Compounds, Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2018), 107(1), 192-202.
Byrn, S. R.; Ekeocha, Z.; Clase, K. L., An Education Strategy to Respond to Medicine Inequality in Africa. J. Pharm. Sci. 2017, 106 (7), 1693-1696.
de Araujo, G. L. B.; Benmore, C. J.; Byrn, S. R., Local Structure of Ion Pair Interaction in Lapatinib Amorphous Dispersions characterized by Synchrotron X-Ray diffraction and Pair Distribution Function Analysis. Sci. Rep. 2017, 7, 46367.
Kalra, A.; Tishmack, P.; Lubach, J. W.; Munson, E. J.; Taylor, L. S.; Byrn, S. R.; Li, T., Impact of Supramolecular Aggregation on the Crystallization Kinetics of Organic Compounds from the Supercooled Liquid State. Mol. Pharmaceutics 2017, 14 (6), 2126-2137.
Nie, H.; Byrn, S. R.; Zhou, Q., Stability of pharmaceutical salts in solid oral dosage forms. Drug Dev. Ind. Pharm. 2017, 43 (8), 1215-1228.
Nie, H.; Xu, W.; Taylor, L. S.; Marsac, P. J.; Byrn, S. R., Crystalline solid dispersion-a strategy to slowdown salt disproportionation in solid state formulations during storage and wet granulation. Int. J. Pharm. (Amsterdam, Neth.) 2017, 517 (1-2), 203-215.
Weber, J. K. R.; Benmore, C. J.; Suthar, K. J.; Tamalonis, A. J.; Alderman, O. L. G.; Sendelbach, S.; Kondev, V.; Yarger, J.; Rey, C. A.; Byrn, S. R., Using containerless methods to develop amorphous pharmaceuticals. Biochim. Biophys. Acta, Gen. Subj. 2017, 1861 (1_Part_B), 3686-3692.
Zeller, M.; Barros de Araujo, G. L.; Parker, T.; Singh Rai, A.; Byrn, S. R., A new solvate of afatinib, a specific inhibitor of the ErbB family of tyrosine kinases. Acta Crystallogr., Sect. E: Crystallogr. Commun. 2017, 73 (3), 417-422.
Nie, Haichen; Xu, Wei; Ren, Jie; Taylor, Lynne S.; Marsac, Patrick J.; John, Christopher T.; Byrn, Stephen R. Impact of Metallic Stearates on Disproportionation of Hydrochloride Salts of Weak Bases in Solid-State Formulations, Molecular Pharmaceutics (2016), 13(10), 3541-3552
Song, Yang; Zemlyanov, Dmitry; Chen, Xin; Su, Ziyang; Nie, Haichen; Lubach, Joseph W.; Smith, Daniel; Byrn, Stephen; Pinal, Rodolfo, Acid-base interactions in amorphous solid dispersions of lumefantrine prepared by spray-drying and hot-melt extrusion using X-ray photoelectron spectroscopy International Journal of Pharmaceutics (Amsterdam, Netherlands) (2016), 514(2), 456-464.
Song, Yang; Zemlyanov, Dmitry; Chen, Xin; Nie, Haichen; Su, Ziyang; Fang, Ke; Yang, Xinghao; Smith, Daniel; Byrn, Stephen R.; Lubach, Joseph W., Acid-Base Interactions of Polystyrene Sulfonic Acid in Amorphous Solid Dispersions Using a Combined UV/FTIR/XPS/ssNMR Study, Molecular Pharmaceutics (2016), 13(2), 483-492.
Benmore, C. J.; Mou, Q.; Benmore, K. J.; Robinson, D. S.; Neuefeind, J.; Ilavsky, J.; Byrn, S. R; Yarger, J. L., A SAXS-WAXS study of the endothermic transitions in amorphous or supercooled liquid itraconazole Thermochimica Acta (2016), 644, 1-5.
Nie, Haichen; Su, Yongchao; Zhang, Mingtao; Song, Yang; Leone, Anthony; Taylor, Lynne S.; Marsac, Patrick J.; Li, Tonglei; Byrn, Stephen, Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions, Molecular Pharmaceutics (2016), 13(11), 3964-3975.
de Araujo, Gabriel L. B.; Zeller, Matthias; Smith, Daniel; Nie, Haichen; Byrn, Stephen R, Unexpected Single Crystal Growth Induced by a Wire and New Crystalline Structures of Lapatinib, Crystal Growth & Design (2016), 16(10), 6122-6130.
Braun, Doris E.; Nartowski, Karol P.; Khimyak, Yaroslav Z.; Morris, Kenneth R.; Byrn, Stephen R ; Griesser, Ulrich J., Structural Properties, Order-Disorder Phenomena, and Phase Stability of Orotic Acid Crystal Forms, Molecular Pharmaceutics (2016), 13(3), 1012-1029
Song, Yang; Yang, Xinghao; Chen, Xin; Nie, Haichen; Byrn, Stephen; Lubach, Joseph W., Investigation of Drug-Excipient Interactions in Lapatinib Amorphous Solid Dispersions Using Solid-State NMR Spectroscopy, Molecular Pharmaceutics (2015), DOI:10.1021/mp500692a.
