title: Chemical drug stability in lipids, modified lipids, and polyethylene oxide-containing formulations.
abstract: To critique the stability complications seen in formulating poorly water-soluble, problematic drugs in lipids, modified lipids, and polyethylene oxide solvents and surfactants in hard and soft gelatin capsules as well as some parenterals, a literature search was performed and personal experiences, and those of colleagues, collated. The literature is replete with examples of molecules undergoing rapid oxidative degradation in the presence of polyethylene oxide based solvents and surfactants as well as in the presence of unsaturated lipids. More recently appreciated is instability caused by the reaction of amine and amide drugs, with formaldehyde, formic acid found in many of these solvents as impurities and other degradation byproducts of the solvents themselves. One would expect acylation and transacylation reactions to be more common than reported but the literature has some good examples. An added complexity is occasionally seen with the use of hard and soft gelatin capsules with these solvents. The chemical stability of drugs in liquid and semi-solid formulations in the presence of lipids, modified lipids, and polyoxyethylene oxide-based solvents and surfactants can be complex, further exacerbated by the use of gelatin capsules, and can lead to a plethora of degradation pathways often not seen when the same drugs are formulated in solid dosage forms.
authors: Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas, 66047, USA, stella@ku.edu.
authors: Valentino J
authors: VJ
authors: Stella
mesh_terms: D000215:Acylation; D000641:Ammonia / Q000737:chemistry; D002214:Capsules / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D005780:Gelatin / Q000737:chemistry; D008055:Lipids / Q000737:chemistry*; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D002214:Capsules; D005079:Excipients; D008055:Lipids; D004364:Pharmaceutical Preparations; D011092:Polyethylene Glycols; D000641:Ammonia; D005780:Gelatin
references: J Anal Toxicol. 2001 Mar;25(2):88-92
references: 11300512
references: J Pharm Biomed Anal. 2007 Apr 11;43(5):1638-46
references: 17224256
references: J Pharm Sci. 2008 Apr;97(4):1499-507
references: 17879378
references: J Pharm Sci. 1984 Oct;73(10):1414-7
references: 6502492
references: J Pharm Sci. 2008 Mar;97(3):1224-35
references: 17680660
references: Chem Pharm Bull (Tokyo). 2009 Oct;57(10):1096-9
references: 19801864
references: Pharm Res. 2012 Oct;29(10):2660-83
references: 22707362
references: J Pharm Sci. 2001 Mar;90(3):253-69
references: 11170019
references: J Pharm Sci. 1994 Jul;83(7):915-21
references: 7965669
references: J Pharm Biomed Anal. 2009 Jan 15;49(1):11-7
references: 18996664
references: J Pharm Sci. 2006 Nov;95(11):2473-85
references: 16886199
references: Pharm Res. 1994 Jul;11(7):1060-4
references: 7937549
references: J Chromatogr A. 2007 Aug 10;1160(1-2):299-305
references: 17586516
references: J Pharm Biomed Anal. 2007 Jan 4;43(1):142-50
references: 16901672
references: J Pharm Sci. 2012 Sep;101(9):3305-18
references: 22610374
references: J Pharm Sci. 2007 Jan;96(1):106-16
references: 16917844
references: Pharm Dev Technol. 2004;9(2):189-95
references: 15202578
references: Pharm Res. 1993 Jul;10(7):1076-82
references: 8378251
references: Pharmazie. 2011 Sep;66(9):666-71
references: 22026121
references: J Pharm Sci. 2011 May;100(5):1773-82
references: 21374613
references: J Chromatogr Sci. 2002 Mar;40(3):170-7
references: 11954655
references: J Pharm Sci. 1978 Oct;67(10):1375-7
references: 702283
references: Pharm Res. 1994 Dec;11(12):1704-6
references: 7899231
references: Eur J Pharm Sci. 2006 Jun;28(3):233-42
references: 16650738
references: J Pharm Sci. 2008 Aug;97(8):3100-8
references: 17963215
references: J Pharm Sci. 2003 Dec;92(12):2411-8
references: 14603486
references: J Pharm Biomed Anal. 2010 Nov 2;53(3):745-50
references: 20627436
references: Biomaterials. 2002 Nov;23(21):4241-8
references: 12194527