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Presented by Moayad Khashoqji Supervised by Professor Barbara Conway

The role of counter-ion in salt formation to improve the solubility of poorly water soluble drugs the case of Flurbiprofen and Tris( hydroxymethyl ) aminomethane salt. Presented by Moayad Khashoqji Supervised by Professor Barbara Conway MSc project in Analytical chemistry September 2011

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Presented by Moayad Khashoqji Supervised by Professor Barbara Conway

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  1. The role of counter-ion in salt formation to improve the solubility of poorly water soluble drugs the case of Flurbiprofen and Tris(hydroxymethyl)aminomethane salt Presented by MoayadKhashoqji Supervised by Professor Barbara Conway MSc project in Analytical chemistry September 2011 The University of Huddersfield MSc presentation project

  2. Outline • Introduction and aim • Materials • Methods • Results and discussion • Conclusion and further work • References MSc presentation project

  3. Introduction Drug solubility is one of the most important physiochemical properties that affects the bioavailability and reproducibility of any pharmaceutical compound. Aim This study shows the role of salt formation in improving the solubility and dissolution rates of Flurbiprofen, which is one of the poorly water soluble drugs. Tris[hydroxymethyl]aminomethanewas used as a counter-ion and the Flurbiprofen-Tris salt was crystallized from acetonitrile as solvent. MSc presentation project

  4. Materials • Flurbiprofen: is a non-steroidal anti-inflammatory drug (NSAID) that readily forms carboxylic acid salts. It is administered for its anti-inflammatory, antipyretic, analgesic effects, and to inhibit intraoperative mitosis. • Tris[hydroxymethyl]aminomethane: was used as a counter-ion . • Acetonitrile: is a polar solvent that used to crystallize the Flurbiprofen-Tris salt . MW= 244.3 g/mol Bp= 110 °C MW= 121.14 g/mol Bp= 168.5 °C MW= 41.05 g/mol Bp= 81.6 °C MSc presentation project

  5. Methods • Salt formation: • Confirmation of salt formation: • Fourier Transforms Infrared Spectroscopy (FT-IR) • Thin Layer Chromatography (TLC) • Nuclear Magnetic Resonance (NMR) • Powder X-Ray Diffraction (XRPD) • Scanning Electron Microscopy (SEM) • Analytical methods: • Differential Scanning Calorimetric (DSC) • ThermoGravimetric Analysis (TGA) • High Pressure Liquid Chromatography (HPLC) • UltraViolet spectroscopy (UV) • Solubility and dissolution studies: • Intrinsic Dissolution Rate (IDR) MSc presentation project

  6. Results and discussion:Salt formation The Flurbiprofen and Tris[hydroxymethyl]aminomethane were combined to prepare an soluble salt, which was then precipitated and yielded the final product. + - 3 The equation reaction Acetonitrile reactants product Tris[hydroxymethyl]aminomethane Flurbiprofen-Tris salt Solvent Flurbiprofen MSc presentation project

  7. - + 3 Salt confirmation:Fourier Transform Infrared Spectroscopy (FT-IR) Hydrogen Bonding –C-O N-H bonds –C-F 4000-3500 cm-1 100 cm-1 3300 cm-1 800 cm-1 1600-1200 cm-1 2700-1900 cm-1 The figure shows a characteristic broad peak of Flurbiprofen-Trissalt spectrum. In the Flurbiprofen-Tris salt, The N-H bonds appear at 3300cm-1. 3050-2850 cm-1 1600 cm-1 & 3300 cm-1 –C-C –CH aromatic resonances Carboxylic group MSc presentation project

  8. Salt confirmation:Thin Layer Chromatography (TLC) From the results obtained in the table, it was noticed that one component was found for both the Flurbiprofen and the Triswhereas the Flurbiprofen-Tris salt gave us two components and the retention factors (Rf values): • The (Rf) of three runs average of Flurbiprofen = 1.36 • The (Rf) of three runs average of Tris = 2.16 • The (Rf) of three runs average of Flurbiprofen-Tris salt = 1.4 and 2.16 MSc presentation project

  9. Salt confirmation:Nuclear Magnetic Resonance (NMR) • δ 1.31 (d, 3H, J1=6.95 Hz, A) • δ 2.55 (s, 6H, F) • δ 3.20 (q, 1H, J1=6.95 Hz, J2=6.95 Hz, B) • δ 3.42 (bs, 6H, D/G) • δ 7.16-7.53 (overlapping m, 8H, C) DMSO D G B F A C A C - The H1-NMR spectra of Flurbiprofen-Tris salt included all hydrogen atoms contained in the compounds. A chemical shift corresponding to the carboxylic group in Flurbiprofenappeared at 3.80 ppm, while it appeared at 3.20 ppm for the Flurbiprofen-Trissalt. This is due to the chemical shift of the proton that was added to the carbon (next to the carboxylic group). B F + 3 D G MSc presentation project

