Soft gelatin capsules (softgels)

Journal of Pharmaceutical Sciences

Volumn 99, Issue 10, 2010, Pages 4107-4148

  Gullapalli, Rampurna Prasad ^a  

^a ELAN PHARMACEUTICALS   (United States)

Author keywords

Bioavailability; Chemical stability; Cross linking; Dissolution; Encapsulation; Formulation; Physical stability; Poorly soluble; Soft gelatin capsule; Softgel

Indexed keywords

CAPTEX; GELATIN; MIGLYOL; UNCLASSIFIED DRUG;

DRUG ABSORPTION; DRUG CAPSULE; DRUG DOSAGE FORM; DRUG MANUFACTURE; DRUG PENETRATION; DRUG SOLUBILITY; REVIEW;

EID: 77957335795     PISSN: 00223549     EISSN: 15206017     Source Type: Journal    
DOI: 10.1002/jps.22151     Document Type: Review

References (319)

1. Shah VP, Noory A, Noory C, McCullough B, Clarke S, Everett R, Naviasky H, Srinivasan BN, Fortman D, Skelly JP. 1995. In vitro dissolution of sparingly water-soluble drug dosage forms. Int J Pharm 125:99-106.
2. Crowley PJ, Martini LG. 2004. Physicochemical approaches to enhancing oral absorption. Pharm Technol Eur 16:18-27.
3. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. 1997. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3-25.
4. Lipinski C. 2003. Physicochemical properties in drug design/development. 2nd International Drug Discovery and Development Summit: Novel Concepts and Technologies to Accelerate Drug Development. Honolulu, HI.
5. Agharkar S, Lindenbaum S, Higuchi T. 1976. Enhancement of solubility of drug salts by hydrophilic counter-ions: Properties of organic salts of an anti-malarial drug. J Pharm Sci 65:747-749.
6. Bastin RJ, Bowker MJ, Slater BJ. 2000. Salt selection and optimisation procedures for pharmaceutical new chemical entities. Org Proc Res Dev 4:427-435.
7. Serajuddin ATM. 2007. Salt formation to improve drug solubility. Adv Drug Deliv Rev 59:603-616.
8. Dannenfelser R, He H, Joshi Y, Bateman S, Serajuddin ATM. 2004. Development of clinical dosage forms for a poorly water soluble drug I: Application of polyethylene glycol-polysorbate 80 solid dispersion carrier system. J Pharm Sci 93:1165-1175.
9. Crew MD, Curatolo WJ, Friesen DT, Gumkowski MJ, Lorenz DA, Nightlingale JAS, Ruggeri RB, Shanker RM. 2007. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors. US Patent Application 2007/0282009.
10. Stella VJ, Nti-Addae KW. 2007. Prodrug strategies to overcome poor water solubility. Adv Drug Deliv Rev 59:677-694.
11. Merisko-Liversidge E, Liversidge GG, Cooper ER. 2003. Nanosizing: A formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci 18:113-120.
12. Kipp JE. 2004. The role of solid nanoparticle technology in the parenteral delivery of poorly water-soluble drugs. Int J Pharm 284:109-122.
13. Kesisoglou F, Panmai S, Wu Y. 2007. Nanosizing-oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev 59:631-644.
14. Hauss DJ. 2007. Oral lipid-based formulations. Adv Drug Deliv Rev 59:667-676.
15. Strickley RG. 2004. Solubilizing excipients in oral and injectable formulations. Pharm Res 21:201-230.
16. Gumkowski MJ, Fournier LA, Tierney NK, Curatolo WJ. 1994. Improved bioavailability through use of soft gelatin capsule formulations of terlakiren, a tripeptide rennin inhibitor. Pharm Res 11:S-286.
17. Yu L, Bridgers A, Polli J, Vickers A, Long S, Roy A, Winnike R, Coffin M. 1999. Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability. J Pharm Sci 16:1812-1817.
18. Hugger ED, Novak BL, Burton PS, Audus KL, Borchardt RT. 2002. A comparison of commonly used polyethoxylated pharmaceutical excipients on their ability to inhibit P-glycoprotein activity in vitro. J Pharm Sci 91:1991-2002.
19. Rege BD, Kao JP, Polli JE. 2002. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci 16:237-246.
20. Seeballuck F, Ashford MB, O'Driscoll CM. 2003. The effects of pluronics block copolymers and cremophor EL on intestinal lipoprotein processing and the potential link with P-glycoprotein in Caco-2 cells. Pharm Res 20:1085-1092.
21. Wandel C, Kim RB, Stein M. 2003. "Inactive" excipients such as Cremophor can affect in vivo drug disposition. Clin Pharmacol Ther 73:394-396.
22. Cornaire G, Woodley J, Hermann P, Cloarec A, Arellano C, Houin G. 2004. Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int J Pharm 278:119-131.
23. Shono Y, Nishihara H, Matsuda Y, Furukawa S, Okada N, Fujita T, Yamamoto A. 2004. Modulation of intestinal P-glycoprotein function by cremophor EL and other surfactants by an in vitro diffusion chamber method using the isolated rat intestinal membranes. J Pharm Sci 93:877-885.
24. Pole DL. 2008. Physical and biological considerations for the use of nonaqueous solvents in oral bioavailability enhancement. J Pharm Sci 97:1071-1088.
25. Scherer RP. 1933. Capsule making machine. Canadian Patent CA333007.
26. Scherer RP. 1943. Capsulating mechanism. Canadian Patent CA416849.
27. Scherer RP. 1943. Capsulating mechanism. Canadian Patent CA416850.
28. Scherer RP. 1944. Capsule forming apparatus. Canadian Patent CA422183.
29. Scherer RP. 1948. Capsulating machine. Canadian Patent CA453243.
30. Holland NJ, Tidy GB. 2004. Gelatin encapsulation techniques. US Patent 6,769,226.
31. Carlson GH, Scherer RP. 1960. Process for improving adhesivity of gelatin used in preparing capsules by continuously agitating the gelatin until casting. US Patent 2,928,128.
