JOURNAL OF CHILEAN CHEMICAL SOCIETY

Vol 62 No 2 (2017): Journal of the Chilean Chemical Society
Original Research Papers

REVIEW ARTICLE IMPURITY PROFILING OF DRUGS TOWARDS SAFETY AND EFFICACY: THEORY AND PRACTICE

Kiran R. Dhangar
Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research
Rakesh B. Jagtap
Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research
Sanjay J. Surana
Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research
Atul A. Shirkhedkar
Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research
Published June 16, 2017
Keywords
  • Impurity Profiling,
  • Regulatory guidelines,
  • Residual solvent,
  • Genotoxicity
How to Cite
Dhangar, K. R., Jagtap, R. B., Surana, S. J., & Shirkhedkar, A. A. (2017). REVIEW ARTICLE IMPURITY PROFILING OF DRUGS TOWARDS SAFETY AND EFFICACY: THEORY AND PRACTICE. Journal of the Chilean Chemical Society, 62(2). Retrieved from https://jcchems.com/index.php/JCCHEMS/article/view/204

Abstract

Last decade has witnessed enormous changes in the studies of impurity profiling of drugs which can be reflected from pharmacopoeia and regulatory guidelines. The present review article is an attempt to provide comprehensive knowledge about various aspects and details about the impurity profiling in context with regulatory guidelines. Article also focused on isolation, separation and characterization techniques of impurities. It gives preliminary idea about applicability of virtual software used for studies on safety limit for impurities. The comprehensive information related to residual solvents, residual metals and genotoxicity studies of isolated impurities have also been incorporated into present article.

References

  1. Pharmacopeia, U.S. US Pharmacopeial convention.Asian edition, 12601 Twin brook, Rockville, MD 20852, 32, 39, 2014.
  2. Pharmacopoeia, I. Ghaziabad: Indian Pharmacopoeial Commission. Govt. of India-Ministry of Health and Family Welfare, 1948, 2014.
  3. Pharmacopoeia, B. British Pharmacopoeia Commission Secretariat, part of the Medicines and Healthcare products Regulatory Agency, 2014.
  4. Medicines, E.D.f.t.Q.o., Commission, E.P.European pharmacopoeia. Council of Europe, 2009.
  5. N. Grekas, Organic impurities in chemical drug substances, 2005.
  6. R. Rajagopalan, Handbook of isolation and characterization of impurities in pharmaceuticals, 27, 2003.
  7. K. Wadekar, M. Bhalme, S. Rao, K. Reddy, L. Kumar, E. Balasubrahmanyam, Pharma. Tech,36, 58-72, 2012.
  8. F. Qiu, D. Norwod, J. Liq.Chroma.Rel.Techn, 30, 877-935, 2007.
  9. Guideline, I.H.T.; Impurities in new drug substances Q3B (R2). Proceedings of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Geneva, Switzerland, 25, 2006.