Byrn, Stephen; Futran, Maricio; Thomas, Hayden; Jayjock, Eric; Maron, Nicola; Meyer, Robert F.; Myerson, Allan S.; Thien, Michael P.; Trout, Bernhardt L., Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them. 2014 Continuous Symposium, May 20-21, Journal of Pharmaceutical Sciences (2015), 104(3), 792-802.
Song, Yang, Yang, Xinghao, Chen, Xin, Nie, Haichen, Byrn, Stephen, Lubach, Joseph W., Investigation of Drug-Excipient Interactions in Lapatinib Amorphous Solid Dispersions Using Solid-State NMR Spectroscopy, Molecular Pharmaceutics (2015), 2015 Mar 2;12(3):857-66. doi: 10.1021/mp500692a. Epub 2015 Jan 28.
Byrn, Stephen, Futran, Maricio, Thomas, Hayden, Jayjock, Eric, Maron, Nicola, Meyer, Robert F., Myerson, Allan S., Thien, Michael P., Trout, Bernhardt L., Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them. 2014 Continuous Symposium, May 20-21, Journal of Pharmaceutical Sciences (2015), 104(3), 792-802.
Fortunak, J.; Byrn, S.R.; Dyson, B.; Ekeocha, Z.; Ellison, T.; King, C.L.; Kulkarni, A.A.; Lee, M.; Conrad, C.; Thompson, K., An efficient, green chemical synthesis of the malaria drug, piperaquine, Tropical Journal of Pharmaceutical Research (2013), 12(5), 791-798.
Lee, J.; Boerrigter, S.X.M.; Jung, Y.W.; Byun, Y.; Yuk, S.H.; Byrn, S.R.; Lee, E.H, Organic vapor sorption method of isostructural solvates and polymorph of tenofovir disoproxil fumarate, European Journal of Pharmaceutical Sciences (2013), 50(3-4), 253-262.
Weber, J.K.R.; Benmore, C.J.; Tailor, A.N.; Tumber, S.K.; Neuefeind, J.; Cherry, B.; Yarger, J.L.; Mou, Q.; Weber, W.; Byrn, S.R. A neutron-X-ray, NMR and calorimetric study of glassy Probucol synthesized using containerless techniques, Chemical Physics (2013), 424, 89-92.
Benmore, C.J.; Weber, J.K.R.; Tailor, A.N.; Cherry, B.R.; Yarger, J.L.; Mou, Q.; Weber, W.; Neuefeind, J.; Byrn, S.R., Structural characterization and aging of glassy pharmaceuticals made using acoustic levitation, Journal of Pharmaceutical Sciences (2013), 102(4), 1290-1300.
Gurvich, V.J; Byrn, S.R., NIPTE: a multi-university partnership supporting academic drug development, Drug Discovery Today (2013), 18(19-20), 916-21.
Byrn, Stephen R, and Henck, Jan-Olav, Optimizing Physical Form – opportunities and limitations. Drug Discovery Today: Technologies 9, no. 2 (2012): e73-e78.
Lee EH, Byrn SR, Pinal R. The solution properties of mefenamic acid and a closely related analogue are indistinguishable in polar solvents but significantly different in nonpolar environments. J Pharm Sci. 101, no. 12 (2012): 4529-4539.
Trasi NS, Byrn SR. Mechanically induced amorphization of drugs: a study of the thermal behavior of cryomilled compounds. AAPS PharmSciTech 13, no. 3 (2012): 772-784.
Weber RJ, Benmore CJ, Tumber SK, Tailor AN, Rey CA, Taylor LS, Byrn SR. Acoustic levitation: recent developments and emerging opportunities in biomaterials research. Eur Biophys J. 2012 Apr;41(4):397-403. doi: 10.1007/s00249-011-0767-3. Epub 2011 Oct 30.
Su Z, Luthra S, Krzyzaniak JF, Agra-Kooijman DM, Kumar S, Byrn SR, Shalaev EY. Crystalline, liquid crystalline, and isotropic phases of sodium deoxycholate in water. J Pharm Sci. 2011 Nov;100(11):4836-44. doi: 10.1002/jps.22690. Epub 2011 Jun 30.
Byrn SR, Tishmack PA, Milton MJ, van de Velde H. Analysis of two commercially available bortezomib products: differences in assay of active agent and impurity profile. AAPS PharmSciTech. 2011 Jun;12(2):461-7. Epub 2011 Apr 1.
Lee, Eun Hee; Boerrigter, Stephan X. M.; Byrn, Stephen R. Epitaxy of a Structurally Related Compound on the (100) Faces of Flufenamic Acid Form I and III Single Crystals. Crystal Growth & Design. 2010;10(2):518–527. doi: 10.1021/cg900549h. Epub January 8, 2010
Ito, Takanori; Byrn, Stephen; Chen, Xin; Carvajal, M. Teresa. Thermal insight of mechanically activated bile acid powders. Int J Pharm. 2011 Nov 25;420(1), 68-75.