  10. Salt confirmation:Powder X-Ray Diffraction (XRPD) Monoclinic crystal structure In monoclinic crystal system, all sides in this crystal are not equal in length, but there are two angles (ɣ, β) equal to 90° and another angle known as (α). - The scan for Flubiprofen-Tris salt looks a bit like a similar version of the one for Flurbiprofen, it is shifted to the higher 2Theta values and looks a bit more simplified, so it’s quite probable that Flurbiprofen was a triclinic system, while the crystal structure is a monoclinic one with one of the angles of the crystal lattice slightly deviating from 90 degrees. + 3 MSc presentation project

  11. Salt confirmation:Scanning Electron Microscopy (SEM) Outside the crystal Inside the crystal • The view of Flurbiprofen-Tris salt showed a slightly smooth surface from the outside of the crystal morphology of the X190 magnification and 100µm of the size. • The internal surface of the crystal shows many filaments and complex morphology at X1,100 magnification and 10µm of the size. MSc presentation project

  12. Analytical methods:Differential Scanning Calorimetric (DSC) Several experiments were attempted to resolve and identify all obtained peaks by once changing the N2 gas flow rate for a better expansion for the DSC curve. Pure Flurbiprofen The DSC curve in Flurbiprofen shows a sharp endothermic peak representing the melting point of pure Flurbiprofen at (113.950C). The sharpness of the peak and absence of any others within the temperature range of the experiment indicates that this material is reasonably pure. 113.950C Melting point Flurbiprofen-Tris salt The DSC curve in Flurbiprofen-Trissalt which formed by using acetonitrile as solvent gave a two exothermic peaks at temperatures of 129.030C - 137.640Cindicating a polymorphic crystalline internal structure for the Flurbiprofen-Trissalt. 137.640C Melting point 129.030C Melting point MSc presentation project

  13. Analytical methods:ThermoGravimetric Analysis (TGA) The weight is steady until 160oC The weight is steady until 160oC A dramatic change from 160oC until 260oC A dramatic change from 160oC until 260oC The weight loss of the Flurbiprofenis 1.637mg (54.5%) The weight loss of the Flurbiprofen-Tris salt is 1.966mg (50.3%) • For Flurbiprofenand its salt, the weights of the samples were steady until 160oC, and then a dramatic change happened from 160oC until 260oC. • The weight loss of the Flurbiprofen was 1.637mg (54.5%). • The weight loss of the Flurbiprofen-Tris salt was 1.966mg (50.3%). MSc presentation project

  14. Analytical methods:High Pressure Liquid Chromatography (HPLC) The figure shows a linear relationship between the concentration and the peak area for both the Flurbiprofenand the Flurbiprofen-Trissalt. Both compounds were soluble, but the Flurbiprofen-Trissalt had lower solubility based on its sigma value, when compared to the sigma value of Flurbiprofen The HPLC calibration curve equations for Flurbiprofen-Trisallowed calculation of the amount of salt that has been dissolved in water at a ratio of 1:1 (water:salt). MSc presentation project

  15. Analytical methods:UltraVioletspectroscopy (UV) The UV calibration curve equations for Flurbiprofen-Trisallowed calculation of the amount of salt that has been dissolved in water at a ratio of 1:1 (water:salt). The figure shows a linear relationship for the absorbances of Flurbiprofenand the Flurbiprofen-Trissalt. The overall absorbance of Flurbiprofen-Trissalt was lower than that for Flurbiprofen. MSc presentation project

  16. Solubility and dissolution studies:Intrinsic Dissolution Rate (IDR) For Flurbiprofen The dissolution curves indicated a linear relationship between the concentration of tablets and time. The amount of dissolved of Flurbiprofen increased with time, as shown by the dissolution curves. MSc presentation project

  17. Solubility and dissolution studies:Intrinsic Dissolution Rate (IDR) For Flurbiprofen-Tris salt The dissolution curves indicated a linear relationship between the concentration of tablets and time. The amount of dissolved of Flurbiprofen-Tris salt increased with time, as shown by the dissolution curves. The Flurbiprofen-Tris salt has a lower solubility and dissolution rate than the Flurbiprofen alone. MSc presentation project