  10. J. Kauffman, BioPhar. Interna, 23, 1, 2009.
  11. L. Shargel, I. Kanfer, Generic drug product development: solid oral dosage forms, CRC Press, 2013.
  12. S. Branch, J. Pharm. Biomed.Anal., 38, 798-805, 2005.
  13. Pharmacopoeia, J.; Society of Japanese Pharmacopoeia. Amended Chapters, 35, 7, 2007.
  14. J. Orr, I. Krull, M. Swartz, LC GC NORTH AMERICA,21, 626-633, 2003.
  15. N. Anderson, Practical process research and development: a guide for organic chemists, Academic Press, 2012.
  16. S. Singh, M. Bakshi, Pharma. Tech., 4, 1-14, 2000.
  17. J. Roy, AAPs Pharm. SciTech, 3, 1-8, 2002.
  18. S. Klick, P. Muijselaar, J. Waterval, et al, Pharma. Tech., 29, 48-66, 2005.
  19. S. Ahuja, Assuring quality of drugs by monitoring impurities, Adv. Drug Del.Rev, 59, 3-11, 2007.
  20. N. Rahman, S. Azmi, H. Wu, Accr. Qual.Ass, 11, 69-74, 2006.
  21. D. Jacobson-Kram, T. McGovern, Adv. Drug Del.Rev, 59, 38-42, 2007.
  22. J. Kovaleski, B. Kraut, A. Mattiuz, M. Giangiulio, G. Brobst, W. Cagno, P. Kulkarni, T. Rauch, 59, 1, 56-63, 2007.
  23. S. Bari, B. Kadam, Y. Jaiswal, A. Shirkhedkar, Eur.J.Anal.Chem, 2, 32- 53, 2007.
  24. S. Poornachary, National University of Singapore Department, 2007.
  25. A. Worth, S. Lapenna, E. Piparo, A. Mostrag-Szlinchtyng, R. Serafimova, Publications Office, 2010.
  26. H. Hatakka, Lappeenranta University of Technology, 2010.
  27. D. Robinson, Org. Process Res. Dev, 14, 946-959, 2010.
  28. A. Ayre, D. Varpe, R. Nayak, N. Vasa, Adv. Res. Pharm.Bio, 1, 6-90, 2011.
  29. S. Pawale, S. Saley, S, D. Mundhada, S. Tilloo, J. Chem. Pharma. Res, 1, 227-1237, 2012.
  30. R. Singh, Z. Rehman, J. Pharma. Edu. Res, 3, 54-64, 2012.
  31. M. Blessy, R. Patel, P. Prajapati, Y. Agrawal, J.Pharma.Anal, 3, 159-165, 2014.
  32. S. Kumar, P. Kumar, A. Ajitha, R. Reddy, R. Maheshwar, Inter. J. Pharma. Res.Anal, 47-57, 2014.
  33. P.Venkatesan, K.Valliappan, J. Pharm. Sci. & Res, 6, 7, 254-258, 2014.
  34. Y. Jiang , X.I. Jun-Ping, Y.A. Jian-Hong, Z.F. ZHANG, H.U. Chang-Qin, Z.R. Zhang, Chinese journal of natural medicines, 13,7, 498-506, 2015.
  35. S. Zaza, S.M. Lucini, F. Sciascia, V. Ferrone, R. Cifelli, G. Carlucci, M. Locatelli, Instrumentation Science & Technology, 43, 2, 182-196, 2015.
  36. V. Desfontaine, D. Guillarme, E. Francotte and L. Nováková, Journal of pharmaceutical and biomedical analysis, 113, 56-71, 2015.
  37. P.P. Patil, V.S. Kasture, International Journal of Pharmaceutical Chemistry, 5, 1, 1-10, 2015.
  38. B. Ramanchandran, Critical Review in Analytical Chemistry, 24-36, 2016.
  39. A. C. Kogawa, R.N. Herida, Salgado, Current Pharmaceutical Analysis, 12, 1, 18- 24, 2016.
  40. S. V. Saibaba, M. SatishKumar and B. Ram, European Journal o f Pharmaceutical and Medical Research, 3, 5, 2016.
  41. R. Solank, International Journal of Drug Research and Technology, 2, 3, 7, 2017.
  42. K. Wadekar, M. Bhalme, S. Rao, K. Reddy, L. Kumar, E. Balasubrahmanyam, Pharma. Tech, 36, 46-51, 2012.
  43. S. Vippagunta, H. Brittain, D. Grant, Adv.Drug Del.Rev, 481, 3-26, 2001.
  44. J. Mullin, Butterworth-Heinemann, 2001.
  45. K. Busch, M. Busch, Elsevier, 2011.
  46. M. Caira, Design Organic Solids, Springer, 163-208, 1998.
  47. M. Ottens, B. Lebreton, M. Zomerdijk, M. Rijkers, O. Bruinsma, L. van der Wielen, Ind. Eng.Chem.Res., 43, 7932-7938, 2004.
