Formulating Weakly Basic HCl Salts: Relative Ability of Common Excipients to Induce Disproportionation and the Unique Deleterious Effects of Magnesium Stearate

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• 作者：Christopher T. John (1)
  Wei Xu (1)
  Lisa K. Lupton (1)
  Paul A. Harmon (1)
  
• 关键词：deliquescent ; disproportionation ; excipient induced ; HCl salt ; Magnesium stearate
• 刊名：Pharmaceutical Research
• 出版年：2013
• 出版时间：June 2013
• 年：2013
• 卷：30
• 期：6
• 页码：1628-1641
• 全文大小：643KB
• 参考文献：1. Lipinski CA. Poor aqueous solubility - An industry wide problem in drug discovery. Am Pharm Rev. 2002;5:82-.
  2. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44:235-9. CrossRef
  3. Gribbon P, Sewing A. High-throughput drug discovery: what can we expect from HTS? Drug Discov Today. 2005;10:17-2. CrossRef
  4. Keck CM, Kobierski S, Mauludin R, Müller RH. Second generation of drug nanocrystals for delivery of poorly soluble drugs: smartcrystals technology. Dosis. 2008;24:124-.
  5. Timpe C. Strategies for formulation development of poorly water soluble candidates - a recent perspective. Am Pharm Rev. 2007;10(3):104-.
  6. Fahr A, Liu X. Drug delivery strategies for poorly water-soluble drugs. Expert Opin Drug Deliv. 2007;4(4):403-6. CrossRef
  7. Hageman M. Solubility, solubilization and dissolution in drug delivery during lead optimization. In: Borchardt R, editor. Optimizing the “Drug Like-properties of leads in drug discovery, biotechnology: Pharmaceutical aspects, vol. IV. New York: Springer; 2006. p. 100-0.
  8. Porter CJ, Wasan KJ, Constantinides P. Lipid-based systems for enhanced delivery of poorly water soluble drugs. Adv Drug Deliv Rev. 2008;59:615-78. CrossRef
  9. Gao P, Morozowich W. Development of supersaturable self-emulsifying drug delivery system formulations for improving oral absorption of poorly soluble drugs. Expert Opin Drug Deliv. 2006;3:97-10. CrossRef
  10. Pole DL. Physical and biological considerations for the use of nonaqueous solvents in oral bioavailability enhancement. J Pharm Sci. 2008;97:1071-8. CrossRef
  11. Kesisoglou F, Panmai S, Wu Y. Application of nanoparticles in oral delivery of immediate release formulations. Curr Nanosci. 2007;3:183-0. CrossRef
  12. Merskio-Liversidge EM, Liversidge GG. Drug nanoparticles: formulating poorly water soluble compounds. Toxicol Pathol. 2008;36:43-. CrossRef
  13. Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo WJ, Nightingale JAS. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm. 2008;5(6):1013-. CrossRef
  14. Maurin MB, Grant DJW, Stahl PH. The physicochemical background: Fundamentals of ionic equilibria. In: Stahl PH, Wermuth CG, editors. Handbook of pharmaceutical salts: Properties, selection, and use. New York: Wiley-VCH; 2002. p. 9-8.
  15. Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007;59:603-6. CrossRef
  16. Rohrs BR, Thamann TJ, Gao P, Stelzer DJ, Bergren MS, Chao RS. Tablet dissolution affected by a moisture mediated solid-state interaction between drug and disintegrant. Pharm Res. 1999;16:1850-. CrossRef
  17. Bogardus JB, Blackwood RK. Solubility of doxycycline in aqueous solution. J Pharm Sci. 1979;68(2):188-4. CrossRef
  18. Guerrieri P, Taylor LS. Role of salt and excipient properties on disproportionation in the solid-state. Pharm Res. 2009;26(8):2015-6. CrossRef
  19. Stephenson GA, Aburub A, Woods TA. Physical stability of salts of weak bases in the solid-state. J Pharm Sci. 2011;100(5):1607-7. CrossRef
  20. Serajuddin ATM, Jarowski CI. Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical acids and their sodium salts. Part 2. Salicylic acid, theophylline, and benzoic acid. J Pharm Sci. 1985;74:148-4. CrossRef
  21. Adeyeye M. C. and Brittain H.G. (eds.). Preformulation in Solid Dosage Form Development, Informa Healthcare, 2008.
  22. Govindarajam R, Zinchuk A, Hancock B, Shalaev E, Suryanarayanan R. Ionization states in the microenvironment of solid dosage forms: effect of formulation variables and processing. Pharm Res. 2006;23(10):2454-8. CrossRef
  23. Zannou EA, Ji Q, Joshi YM, Serajuddin ATM. Stabilization of the maleate salt of a basic drug by adjustment of microenvironmental pH in solid dosage form. Int J Pharm. 2007;337(1-):210-. CrossRef
  24. Scheef CA, Oelkrug D, Schmidt PC. Surface acidity of solid pharmaceutical excipients III: excipients for solid dosage forms. Eur J Pharm Biopharm. 1998;46(2):209-3. CrossRef
  25. Glombitza BW, Oelkrug D, Schmidt PC. Surface acidity of solid pharmaceutical excipients I. Determination of the surface acidity. Eur J Pharm Biopharm. 1994;40:289-3.
  26. Pudipeddi M, Zannou EA, Vasanthavada M, Dontabhaktuni A, Royce AE, Joshi YM, / et al. Measurement of surface pH of pharmaceutical solids: a critical evaluation of indicator dye-sorption method and its comparison with slurry pH method. J Pharm Sci. 2008;97:1831-2. CrossRef
  27. Merritt JA, Viswanath SK, Stephenson GA. Implementing quality by design in pharmaceutical salt selection: a modeling approach to understanding disproportionation. Pharm Res. 2013;30:203-.
  28. Swaminathan V., Kildsig O., An Examination of the moisture sorption characteristics of Commercial Magnesium Stearate. / AAPS PharmSciTech. 2001; 2(4) article 28.
  29. Kararli TT, Needham TE, Seul CJ, / et al. Solid-state interaction of magnesium oxide and ibuprofen to form a salt. Pharm Res. 1989;6:804. CrossRef
  30. Serajuddin ATM, Thakur AB, Ghosal RN, Fakes MG, Ranadive SA, Morris KR, / et al. Selection of solid dosage form composition throughdrug-excipient compatability testing. J Pharm Sci. 1999;88:696-04. CrossRef
  31. Chen D, Haugstad G, Li ZJ, Suryanarayanan R. Water sorption induced transformations in crystalline solid surfaces: characterization by atomic force microscopy. J Pharm Sci. 2010;99(9):4032-3.
  32. Ghosal S, Verdaguer A, Hemminger JC, Salmeron M. / In situ study of water- induced segregation of bromide in bromide-doped sodium chloride by scanning polarization forcemicroscopy. J Phys Chem. 2005;109:4744-. CrossRef
  33. Colchero AGJ, Luna M, Gómez-Herrero J, Baro AM. Adsorption of water on solid surfaces studied by scanning force microscopy. Langmuir. 2000;16:5086-2. CrossRef
  34. Rahaman A, Grassian VH, Margulis CJ. Dynamics of water adsorption onto a calcite surface as a function of relative humidity. J Phys Chem. 2008;112:2109-5.
  35. Greenspan L. Humidity fixed points of binary saturated aqueous solutions. J Res Natl Bur Stan. 1977;81A:89-6. CrossRef
  36. Tang IN, Munkelwitz HR, Davis JG. Aerosol growth studies. IV. Phase transformation of mixed salt aerosols in a moist atmosphere. J Aerosol Sci. 1978;9(6):505-1. CrossRef
  37. Cantrell W, McCrory C, Ewing G. Nucleated deliquescence of salt. J Chem Phys. 2002;116(5):2116-0. CrossRef
  38. Mauer LJ, Taylor LS. Water-solids interactions: deliquescence. Annu Rev Food Sci Technol. 2010;1:41-3. CrossRef
  