32. Schmidt W. 1999. Method for the purification and recovery of waste gelatin using diafilters. US Patent 5,945,001.
33. Stanley JP. 1986. Soft gelatin capsules. In: Lachman L, Lieberman HA, Kanig JL, editors. The theory and practice of industrial pharmacy. 3rd edition. Philadelphia: Lea and Febiger. pp. 398-412.
34. Ling WC. 1978. Thermal degradation of gelatin as applied to processing of gel mass. J Pharm Sci 67:218-223.
35. Alex R, Gerhards J, Kraemer-Pittrof I, Oeschger R, Rades T. 2000. Process for the manufacture of liquid filled capsules. WO/2000/028942.
36. Scherer RP. 1958. Film forming device. US Patent 2,842,797.
37. Brox W, Meinzer A, Zande H. 2006. Soft gelatin capsule manufacture. US Patent 7,078,054.
38. Scherer RP. 1958. Method for drying gelatin capsules. US Patent 2,851,786.
39. Seager H. 1985. Soft gelatin capsules: A solution to many tableting problems. Pharm Technol 9:84-104.
40. Brox W. 1988. Soft gelatin capsules and methods for their production. US Patent 4,744,988.
41. Brox W. 1988. Gelatin capsule. US Patent 4,780,316.
42. Steele D, Dietel G. 1993. Softgel manufacturing process. US Patent 5,200,191.
43. Hom FS, Veresh SA, Ebert WR. 1975. Soft gelatin capsules II. Oxygen permeability study of capsule shells. J Pharm Sci 64:851-857.
44. Kozlov PV, Burdygina GI. 1983. The structure and properties of solid gelatin and the principles of their modification. Polymer 24:651-666.
45. Yakimets I, Wellner N, Smith AC, Wilson RH, Farhat I, Mitchell J. 2005. Mechanical properties with respect to water content of gelatin films in glassy state. Polymer 46:12577-12585.
46. Marques MRC, Cole E, Kruep D, Gray V, Murachanian D, Brown WE, Giancaspro GI. 2009. Liquid-filled gelatin capsules. Pharmacopeial Forum 35:1029-1041.
47. Reich VG. 1995. Effect of drying conditions on structure and properties of gelatin capsules: Studies with gelatin films. Pharm Ind 57:63-67.
48. Julius K, Bagusche C. 1998. Method and apparatus for sorting capsules. US Patent 5,819,953.
49. Benford S, Scherer RP, Moreland ST. 1956. Machine for branding gelatine capsules. Canadian Patent CA530590.
50. Jimerson RF. 1986. Soft gelatin capsule update. Drug Dev Ind Pharm 12:1133-1144.
51. Wilkinson PK, Hom FS. 1990. Softgels: Manufacturing considerations. In: Tyle P, editor. Specialized drug delivery systems - Manufacturing and production technology. New York: Marcel Dekker, Inc. pp. 409-449.
52. Gao P, Charton M, Morzowich W. 2006. Speeding development of poorly soluble/poorly permeable drugs by SEDDS/SSEDDS formulations and prodrugs (Part II). Am Pharm Rev 9:16-23.
53. Amidon GL, Lennernas H, Shah VP, Crison JR. 1995. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12:413-420.
54. Nazzal S, Wang Y. 2001. Characterization of soft gelatin capsules by thermal analysis. Int J Pharm 230:35-45.
55. Dhabhar DJ. 1996. Process for reducing the precipitation of difficulty soluble pharmaceutical actives. US Patent 5,484,606.
56. Dhabhar DJ. 1996. Concentrated acetaminophen solution compositions. US Patent 5,510,389.
57. Cao N, Yang X, Fu Y. 2009. Effects of various plasticizers on mechanical and water vapor barrier properties of gelatin films. Food Hydrocolloids 23:729-735.
58. Tralhao AML, Watkinson AC, Brain KR, Hadgraft J, Armstrong NA. 1995. Use of ATR-FTIR spectroscopy to study the diffusion of ethanol through glycerogelatin films. Pharm Res 12:572-575.
59. Kim JW, Shin HJ, Yang SG. 1997. Cyclosporine-containing pharmaceutical composition. WO/1997/036610.
60. Moreton RC, Armstrong NA. 1998. The effect of film composition on the diffusion of ethanol through soft gelatin films. Int J Pharm 161:123-131.
61. Mallis GI, Schmidt DH, Lindenbaum J. 1975. Superior bioavailability of digoxin solution in capsules. Clin Pharnac Ther 18:761-768.
62. Gardella LA, Kesler H. 1977. Gelatin-encapsulated digoxin solutions and method of preparing the same. US Patent 4,002,718.
63. Ghirardi P, Catenazzo G, Mantero O, Merotti GC, Marzo A. 1977. Bioavailability of digoxin in a new soluble pharmaceutical formulation in capsules. J Pharm Sci 66:267-269.
64. Johnson BF, Smith G, French J. 1977. The comparability of dosage regimens of lanoxin tablets and lanoxicaps. Br J Clin Pharmacol 4:209-211.
65. Grainger N. 1980. Pharmaceutical compositions. US Patent 4,198,391.
66. Launchbury AP, Morton FSS, Rowe D. 1991. Pharmaceutical Compositions. WO/1991/007950.
67. Erlich L, Yu D, Pallister DA, Levinson RS, Gole DG, Wilkinson PA, Erlich RE, Reeve LE, Viegas TX. 1999. Relative bioavailability of danazol in dogs from liquid-filled hard gelatin capsules. Int J Pharm 179:49-53.
68. Groves MJ, Bassett B, Sheth V. 1984. The solubility of 17 β-oestradiol in aqueous polyethylene glycol 400. J Pharm Pharmacol 36:799-802.