  48. X. Yang, G. Qian, X. Duan, X. Zhou, Impurity Effect of l-Valine on l-Alanine Crystal Growth. Cryst. Growth Des, 13 (2013) 1295-1300.
  49. M. Okamura, M. Hanano, S. Awazu, Chem. Pharm. Bul, 28, 578-584, 1980.
  50. M. Pikal, A. Lukes, J. Lang, K. Gaines, J. Pharm. Sci. 67, 767-773, 1978.
  51. A. Templeton, S. Byrn, R. Haskell, T. Prisinzano, Springer, 2015.
  52. H. Clarke, Crystal Engineering of Multi-Component Crystal Forms: The Opportunities and Challenges in Design, 2012.
  53. S. Reutzel-Edens,J. Bush, P. Magee, G. Stephenson, S. Byrn, Cry. Gro. Des, 3, 897-907, 2003.
  54. G. Zhang, D. Law, E. Schmitt, Y. Qiu, Adv. Drug Del. Rev. 56, 371-390, 2004.
  55. H. Tong, B. Shekunov, P. York, A. Phar. Res, 19,640-648, 2002.
  56. I. Wainer, Drug stereochemistry: analytical methods and pharmacology. CRC Press, 1993.
  57. S. Ahuja, S. Scypinski, Handbook of modern pharmaceutical analysis. Academic press, 2010.
  58. K. Pilaniya, H. Chandrawanshi, U. Pilaniya, P. Manchandani, P. Jain, N. Singh, Recent J. Adv. Pharm. Tech. Res. 1, 302, 2010.