Emeje, Martins; Isimi, Christiana; Byrn, Stephen; Fortunak, Joseph; Kunle, Olobayo; Ofoefule, Sabinus. Extraction and physicochemical characterization of a new polysaccharide obtained from the fresh fruits of Abelmoschus esculentus. Iranian Journal of Pharmaceutical Research. 2011; 10(2):237-246.
Byrn, Stephen R.; Tishmack, Patrick A.; Milton, Mark J.; Velde, Helgi. Analysis of Two Commercially Available Bortezomib Products: Differences in Assay of Active Agent and Impurity Profile. AAPS PharmSciTech. 2011 Jun;12(2):461-7. Epub 2011 Apr 1.
Yamauchi, Masahiro; Lee, Eun Hee; Otte, Andrew; Byrn, Stephen R.; Carvajal, M. Teresa. Contrasting the Surface and Bulk Properties of Anhydrate and Dehydrated Hydrate Materials. Crystal Growth & Design. 2011;11(3):692-698.
Trasi, Niraj S.; Boerrigter, Stephan X. M.; Byrn, Stephen R.; Carvajal, Teresa M. Investigating the effect of dehydration conditions on the compactibility of glucose. International Journal of Pharmaceutics. 2011;406(1-2):55-61.
Mao, Chen; Prasanth Chamarthy, Sai; Byrn, Stephen R.; Pinal, Rodolfo. Theoretical and Experimental Considerations on the Enthalpic Relaxation of Organic Glasses using Differential Scanning Calorimetry. Journal of Physical Chemistry B. 2010;114(1):269-279.
Emeje, Martins; Olaleye, Olajide; Isimi, Christiana; Fortunak, Joseph; Byrn, Stephen; Kunle, Olobayo; Ofoefule, Sabinus. Oral sustained release tablets of zidovudine using binary blends of natural and synthetic polymers. Biological & Pharmaceutical Bulletin (2010), 33(9), 1561-157.
Ripin, David H. Brown; Teager, David S.; Fortunak, Joseph; Basha, Shaik Mahaboob; Bivins, Nylea; Boddy, Christopher N.; Byrn, Stephen; Catlin, Kelly K.; Houghton, Stephen R.; Jagadeesh, S. Tirumala; et al. Process Improvements for the Manufacture of Tenofovir Disoproxil Fumarate at Commercial Scale. Organic Process Research & Development (2010), 14(5), 1194-1201.
Lee, Eun Hee; Byrn, Stephen R. Stabilization of metastable flufenamic acid by inclusion of mefenamic acid: solid solution or epilayer? Journal of Pharmaceutical Sciences (2010), 99(9), 4013-4022.
Engers, David; Teng, Jing; Jimenez-Novoa, Jonathan; Gent, Philip; Hossack, Stuart; Campbell, Cheryl; Thomson, John; Ivanisevic, Igor; Templeton, Alison; Byrn, Stephen; et al. A solid-state approach to enable early development compounds: selection and animal bioavailability studies of an itraconazole amorphous solid dispersion. Journal of Pharmaceutical Sciences (2010), 99(9), 3901-3922.
Li, Hui; Weng, Hong; Stowell, Joseph G.; Morris, Kenneth R.; Byrn, Stephen R. Crystal quality and physical reactivity in the case of flufenamic acid (FFA). Journal of Pharmaceutical Sciences (2010), 99(9), 3839-3848.
Byrn, Stephen R.; Zografi, George; Chen, Xiaoming. Accelerating proof of concept for small molecule drugs using solid-state chemistry. Journal of Pharmaceutical Sciences (2010), 99(9), 3839-3848.
Atassi, Faraj; Mao, Chen; Masadeh, Ahmad S.; Byrn, Stephen R. Solid-state characterization of amorphous and mesomorphous calcium ketoprofen. Journal of Pharmaceutical Sciences (2010), 99(9), 3684-3697.
Trasi, Niraj S.; Boerrigter, Stephan X. M.; Byrn, Stephen Robert. Investigation of the Milling-Induced Thermal Behavior of Crystalline and Amorphous Griseofulvin. Pharmaceutical Research (2010), 27(7), 1377-1389.
Lee, Eun Hee; Smith, Daniel T.; Fanwick, Phillip E.; Byrn, Stephen R. Characterization and Anisotropic Lattice Expansion/Contraction of Polymorphs of Tenofovir Disoproxil Fumarate. Crystal Growth & Design (2010), 10(5), 2314-2322.
Lee, Eun Hee; Boerrigter, Stephan X. M.; Byrn, Stephen R. Epitaxy of a Structurally Related Compound on the (100) Faces of Flufenamic Acid Form I and III Single Crystals. Crystal Growth & Design (2010), 10(2), 518-527.
Chen, Xiaoming; Stowell, Joseph G.; Morris, Kenneth R.; Byrn, Stephen R. Quantitative study of solid-state acid-base reactions between polymorphs of flufenamic acid and magnesium oxide using X-ray powder diffraction. Journal of Pharmaceutical and Biomedical Analysis (2010), 51(4), 866-874.