69. Serajuddin ATM, Sheen PC, Augustine MA. 1986. Water migration from soft gelatin capsule shell to fill material and its effect on drug solubility. J Pharm Sci 75:62-64.
70. Aungst BJ, Nguyen NH, Rogers NJ, Rowe SM, Hussain MA, White SJ, Shum L. 1997. Amphiphilic vehicles improve the oral bioavailability of a poorly soluble HIV protease inhibitor at high doses. Int J Pharm 156:79-88.
71. Pouton CW. 2000. Lipid formulations for oral administration of drugs: Non-emulsifying, self-emulsifying and 'self-microemulsifying' drug delivery systems. Eur J Pharm Sci 11:S93-S98.
72. Roy A, Winnike R, Long S, Rhodes C, Bao Z, Robertson G. 2001. Development of a soft gelatin capsule formulation of a poorly soluble compound X using a self emulsifying delivery system. In: Oral Drug Absorption: A Renaissance, B.T. Saint-Priest, Cedex, France: Gattefossé No 94. Gattefossé Corporation. pp. 141-149.
73. Sukuru K. 2007. Hydrophilic vehicle-based dual controlled release matrix system. WO/2007/050975.
74. Cody SL, Devlin BT, Dubek J, Hoy MR. 1999. Fill material for soft gelatin pharmaceutical dosage form. US Patent 5,919,481.
75. Cody SL, Hoy MR, Walter EJ. 1997. Gelling agent for polyethylene glycol. US Patent 5,660,859.
76. Chadwick VS, Phillips SF, Hofmann AF. 1977. Measurements of intestinal permeability using low molecular weight polyethylene glycols (PEG-400). 2. Application to normal and abnormal permeability states in man and animals. Gastroenterology 73:247-251.
77. Chadwick VS, Phillips SF, Hofmann AF. 1977. Measurements of intestinal permeability using low molecular weight polyethylene glycols (PEG 400). I. Chemical analysis and biologic properties of PEG 400. Gastroenterology 73:241-246.
78. Basit AW, Podczeck F, Newton JM, Waddington WA, Ell PJ, Lacey LF. 2002. Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine. Pharm Res 19:1368-1374.
79. Krugliak P, Hollander D, Ma TY, Tran D, Dadufalza VD, Katz KD, Le K. 1989. Mechanisms of polyethylene glycol 400 permeability of perfused rat intestine. Gastroenterology 97:1164-1170.
80. Shaffer CB, Critchfield FH. 1947. The absorption and excretion of the solid polyethylene glycols (carbowax compounds). J Am Pharm Assoc Sci Ed 36:152-157.
81. Shaffer CB, Critchfield FH, Nair JH III. 1950. The absorption and excretion of a liquid polyethylene glycol. J Am Pharm Assoc Sci Ed 39:340-344.
82. DiPiro JT, Michael KA, Clark BA, Dickson P, Tedesco FJ. 1986. Absorption of polyethylene glycol after administration of a PEG-electrolyte lavage solution. Clin Pharm 5:153-155.
83. Leung HW, Ballantyne B, Hermansky SJ, Frantz SW. 2000. Peroral subchronic, chronic toxicity and pharmacokinetic studies of a 100-kDa polymer of ethylene oxide (Polyox N-10) in the Fischer 344 rat. Int J Toxicol 19:305-312.
84. Fruijtier-Polloth C. 2005. Safety assessment on polyethylene glycols (PEGs) and their derivatives as used in cosmetic products. Toxicology 214:1-38.
85. Basit AW, Newton JM, Short MD, Waddington WA, Ell PJ, Lacey LF. 2001. The effect of polyethylene glycol 400 on gastrointestinal transit: Implications for the formulation of poorly-water soluble drugs. Pharm Res 18:1146-1150.
86. Schulze JDR, Waddington WA, Ell PJ, Parsons GE, Coffin MD, Basit AW. 2003. Concentration-dependent effects of polyethylene glycol 400 on gastrointestinal transit and drug absorption. Pharm Res 20:1984-1988.
87. Schulze JDR, Peters EE, Vickers AW, Staton JS, Coffin MD, Parsons GE, Basit AW. 2005. Excipient effects on gastrointestinal transit and drug absorption in beagle dogs. Int J Pharm 300:67-75.
88. Haruta S, Iwasaki N, Ogawara K, Higaki K, Kimura T. 1998. Absorption behaviour of orally administered drugs in rats treated with propantheline. J Pharm Sci 87:1081-1085.
89. Johnson BM, Charman WN, Porter CJH. 2002. An in vitro examination of the impact of polyethylene glycol 400, Pluronic P85, and vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine. AAPS PharmSci 4:1-13.
90. Yu MS, Hom FS, Chakrabarti S, Huang C, Patel M. 1991. Solvent system enhancing the solubility of pharmaceuticals for encapsulation. US Patent 5,071,643.
91. Morton FSS, Shelley R, Patel MS. 1994. Enhanced solubility pharmaceutical solutions. US Patent 5,376,688.
92. Shelley RS, Wei Y, Linkin D. 1996. Gelatin capsules containing a highly concentrated acetaminophen solution. US Patent 5,505,961.
93. Seager H. 1993. Soft gelatin capsule technology - A route to improved drug delivery. Pharm Mfg Rev 5:9-10.
94. Croome RJ. 1953. Acid and alkaline hydrolysis of gelatin. J Appl Chem 3:280-286.
95. Bindra DS, Williams TD, Stella VJ. 1994. Degradation of O6-benzylguanine in aqueous polyethylene glycol 400 (PEG 400) solutions: Concerns with formaldehyde in PEG 400. Pharm Res 11:1060-1064.
96. Argiriadi AA, Blank RG, Giamalva DH. 1995. Ibuprofen enhancing solvent system. US Patent 5,468,502.
97. Li G, Zheng X, Shelley R, Waranis RP. 2003. Acetaminophen (APAP) solubilization for softgels. AAPS Annual Meeting, Poster 2641.