  59. T. Eriksson, S. Björkman, P. Höglund, Eur.J. Clin. Pharm.57, 365-376, 2001.
  60. J. Roy, Elsevier, 2011.
  61. S. Chander, C. Monika, P. Rakesh, S. Archana, D. Mamta, Inter. J. Pharm. Inno., 1, 1-8, 2011.
  62. A. Peepliwala, C. Bonde, J. Biomed. Sci. Res. 2, 29-45, 2010.
  63. P. Jacobs, W. Dewe, A. Flament, M. Gibella, A. Ceccato, J.Pharma. Biomed. Anal.40, 294-304, 2006.
  64. C. B’Hymer, Pharm. Res, 20, 337-344, 2003.
  65. S. Görög, Elsevier, 2000.
  66. L. Dujourdy, V. Dufey, F, Besacier, et al, Foren. Sci. Intern, 177, 153- 161, 2008.
  67. W. Cheng, N. Poon, M. Chan, J.Foren.Sci, 48, 1249-1259, 2003.
  68. N. Stojanovska, M. Tahtouh, T. Kelly, A. Beavis, K. Kirkbride, Foren. Sci.Intern, 224, 8- 26, 2013.
  69. S. Görög, A. Laukó, B. Herényi, J.Pharma. Biomed. Ana, 6, 697-705, 1988.
  70. S.P. Chaudhari, P.S. Patil, Intern. J. Adv. Pharn. Bio. Chem., 1, 21-34, 2012.
  71. Food and Drug Administration for Intermediate release consumer media: 888- Info-FDA, May 6, 1998.
  72. S. Ahuja, Informa Health Care, 1998.
  73. J. Roy, M. Islam, A. Khan,et al, J. Pharm. Sci.90, 541-544, 2001.
  74. J. Roy, M. Mahmud, A. Sobhan, et al. Drug Dev.Ind.Pharm, 20, 2157- 2163, 1994.
  75. H.G. Brittain, Analytical Profiles of Drug Substances and Excipients, 29, 1-5, 2002.
  76. S. Baertschi, K. Alsante, R. Reed, CRC Press, 2011.
  77. C. Zhan, QSAR and Molec.Model. Stud. Heter. Drugs II. Springer 107- 159, 2006.
  78. D. Sriram, Medicinal chemistry. Pearson Education India, 2010.
  79. P. Reddy, S. Sait, K. Hotha, Ame. J. Pharm. Tech. Res, 2, 848-862, 2012.
  80. N. Barbarin, B. Tilquin, E. de Hoffmann, J. Chrom. A, 929, 51-61, 2001.
  81. A. Fulias, I. Ledeti, G. Vlase, et al, Chem. Cent. J, 7, 140, 2013.
  82. S. Yoshioka, V. Stella, Springer, 2000.
  83. M. Blessy, R. Patel, P. Prajapati, Y. Agrawal, J. Pharm. Ana,4, 159-165, 2014.
  84. R. Kumar, R. Singla, Impurities in Pharmaceutical Dosage Form: A Subject Matter of Great Concern. 2012.
  85. A. Kasal, M. Budesinsky, W. Griffiths, Ster. Ana. Springer, 27-161, 2010.
  86. R. Heacock, Chem. Rev, 59, 181-237, 1959.
  87. A. Gupta, J. Yadav, S. Rawat, M. Gandhi, Asi. J. Pharm. Anal., 1, 14-18, 2011.
  88. G. Boccardi, Drug.Pharm.Sci, 153, 205, 2005.
  89. S. Görög, Steroid analysis in the pharmaceutical industry: hormonal steroids, sterols, vitamins D, cardiac glycosides. E. Horwood, 1989.
  90. E. Marguí, C. Fontas, A. Buendía, M. Hidalgo, I. Queralt, J. Ana. Atom. Spectr, 24, 1253-1257, 2009.
  91. Use, C.f.M.P.f.H.; Guideline on the specification limits for residues of metal catalysts or metal reagents. London, Eur. Med. Agen, 2008.
  92. C. Vinod., V. Budhwaar A. Inter. J. Pharma. Biosci, 4, 54-70, 2015.
  93. D. H. Brummer, Life Sci. Tech. Sol. 31, 1-6, 2011.
  94. R. Chakole, M. Charde, J. Kumar, A. Welankiwar, Inter. J. Adv. Pharmaceut., 2, 34-39, 2013.
  95. K. Huynh-Ba, Pharmaceutical stability testing to support global markets, Sprin. Sci. Buss. Med, 2009.
  96. J. Piechocki, K. Thoma, Pharmaceutical photostability and stabilization technology. CRC Press, 2006.
  97. Guideline, I.H.T.; Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances. Q6A. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Geneva, Switzerland, 1999.