  18. Conclusion • Overall, the experiment was successful, since the main purpose was to prepare a Flurbiprofen salt and then to recrystallize it. • As a result, a polymorphism crystal salt was obtained and by comparing the results of the actual Flurbiprofensalt, solubility and dissolution rate of the new crystal form salt, the first showed a higher dissolution and solubility rates. • The results presented here confirm that Flurbiprofen is a poorly water-soluble drug, even when converted to its Tris salt. That means the Tris salt was really not much more soluble than Flurbiprofen alone. And in my opinion, a pharmaceutical company would not want to spend lots of money making a Tris formulation of Flurbiprofen if it was not going to work well as a medicine. So the Tris salt could be not a good choice for a medicine. MSc presentation project

  19. Further work • The results could be improved by a more in-depth study of the properties of the crystal produced more to re-test the precision of the methods used. • A different solvent such as methanol could also be tested for salt formation to see if the crystal would form with same properties. • The use of a vacuum oven during the preparation process rather than a normal vacuum could improve crystal formation by removing more residual solvent. • The HPLC technique could be tested using a different column more suited to the conditions of experiment to give clearer results. • The TGA technique could be improved by using a lid on the crucible to improve accuracy. • For the DSC method, it is important that ensure that the atmosphere around the instrument clean and ready for sample analysis. • I encountered difficulties in obtaining accurate results because other materials analysed using the same device became an obstacle in obtaining correct readings. • Finally, I would suggest that future work should look at different counter-ions such as dimethylamin (DMA) to be studied, and see if it can find a salt that has a better solubility and dissolution rate than the Flurbiprofen alone. MSc presentation project

  20. References • Baek, H. Kwon, S. Rho,S. Lee, W. Yang , H. Hah, J. Choi , H. Kim , Y. Yong , C. (2011). Enhanced solubility and bioavailability of flurbiprofen by cycloamlose. Archives Pharmacal Research. 34 (3), 391-397. • Brittain, H. (2011). Polymorphism and Solvatomorphism 2009. Journal of Pharmaceutical Sciences. 100 (4), 1260-1279. • Castelli, F. Messina, C. Sarpietro, M. Pignatello, R. Puglisi, G. (2002). Flurbiprofen release from eudragit RS and RL aqueous nanosus-pensions: a kinetic study by DSC and dialysis experiments. AAPS Pharm Sic Tech. 3 (2), 1-8. • Currell, G (2000). Analytical instrumentation performance characteristics and quality. England: John Wiley & Sons Ltd. • James, N.M, Jane, C.M, 2005. Statistics and Chemometrics for analytical chemistry. 5th ed. London. • James, W.R, Eileen, M., 2005, Undergraduate Instrumental Analysis. 6th Ed. New York: M, Decker. • Kazakevich, Y. Lobrutto, R (2007). HPLC for pharmaceutical scientists. New Jersey. USA: John Wiley & Sons, Inc. • Kobayashi, Y. Ito, S. Itai, S. Yamamoto,K. (2000). Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate. International Journal of Pharmaceutics. 193, 137–146. • Lacoulonche, F. Chauvet,A. Masse, J. (1997). An investigation of flurbiprofen polymorphism by thermoanalytical and spectroscopic methods and a study of its interactions with poly-(ethylene glycol) 6000 by differential scanning calorimetry and modelling. International Journal of Pharmaceutics. 153, 167–179. • Menczel, J. Prime, R (2009). Thermal Analysis of Polymers Fundamentals and Applications. New Jersey, USA: John Wiley & Sons. • Patel, D. Mashru, R. (2011). Enantiomeric Resolution of (±)Flurbiprofen-(-)-serine-impregnantrd silica as stationary phase by thin layer chromatography. International Journal of Pharmacy and Pharmaceutical Sciences. 3 (2), 131-133. • Tsinman,K.Avdeef, A. Tsinman, O. Voloboy, D. (2009). Powder Dissolution Method for Estimating Rotating Disk Intrinsic Dissolution Rates of Low Solubility Drugs. Pharmaceutical Research. 26 (9), 2093-2100. MSc presentation project

  21. Acknowledgements I would particularly like to thank Prof Barbara Conwayfor all her help, support and patience during the construction of this study. Many thanks also go to the course leader Dr. Peter Clemenson for his cooperation and guidance during my time at the University of Huddersfield. I would like to express my heartfelt gratitude to the many people who contributed directly and indirectly to the creation of this study specially Dr. James Rooney. Finally, Thanks to the department for providing the opportunity to study. MSc presentation project

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