98. Gullapalli RP. 2001. Ibuprofen-containing softgels. US Patent 6,251,426.
99. Kibbe AH. 2006. Povidone. In: Rowe RC, Sheskey PJ, Owen SC, editors. Handbook of pharmaceutical excipients. 5th edition. London: Pharmaceutical Press and Washington, DC: American Pharmacists Association. pp. 611-616.
100. Patel MS, Morton FSS, Seager H, Howard D. 1992. Factors affecting the chemical stability of carboxylic acid drugs in enhanced solubility system (ESS) softgel formulations based on polyethylene glycol (PEG). Drug Dev Ind Pharm 18:1-19.
101. Pouton CW. 2005. Formulation of poorly water-soluble drugs for oral administration. In: Drug Candidate Optimization, Formulation and Early Development, B.T. Gattefossé No 98. Saint-Priest, Cedex, France: Gattefossé Corporation. pp. 39-51.
102. Pouton CW. 2006. Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci 29:278-287.
103. Charman SA, Charman WN, Rogge MC, Wilson TD, Dutko FJ, Pouton CW. 1992. Self-emulsifying drug delivery systems: Formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharm Res 9:87-93.
104. Perlman ME, Murdande SB, Gumkowski MJ, Shah TS, Rodricks CM, Thornton-Manning J, Freel D, Erhart LC. 2008. Development of a self-emulsifying formulation that reduces the food effect for torcetrapib. Int J Pharm 351:15-22.
105. Porter CJH, Pouton CW, Cuine JF, Charman WN. 2008. Enhancing intestinal drug solubilization using lipid-based delivery systems. Adv Drug Deliver Rev 60:673-691.
106. MacGregor KJ, Embleton JK, Lacy JE, Perry EA, Solomon LJ, Seager H, Pouton CW. 1997. Influence of lipolysis on drug absorption from the gastro-intestinal tract. Adv Drug Delivery Rev 25:33-46.
107. Lacy JE, Embleton JE, Perry EA. 2000. Delivery systems for hydrophobic drugs. US Patent 6,096,338.
108. Sunesen VH, Vedelsdal R, Kristensen HG, Christrup L, Mullertz A. 2005. Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug. Eur J Pharm Sci 24:297-303.
109. Fleisher D, Li C, Zhou Y, Pao LH, Karim A. 1999. Drug, meal and formulation interactions influencing drug absorption after oral administration. Clinical implications. Clin Pharmacokinet 36:233-254.
110. Kossena GA, Charman WN, Wilson CG, O'Mahony B, Lindsay B, Hempenstall JM, Davison CL, Crowley PJ, Porter CJH. 2007. Low dose lipid formulations: Effects on gastric emptying and biliary Secretion. Pharm Res 24:2084-2096.
111. Lentz KA. 2008. Current methods for predicting human food effect. AAPS J 10:282-288.
112. Hernell O, Staggers JE, Carey MC. 1990. Physical-chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 2. Phase analysis and aggregation states of luminal lipids during duodenal fat digestion in healthy adult human beings. Biochemistry 29:2041-2056.
113. Staggers JE, Hernell O, Stafford RJ, Carey MC. 1990. Physical-chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 1. Phase behavior and aggregation states of model lipid systems patterned after aqueous duodenal contents of healthy adult human beings. Biochemistry 29:2028-2040.
114. Clement J. 1980. Intestinal absorption of triglycerols. Reprod Nutr Dev 20:1285-1307.
115. Nordskog BK, Phan CT, Nutting DF, Tso P. 2001. An examination of the factors affecting intestinal lymphatic transport of dietary lipids. Adv Drug Deliv Rev 50:21-44.
116. Charman WN, Stella VJ. 1986. Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules. Int J Pharm 34:175-178.
117. Nankervis R, Davis SS, Day NH, Shaw PN. 1995. Effect of lipid vehicle on the intestinal lymphatic transport of isotretinoin in the rat. Int J Pharm 119:173-181.
118. Nankervis R, Davis SS, Day NH, Shaw PN. 1996. Intestinal lymphatic transport of three retinoids in the rat after oral administration: Effect of lipophilicity and lipid vehicle. Int J Pharm 130:57-64.
119. Porter CJH. 1997. Drug delivery to the lymphatic system. Crit Rev Ther Drug Carrier Syst 14:333-393.
120. Porter CJH, Charman WN. 1997. Uptake of drugs into the intestinal lymphatics after oral administration. Adv Drug Deliv Rev 25:71-89.
121. Caliph SM, Charman WN, Porter CJH. 2000. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J Pharm Sci 89:1073-1084.
122. Fischler M, Frisch EP, Ortengren B. 1973. Plasma concentrations after oral administration of different pharmaceutical preparations of clomethiazole. Acta Pharm Suec 10:483-492.
123. Palin KJ, Bell GD, Wilson CG. 1984. The effect of oil on the absorption of probucol in the rat. J Pharm Pharmacol 36:85P.
124. Palin KJ, Wilson CG. 1984. The effects of different oils on the absorption of probucol in the rat. J Pharm Pharmacol 36:641-643.
125. Khoo SM, Shackleford DM, Porter CJH, Edwards GA, Charman WN. 2003. Intestinal lymphatic transport of halofantrine occurs after oral administration of a unit-dose lipid-based formulation to fasted dogs. Pharm Res 20:1460-1465.
126. Porter CJH, Kaukonen AM, Boyd BJ, Edwards GA, Charman WN. 2004. Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation. Pharm Res 21:1405-1412.
127. Khoo SM, Edwards GA, Porter CJH, Charman WN. 2001. A conscious dog model for assessing the absorption, enterocyte based metabolism, and intestinal lymphatic transport of halofantrine. J Pharm Sci 90:1599-1607.
128. Shiau YF, Popper DA, Reed M, Umstetter C, Capuzzi D, Levine GM. 1985. Intestinal triglycerides are derived from both endogenous and exogenous sources. Am J Physiol Gastrointest Liver Physiol 248:G164-G169.