  98. M. R. Patel M. R. Patel, M, N, Patel, Inter. Res. J. Pharm. 2011.
  99. D. Saimalakondaiah, V. Kumar, T. Reddy, A. Ajitha, V. Rao, Inter. J. Pharm. Res. Rev,3, 46-57, 2014.
  100. L. Müller, R. Mauthe, C. Riley, et al, Reg. Toxic. Pharmaco, 44, 198- 211, 2006.
  101. D. Pierson, B. Olsen, D. Robbins, K. DeVries, D. Varie, Org. Proc. Res. Dev,13, 285-291, 2008.
  102. S. Prabu, T. Suriyaprakash, Inter.J. Pharmac. Sci. Rev.Res, 3, 266-71, 2010.
  103. J. Cazes, Analytical instrumentation handbook. CRC Press, 2004.
  104. R. Smith, M. Webb, Analysis of drug impurities, John Wiley & Sons, 2008.
  105. N. Gonnella, LC-NMR: Expanding the limits of structure elucidation, CRC Press, 2013.
  106. R. Maggio, N. Calvo, S. Vignaduzzo, T. Kaufman, J. Pharm. Biomed. Ana.,101, 102-122, 2014.
  107. S. Hiriyanna, K. Basavaiah, J. Braz. Chem. Soc.,19, 397-404, 2008.
  108. C. Riley, T. Rosanske, S. Riley, Newnes, 2013.
  109. K. Alsante, P. Boutros, M. Couturier, et al, J.Pharma.Sci, 93, 2296-2309, 2004.
  110. N. Pai, S. Sawant, Der. Pharma. Chem., 54, 274-281, 2013.
  111. S. Sait, G. Vasudevmurthy, M. Natarajan, V. Prasad, S. Reddy, J. Chem. Pharma. Res, 4, 6, 2012.
  112. A. Kumar, V. Ganesh, D. Rao, et al. J. Pharma.Biomed.Ana, 46, 792- 798, 2008.
  113. P. Gavin, B. Olsen, J. Pharma. Biomed.Anal, 46, 431-441, 2008.
  114. A. Kadav, D. Vora, J.Pharm. Biomed. Ana, 48, 120-126, 2008.
  115. L. Gupta, Spectrochim. Acta Part A: Molec. Biomol. Spectr, 97, 495-501, 2012.
  116. A. Mohan, M. Hariharan, E. Vikraman, G. Subbaiah, B. Venkataraman, D. Saravanan, J. Pharma. Biomed. Ana, 47, 183-189, 2008.