• 作者单位：Christopher T. John (1)
  Wei Xu (1)
  Lisa K. Lupton (1)
  Paul A. Harmon (1)
  
  1. West Point Analytical Sciences, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania, 19486, USA
  
• ISSN：1573-904X

文摘

Purpose Nine common excipients were examined to determine their ability to cause disproportionation of the HCl salt of a a weakly basic compound. The goal was to determine which excipients were problematic and correlate the results to known properties such as surface pH, slurry pH, or molecular structure. Such a correlation enables a general, simple excipient selection process. Methods Binary compacts and “pseudo formulations-are studied after stressing at 40°C/75%RH and 40°C/35% RH for up to 28?days. Near-Infrared (NIR) and X-Ray powder diffraction (XRPD) measurements monitored the conversion of the HCl salt to the free base. Results The excipients which induced measureable disproportionation were magnesium stearate, sodium croscarmellose, and sodium stearyl fumarate. Magnesium stearate induced the most extensive and rapid disproportionation at 40°C/75%RH and 40°C/35%RH. Samples containing magnesium stearate showed a unique and significant water uptake above 31%RH. Conclusions The problematic excipients are best explained by the proton accepting capacity of excipient carboxylate groups which have pKa’s higher than the pHmax of the drug salt. Alternative lubricants and disintegrants are suggested and a simple excipient screening process is proposed. Magnesium stearate was the most deleterious excipient for HCl salts due to the formation of the deliquescent salt magnesium chloride.