129. Holm R, Porsgaard T, Porter CJH, Hoy CE, Edwards GA, Müllertz A, Kristensen HG, Charman WN. 2006. Lymphatic fatty acids in canines dosed with pharmaceutical formulations containing structured triacylglycerols. Eur J Lipid Sci Technol 108:714-722.
130. Zangenberg NH, Mullertz A, Kristensen HG, Hovgaard L. 2001. A dynamic in vitro lipolysis model II: Evaluation of the model. Eur J Pharm Sci 14:237-244.
131. Vonderscher J, Meinzer A. 1994. Rationale for the development of Sandimmune Neoral. Transplant Proc 26:2925-2927.
132. Reymond J, Sucker H. 1988. In vitro model for ciclosporin intestinal absorption in lipid vehicles. Pharm Res 5:673-676.
133. Reymond J, Sucker H, Vonderscher J. 1988. In vivo model for ciclosporin intestinal absorption in lipid vehicles. Pharm Res 5:677-679.
134. Kovarik JM, Mueller EA, Van Bree JB, Tetzloff W, Kutz K. 1994. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci 83:444-446. (Pubitemid 24224228)
135. Mueller EA, Kovarik JM, Van Bree JB, Tetzloff W, Grevel J, Kutz K. 1994. Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation. Pharm Res 11:301-304. (Pubitemid 24076228)
136. Mountfield RJ, Senepin S, Schleimer M, Walter I, Bittner B. 2000. Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450. Int J Pharm 211:89-92.
137. Grove M, Pedersen GP, Nielsen JL, Mullertz A. 2005. Bioavailability of seocalcitol. I. Relating solubility in biorelevant media with oral bioavailability in rats-effect of medium and long chain triglycerides. J Pharm Sci 94:1830-1838.
138. Grove M, Mullertz A, Nielsen JL, Pedersen GP. 2006. Bioavailability of seocalcitol II: Development and characterization of self-microemulsifying drug delivery systems (SMEDDS) for oral administration containing medium and long chain triglycerides. Eur J Pharm Sci 28:233-242.
139. Shan Y, Post N, Speer J, Flynn J, Gullapalli R, Agarwal R, Muffuid P. 2005. Investigation of non-aqueous vehicles for a poorly soluble compound intended for softgel dosage form development. AAPS Annual Meeting and Exposition, Nashville, TN. www.aapsj.org/abstracts/AM-2005/AAPS2005-000990.pdf.
140. Raikes M, Taylor N, Field C. 2009. Moisture sorption experiment on soft gel capsules containing a self-emulsifying drug delivery system. Am Pharm Rev 12:12-17.
141. Neisingh SE, Sam AP, de Nijs H. 1986. A dissolution method for hard and soft gelatin capsules containing testosterone undecanoate in oleic acid. Drug Dev Ind Pharm 12:651-663.
142. Ahmed HA, Infeld MH, Shah NH. 2000. Compositions of and process for producing isotretinoin having low particle size. WO/2000/25772.
143. Chopra SK, Makadia TT. 1991. Pharmaceutical capsules containing panetidine. US Patent 5,028,432.
144. Anderson NR, Gullapalli RP. 2005. β-Carboline pharmaceutical compositions. US Patent 6,841,167.
145. Craig DQM. 1996. The physical characterization of Gelucire 50/13. In: Semi-solid Formulations and Oral Absorption Enhancement, B.T. Gattefossé No 89. Gattefossé Corporation, Saint-Priest, Cedex, France. pp. 39-51.
146. Singhal D, Curatolo W. 2004. Drug polymorphism and dosage form design: A practical perspective. Adv Drug Deliv Rev 56:335-347.
147. Stahly GP. 2007. Diversity in single- and multiple-component crystals. The search for and prevalence of polymorphs and cocrystals. Cryst Growth Des 7:1007-1026.
148. Aguiar AJ, Krc J, Kinkel AW, Samyn JC. 1967. Effect of polymorphism on the absorption of chloramphenicol from chloramphenicol palmitate. J Pharm Sci 56:847-853.
149. Aguiar AJ, Zelmer JE. 1969. Dissolution behavior of polymorphs of chloramphenicol palmitate and mefanamic acid. J Pharm Sci 58:983-987.
150. Brice GW, Hammer HF. 1969. Therapeutic nonequivalence of oxytetracycline capsules. J Am Med Assoc 208:1189-1190.
151. Liebenberg W, de Villiers M, Wurster DE, Swanepoel E, Dekker TG, Lotter AP. 1999. The effect of polymorphism on powder compaction and dissolution properties of chemically equivalent oxytetracycline hydrochloride powders. Drug Dev Ind Pharm 25:1027-1033.
152. Chemburkar SR, Bauer J, Deming K, Spiwek H, Patel K, Morris J, Henry R, Spanton S, Dziki W, Porter W, Quick J, Bauer P, Donaubauer J, Narayanan BA, Soldani M, Riley D, McFarland K. 2000. Dealing with the impact of ritonavir polymorphs on the late stages of bulk drug process development. Org Process Res Dev 4:413-417.
153. Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J. 2001. Ritonavir: An extraordinary example of conformational polymorphism. Pharm Res 18:859-866.
154. Davis JD, Touitou E, Rubinstein A. 1990. Targeted enternal delivery system. US Patent 4,910,021.
155. Sobral PJA, Menegalli FC, Hubinger MD, Roques MA. 2001. Mechanical, water vapor barrier and thermal properties of gelatin based edible films. Food Hydrocolloids 15:423-432.
156. Singh S, Rama Rao KV, Venugopal K, Manikandan R. 2002. Alteration in dissolution characteristics of gelatin-containing formulations. A review of the problem, test methods, and solutions. Pharm Technol 26:36-58.
157. Chiou BS, Avena-Bustillos RJ, Shey J, Yee E, Bechtel PG, Imam SH, Glenn GM, Orts WJ. 2006. Rheological and mechanical properties of cross-linked fish gelatins. Polymer 47:6379-6386.