  117. A. Gaona-Galdos, P. García, M. Aurora-Prado, M. Santoro, E. Kedor- Hackmann, Talanta, 77, 673-678, 2008.
  118. P. Sun, X. Wang, L. Alquier, C. Maryanoff, J. Chromat. A, 117, 87-91, 2008.
  119. M. Shou, W. Galinada, Y. Wei, Q. Tang, R. Markovich, A. Rustum, J.Pharm.Biomed Ana,50, 356-361, 2009.
  120. P. Kalafut, R. Kučera, J. Klimeš, J. Sochor, J. Pharma. Biomed. Ana, 49, 1150-1156, 2009.
  121. P. Novak, P. Tepeš, M. Ilijaš, et al. J. Pharma. Biomed. Ana, 50, 68-72, 2009.
  122. R. Rao, P. Maurya, A. Raju, J. Pharma. Biomed. Ana, 4, 1287-1291, 2009.
  123. R. Bianchini, P. Castellano, T. Kaufman, Analyt. Chim. Act, 654, 141- 147, 2009.
  124. T. Raj, C. Bharathi, M. Kumar, et al. J. Pharma. Biomed. Ana, 49, 156- 162, 2009.
  125. B. Jancic-Stojanovic, A. Malenovic, D. Ivanovic, T. Rakic, M. Medenica, J. chromatogr. A, 1216, 1263-1269, 2009.
  126. U. Holzgrabe, C. Nap, S. Almeling, J. Chromatogr. A, 1217, 294-301, 2010.
  127. D. Tippa, N. Singh, Pelagia Research LibraryD. Pharm. Sin, 1, 113-121, 2010.
  128. B. Satheesh, K. Ganesh, D. Saravanan, Sci. Pharmac., 80, 329, 2012.
  129. G. Lehr, T. Barry, G. Petzinger, G. Hanna, S. Zito, J. Pharma. Biomed. Ana, 19, 373-38, 1999.
  130. P. Sajonz, Y. Wu, T. Natishan, N. McGachy, D. DeTora, J. Chrom. Sci, 44, 132-140, 2006.
  131. T. Raju, R. Seshadri, S. Arutla, T. Mohan, I. Rao, S. Nittala, Sci. Pharma, 81, 123, 2013.
  132. S. Guntupalli, U. Ray, N. Murali, et al, J. Pharm. Biomed.Ana, 88, 385- 390, 2014.
  133. D. Zhang, X. Song, J. Su, J. Pharma. Biomed. Ana, 99, 22-27, 2014.
  134. B. Sivakumar, R. Murugan, A. Baskaran, B. Khadangale, S. Murugan, U. Senthilkumar, Sci. Pharm., 81, 683, 2013.
  135. A. Darcsi, G. Tóth, J. Kökösi, S. Bni, J. Pharma. Biomed. Ana, 96, 272-277, 2014.
  136. K. Gadapayale, R. Kakde, V. Sarma, J. é Sep. Sci, 38, 218-230, 2015.
  137. N. Goswami, J. Adv. Pharm. Tech. Res, 5, 33, 2014.
  138. M. Łaszcz, M. Kubiszewski, L. Jedynak, et al, Mol, 18, 15344-15356, 2013.
  139. D. Zhang, X. Song, J. Su, J. Pharma. Biomed. Ana, 90, 27-34, 2014.
  140. Y. Zhou, W. Zhou, L. Sun, Q. Zou, P. Wei, P. OuYang, J. Sep. Sci., 37, 1248-1255, 2014.
  141. P. Zhu, W. Yang, L. Hong, et al, Ana, 107, 437-443, 2015.
  142. Q. Li, T. Tougas, K. Cohen, et al, J. Chrom. Sci, 38, 246-254, 2000.
  143. F. Qiu, D. Cobice, S. Pennino, M. Becher, D. Norwood, J. Liq. Chrom. Rel. Tech., 31, 2331-2336, 2008.SS
  144. Q. Li, T. Tougas, K. Cohen, et al, J. Chrom. Sci., 38, 246-254, 2000.
  145. S. Ertürk, E. Aktaş, L. Ersoy, S. Fıçıcıoğlu, J. Pharm. Biomed. Ana, 33, 1017-1023, 2003.
  146. H. Inoue,Y. Iwata, K. Kuwayama, J. Hea. Sci., 54, 615-62, 2008.
  147. P. Horvath, G. Balogh, J. Brlik, et al. J. Pharma. Biomed. Ana, 15, 1343- 1349, 1997.
  148. A. Muntean, Anal, 61, 6, 2013.
  149. Z. Fu, L. Wang, Y. Wang, Anal. Chim. Act, 638, 220-224, 2009.
  150. M. Hilhorst, G. Somsen, G. De Jong, J. Pharma. Biomed. Ana, 16, 1251- 1260, 1998.
  151. S. Ahuja, M. Jimidar, Capillary electrophoresis methods for pharmaceutical analysis, Elsevier, 2011.
  152. C. Flurer, Electrophoresis, 24, 4116-4127, 2003.
  153. P. Emaldi, S. Fapanni, A. Baldini, J. Chrom.A, 711, 339-346, 1995.
  154. G. Penalvo, E. Julien, H. Fabre, Chromatographia, 42, 159-164, 1996.
  155. C. Flurer, Electrophesis, 22, 4249-4261, 2001.
  156. Y. Li, A. Van Schepdael, E. Roets, J. Hoogmartens, J. Pharma. Biomed. Ana, 14, 1095-1099, 1996.
  157. M. Wedig, N. Novatchev, T. Worch, S. Laug, U. Holzgrabe, J. Pharma. Biomed. Ana, 28, 983-990, 2002.
  158. M. Khan, S. Sinha, M. Todkar, V. Parashar, K. Reddy, U. Kulkarni, Int. J. Pharm, 2, 128-134, 2011.
  159. E. Nicolas, T. Scholz, J. Pharma. Biomed. Ana, 16, 825-836, 1998.
  160. P. Kovaříková, K. Vávrová, K., Tomalová, et al. J. Pharma. Biomed. Ana, 48, 295-302, 2008.
  161. C. Walker, D. Cowan, V. James, J. Lau, A. Kicman, Stereochemistry, 743, 5-340, 2009.
  162. S. Chopra, M. Pendela, J. Hoogmartens, A. Van Schepdael, E. Adams, Talanta,100, 113-122, 2012.
  163. A. Protić, L. Zivanovic, M. Radišić, M. Lušević, J. Liq. Chrom. Rel. Techn, 34, 1014-1035, 2011.
  164. O. Denk, G. Skellern, D. Watson, J. Pharm. Pharmcol, 54, 87-98, 2002.
  165. M. Bragieri, A. Liverani, M. Zanotti, et al, J. Sep. Sci., 27, 89-95, 2004.
  166. L. Sridhar, P. Goutami, D. Darshan, K. Ramakrishna, R. Rao, S. Prabhakar, Anal. Methods, 6, 8212-8221, 2014.
  167. ] R. Rao, B. Ramachandra, R. Vali, S. Raju, J.Pharm.Biomed.Ana, 53, 833-842, 2010.