158. Price JC. 2006a. Gelatin. In: Rowe RC, Sheskey PJ, Owen SC, editors. Handbook of pharmaceutical excipients. 5th edition. London: Pharmaceutical Press and Washington, DC: American Pharmacists Association. pp. 295-298.
159. Eastoe JE, Leach AA. 1977. Chemical constitution of gelatin. In: Ward AG, Courts A, editors. The science and technology of gelatin. New York: Academic Press. pp. 91-92.
160. Bowman BJ, Ofner CM. 2002. Hard gelatin capsules. In: Gennadios A, editor. Protein-based films and coatings. Florida: CRC Press. pp. 367-392.
161. Hom FS, Veresh SA, Miskel JJ. 1973. Soft gelatin capsules I: Factors affecting capsule-shell dissolution rate. J Pharm Sci 62:1001-1006.
162. Ames WM. 1947. Heat degradation of gelatin. J Soc Chem Ind 66:279-284.
163. Courts A. 1954. The N-terminal amino acid residues of gelatin. 2. Thermal degradation. Biochem J 58:74-79.
164. Yannas JB, Tobolsky AV. 1964. Viscoelastic properties of plasticized gelatin films. J Phys Chem 68:3880-3882.
165. Marshall AS, Petrie SEB. 1980. Thermal transitions in gelatin and aqueous gelatin solutions. J Photographic Sci 28:128-134.
166. Fraga AN, Williams RJJ. 1985. Thermal properties of gelatin films. Polymer 26:113-118.
167. Pinhas MF, Blanshard JMV, Derbyshire W, Mitchell JR. 1996. The effect of water on the physicochemical and mechanical properties of gelatin. J Therm Anal 47:1499-1511.
168. Martucci JF, Ruseckaite RA, Vazquez A. 2006. Creep of glutaraldehyde-crosslinked gelatin films. Mater Sci Eng A 435-436: 681-686.
169. Coppola M, Djabourov M, Ferrand M. 2008. Phase diagram of gelatin plasticized by water and glycerol. Macromol Symp 273:56-65.
170. Ni BY, LeFaou A. 1993. Crystalline structure and moisture effects on deformation mechanisms of gelatin films under mode I stress field. Mater Res Soc Symp Proc (Biomol Mater) 292:229-234.
171. Reich VG. 1994. Action and optimization of plasticizers in soft gelatin capsules. Pharm Ind 56:915-920.
172. Reich G. 1996. Effect of sorbitol specification on structure and properties of soft gelatin capsules. Pharm Ind 58:941-946.
173. Sanchez AC, Popineau Y, Mangavel C, Larre C, Gueguen J. 1998. Effect of different plasticizers on the mechanical and surface properties of wheat gliadin films. J Agric Food Chem 46:4539-4544.
174. Vanin FM, Sobral PJA, Menegalli FC, Carvalho RA, Habitante AMQB. 2005. Effects of plasticizers and their concentrations on thermal and functional properties of gelatin-based films. Food Hydrocolloids 19:899-907.
175. Thomazine M, Carvalho RA, Sobral PJA. 2005. Physical properties of gelatin films plasticized by blends of glycerin and sorbitol. J Food Sci 70:172-176.
176. Vrana A. 2003. Reduction of gelatin cross-linking. WO/2003/103582.
177. Bergo P, Sobral PJA. 2007. Effects of plasticizer on physical properties of pigskin gelatin films. Food Hydrocolloids 21:1285-1289.
178. Cuq B, Gontard N, Cuq JL, Guilbert S. 1997. Selected functional properties of fish myofibrillar protein-based films as affected by hydrophilic plasticizers. J Agric Food Chem 45:622-626. (Pubitemid 127483678)
179. Oses J, Fernandez-Pan I, Mendoza M, Mate JI. 2009. Stability of the mechanical properties of edible films based on whey protein isolate during storage at different relative humidity. Food Hydrocolloids 23:125-131.
180. Cherian G, Gennadios A, Weller C, Chinachoti P. 1995. Thermomechanical behavior of wheat gluten films: Effect of sucrose, glycerin, and sorbitol. Cereal Chem 72:1-6.
181. Laohakunjit N, Noomhorm A. 2004. Effect of plasticizers on mechanical and barrier properties of rice starch film. Starch/Starke 56:348-356.
182. Sakanaka LS, Sobral PJA, Menegalli FC. 2001. Proceeding of a meeting on cross-linked gelatin biofilms mechanical and permeability properties as affected by storage conditions. III Congreso Ibero-Americano de Ingenieria de Alimentos. Valencia, Espana: Press of the Politechnique University. pp. 197-202.
183. Moreton RC, Armstrong NA. 1995. Design and use of an apparatus for measuring diffusion through glycerogelatin films. Int J Pharm 122:79-89.
184. Amidon GE, Peck GE, Block LH, Moreton RC, Katdare A, Lafaver R, Sheehan C. 2007. Proposed new USP general information chapter, excipient performance. Pharmacopeial Forum 33:1311-1323.
185. Cooper JW, Ansel HC, Cadwallader DE. 1973. Liquid and solid interactions of primary certified colorants with pharmaceutical gelatins. J Pharm Sci 62:1156-1164.
186. Weller PJ. 2006. Titanium dioxide. In: Rowe RC, Sheskey PJ, Owen SC, editors. Handbook of pharmaceutical excipients. 5th edition. London: Pharmaceutical Press and Washington, DC: American Pharmacists Association. pp. 782-784.
187. Samura K, Kato Y, Morita Y, Kawamura M, Koyama N, Osawa S. 1993. Effect of water-insoluble powder addition on physical properties of gelatin gel. Drug Dev Ind Pharm 19:2579-2594.
188. Hewitt JP. 1992. Titanium dioxide: A different kind of sunshield. Drug Cosmet Ind 151:26-32.
189. Allen NS, Edge M, Ortega A, Liauw CM, Stratton J, McIntyre RB. 2002. Behaviour of nanoparticle (ultrafine) titanium dioxide pigments and stabilisers on the photooxidative stability of water based acrylic and isocyanate based acrylic coatings. Polym Degrad Stab 78:467-478.
190. Matsuda Y, Itooka T, Mitsuhashi Y. 1980. Photostability of indomethacin in model gelatin capsules: Effects of film thickness and concentration of titanium dioxide on the coloration and photolytic degradation. Chem Pharm Bull 28:2665-2671.
191. Su KSE, Snyder RR, Scott RR. 1976. Pharmaceutical suspension for opaqing empty gelatin capsules. US Patent 3,992,215.
192. Yannas IV, Tobolsky AV. 1967. Cross-linking of gelatine by dehydration. Nature 215:509-510.
193. Welz MM, Ofner CM. 1992. Examination of self-crosslinked gelatin as a hydrogel for controlled release. J Pharm Sci 81:85-90.
194. Bessho M, Kojima T, Okuda S, Hara M. 2007. Radiation-induced cross-linking of gelatin by using γ-rays: Insoluble gelatin hydrogel formation. Bull Chem Soc Jpn 80:979-985.
195. Sheehan JC, Hlavka JJ. 1957. The cross-linking of gelatin using a water-soluble carbodiimide. J Am Chem Soc 79:4528-4529.
196. Davis P, Tabor BE. 1963. Kinetic study of the crosslinking of gelatin by formaldehyde and glyoxal. J Polymer Sci Part A General Papers 1:799-815.
197. Digenis GA, Gold TB, Shah VP. 1994. Cross-linking of gelatin capsules and its relevance to their in vitro-in vivo performance. J Pharm Sci 83:915-921.
198. Tomihata K, Ikada Y. 1996. Cross-linking of gelatin with carbodiimides. Tissue Eng 2:307-313.
199. Bottom CB, Clark M, Carstensen JT. 1997. Dissolution testing of soft shell capsules-acetaminophen and nifedipine. J Pharm Sci 86:1057-1061.
200. Gold TB, Buice RG, Lodder RA, Digenis GA. 1998. Detection of formaldehyde-induced crosslinking in soft elastic gelatin capsules using near-infrared spectrophotometry. Pharm Dev Technol 3:209-214.
201. Fan H, Dash AK. 2001. Effect of cross-linking on the in vitro release kinetics of doxorubicin from gelatin implants. Int J Pharm 213:103-116.
202. Liang HC, Chang WH, Liang HF, Lee MH, Sung HW. 2004. Crosslinking structures of gelatin hydrogels crosslinked with genipin or a water-soluble carbodiimide. J Appl Polymer Sci 91:4017-4026.
203. Carstensen JT, Rhodes CT. 1993. Pellicule formation in gelatin capsules. Drug Dev Ind Pharm 19:2709-2712.
204. Hakata T, Sato H, Watanabe Y, Matsumoto M. 1994. Effect of formaldehyde on the physicochemical properties of soft gelatin capsule shells. Chem Pharm Bull 42:1138-1142. (Pubitemid 24183764)
205. Hakata T, Sato H, Watanabe Y, Matsumoto M. 1994. Effect of storage temperature on the physicochemical properties of soft gelatin capsule shells. Chem Pharm Bull 42:1496-1500. (Pubitemid 24244098)
206. Fraenkel-Conrat H, Cooper M, Olcott HS. 1945. Reaction of formaldehyde with proteins. J Am Chem Soc 67:950-954.
207. Taylor SK, Davidson F, Ovenall DW. 1978. Carbon-13 nuclear magnetic resonance studies on gelatin crosslinking by formaldehyde. Photogr Sci Eng 22:134-138.
208. Albert K, Peters B, Bayer E, Treiber U, Zwilling M. 1986. Crosslinking of gelatin with formaldehyde: A 13C NMR study. Z Naturforsch 41:351-358.
209. Albert K, Bayer E, Worsching A, Vogele H. 1991. Investigation of the hardening reaction of gelatin with 13C labeled formaldehyde by solution and solid state 13C NMR spectroscopy. Z Naturforsch 46:385-389.
210. Gold TB, Smith SL, Digenis GA. 1996. Studies on the influence of pH and pancreatin on 13C-formaldehyde induced gelatin crosslinks using nuclear magnetic resonance. Pharm Dev Technol 1:21-26.
211. Ofner CM, Zhang Y, Jobeck VC, Bowman BJ. 2001. Crosslinking studies in gelatin capsules treated with formaldehyde and in capsules exposed to elevated temperature and humidity. J Pharm Sci 90:79-88.
212. Gautam J, Schott H. 1994. Interaction of anionic compounds with gelatin I: Binding studies. J Pharm Sci 83:922-930.
213. Azaz E, Donbrow M, Hamburger R. 1973. Incompatibility of non-ionic surfactants with oxidisable drugs. Pharm J 211:15.
214. Hamburger R, Azaz E, Donbrow M. 1975. Autoxidation of polyoxyethylenic non-ionic surfactants and of polyethylene glycols. Pharm Acta Helv 50:10-17.
215. McGinity JW, Hill JA, La Via AL. 1975. Influence of peroxide impurities in polyethylene glycols on drug stability. J Pharm Sci 64:356-357.
216. Donbrow M, Azaz E, Pillersdorf A. 1978. Autoxidation of polysorbates. J Pharm Sci 67:1676-1681.
217. Chafetz L, Hong W, Tsilifonis DC, Taylor AK, Philip J. 1984. Decrease in the rate of capsule dissolution due to formaldehyde from Polysorbate 80 autooxidation. J Pharm Sci 73:1186-1187.
218. Johnson DM, Taylor WF. 1984. Degradation of fenprostalene in Polyethylene glycol 400 solution. J Pharm Sci 73:1414-1417.