  168. G. Bansal, P. Maddhesia, Y. Bansal, Analyst, 136, 5218-5228, 2011.
  169. Lemasson, S. Bertin, P. Hennig, H. Boiteux, E. Lesellier and C, West, Journal of Chromatography A, 1408, 217-226, 2015.
  170. C. Galea, D. Mangelings, H. Y. Vander, Journal of pharmaceutical and biomedical analysis, 111, 333-343, 2015.
  171. E. Lemansson, S. Bertin , P.Hennin and E. Lesellier, C. West, J. chromatograpy, 117-128 , 2016.
  172. Sandor Gorog , The importance and the challenges of impurity profiling in modern pharmaceutical analysis Vol. 25 , issue 8, 2006, 755-775.
  173. J. Alexander, T.F. Hooker, F.P. Tomasella, Journla of pharmaceutical and biomedical analysis Vol. 70, 77- 86, 2012.
  174. A. Dispas, V. Desfontaine, B. Andri, P. Lebrun, D. Kotoni, A. Clarke, Journal of Pharmaceutical and Biomedical analysis, 134, 170- 180, 2017.
  175. Guideline, I.H.T.; Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals S1A. International Conference on Harmonization1996.
  176. Guideline, H.T.; S2 (R1) Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), 1-26, 2008.
  177. A. Jouyban, H. Parsa, INTECH Open Access Publisher, 2012.
  178. D. Jacobson-Kram, T. McGovern, Adv. Drug Del. Rev.59, 38-42, 2007.
  179. K. Alsante, K. Huynh-Ba, S. Baertschi, et al. AAPS Pharm. Sci. Tech, 15, 237-251, 2014.
  180. L. Müller, R. Mauthe, C. Riley, et al, Regul.Toxic. Pharmacol, 44, 198- 211, 2006.
  181. C. Yadav, N. Pkm, S. Yadav, Asi. J. Pharma. Clin. Res, 8, 3, 2015.
  182. S. Glowienke, C. Hasselgren, Gen. Imp, 97-120, 2011.
  183. J. Ashby, R. Tennant, Mut. Res. Gene. Tox, 204, 17-115, 1988.
  184. M. O’Donovan, Gen. Imp.65-96, 2011.
  185. A. Giordani, W. Kobel, H. Gally, Eur. J. Pharm. Sci, 43, 1-15, 2011.
  186. A. Teasdale, D. Elder, S. Chang, S.Wang, R. Thompson, N. Benz, H. Ignacio, S. Flores, Org. Proc. Res. Develop, 17, 221-230, 2013.
  187. P. Singh, M. Pande, L. Singh, R. Tripathi, Inter. Res. J. Pharm. Appl. Sci, 3, 74-80, 2013.
  188. T. Rogers, K. Milkman, K. Volpp, JAMA, 311, 2065-2066, 2014.
  189. Organization, W.H.Environmental health criteria. World Health Organization, 2002.
  190. Epa, U.; Integrated Risk Information System (IRIS). EPA, 1999.
  191. E. BOARD, International Programme on Chemical Safety (IPCS).1992.
  192. S. Niazi, Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products. CRC press, 2009.

Copyright @2019 | Designed by: Open Journal Systems Chile Logo Open Journal Systems Chile Support OJS, training, DOI, Indexing, Hosting OJS

Code under GNU license: OJS PKP