219. Hartauer KJ, Bucko JH, Cooke GG, Mayer RF, Schwier JR, Sullivan GR. 1993. The effect of rayon coiler on the dissolution stability of hard-shell gelatin capsules. Pharm Technol 17:76-83.
220. Schwier JR, Cooke GG, Hartauer KJ, Yu L. 1993. Rayon: Source of furfural - A reactive aldehyde capable of insolublizing gelatin capsules. Pharm Technol 17:78-80.
221. Yamamoto T, Kobayashi M, Matsuura S. 1995. Gelatin coating composition and hard gelatin capsule. US Patent 5,419,916.
222. Gholap D, Singh S. 2004. The influence of drugs on gelatin cross-linking. Pharm Technol 28:94-102.
223. Hwan YJ. 2003. Method of manufacturing succinylated gelatin. Patent Publication KR20030077501.
224. Adesunloye TA, Stach PE. 1998. Effect of glycine/citric acid on the dissolution stability of hard gelatin capsules. Drug Dev Ind Pharm 24:494-500.
225. Adesunloye TA, Stach PE. 1999. Filled gelatin capsules. US Patent 5,874,106.
226. Rama Rao KV, Pakhale SP, Singh S. 2003. A film approach for the stabilization of gelatin preparations against cross-linking. Pharm Technol 27:54-63.
227. US Pharmacopeia 32. 2009. General Chapter 〈711〉 Dissolution and General Chapter 〈2040〉 Disintegration and dissolution of dietary supplements. Rockville, MD: US Pharmacopeial Convention. pp. 263-264, 783.
228. Piper DW, Fenton BH. 1965. pH stability and activity curves of pepsin with special reference to their clinical importance. Gut 6:506-508.
229. Shiu GK. 1996. Pharmaceutical product quality research: An overview for solid oral dosage forms. J Food Drug Analysis 4:293-300.
230. Meyer MC, Straughn AB, Mhatre RM, Hussain A, Shah VP, Bottom CB, Cole ET, Lesko LL, Mallinowski H, Williams RL. 2000. The effect of gelatin cross-linking on the bioequivalence of hard and soft gelatin acetaminophen capsules. Pharm Res 17:962-966.
231. Digenis GA, Sandefer EP, Page RC, Doll WJ, Gold TB, Darwazeh NB. 2000. Bioequivalence study of stressed and non-stressed hard gelatin capsules using amoxicillin as a drug marker and gamma scintigraphy to confirm time and GI location of in vivo capsules rupture. Pharm Res 17:572-582.
232. Shah VP, Konecny JJ, Everett RL, McCullough B, Noorizadeh AC, Skelly JP. 1989. In vitro dissolution profile of water-insoluble drug dosage forms in the presence of surfactants. Pharm Res 6:612-618.
233. Noory C, Tran N, Ouderkirk L, Shah V. 2002. Steps for development of a dissolution test for sparingly water-soluble drug products. Am Pharm Rev 5:16-21.
234. Brown CK, Chokshi HP, Nickerson B, Reed RA, Rohrs BR, Shah PA. 2004. Acceptable analytical practices for dissolution testing of poorly soluble compounds. Pharm Technol 28:56-65.
235. Nishimura H, Hayashi C, Aiba T, Okamoto I, Miyamoto Y, Nakade S, Takeda K, Kurosaki Y. 2007. Application of the correlation of in vitro dissolution behavior and in vivo plasma concentration profile (IVIVC) for soft-gel capsules-a pointless pursuit? Biol Pharm Bull 30:2221-2225.
236. Rossi RC, Dias CL, Donato EM, Martins LA, Bergold AM, Froehlich PE. 2007. Development and validation of dissolution test for ritonavir soft gelatin capsules based on in vivo data. Int J Pharm 338:119-124.
237. Buri P, Humbert-Droz J. 1983. Solubilisation de principes actifs insolubles par des constituants des sucs digestifs. 3rd Int Cong Pharm Technol Paris 4:136-143.
238. Larson CE, Greenberg DM. 1933. A paradoxical solubility phenomenon with gelatin. J Am Chem Soc 55:2798-2799.
239. Pillay V, Fassihi R. 1999. Unconventional dissolution methodologies. J Pharm Sci 88:843-851.
240. Pillay V, Fassihi R. 1999. A new method for dissolution studies of liquid-filled capsules employing nifedipine as a model drug. Pharm Res 16:333-337.
241. Zhao F, Malayev V, Rao V, Hussain M. 2004. Effect of sodium lauryl sulfate in dissolution media on dissolution of hard gelatin capsule shells. Pharm Res 21:144-148.
242. Bartnik FG. 1992. Interaction of anionic surfactants with proteins, enzymes and membranes. In: Gloxhuber C, Kunstler K, editors. Anionic surfactants: Biochemistry, toxicology, dermatology. 2nd edition (Surfactant Science Series; Vol. 43). New York: Marcel Dekker, Inc. pp. 1-42.
243. Marchais H, Cayzeele G, Legendre JV, Skiba M, Arnaud P. 2003. Cross-linking of hard gelatin carbamazepine capsules: Effect of dissolution conditions on in vitro drug release. Eur J Pharm Sci 19:129-132.
244. Joseph M, Mayberry C, Schiermeyer C. 2005. A 2-step dissolution method for the elimination of crosslinking in nimodipine soft gelatin capsules while providing solubility of a water-insoluble drug. AAPS Annual Meeting and Exposition, Nashville, TN. www.aapsj.org/abstracts/AM-2005/AAPS2005-001000.pdf.
245. Speer J, Flynn J, Gullapalli R, Agarwal R, Muffuid P. 2005. Influence of digestive enzymes on dissolution of a poorly water soluble compound from cross-linked capsules in sodium lauryl sulfate medium. AAPS Annual Meeting and Exposition, Nashville, TN. www.aapsj.org/abstracts/AM-2005/AAPS2005-000998.pdf.
246. Tamaki K, Tamamushi B. 1955. The interactions of gelatin molecule with surface active ions. Bull Chem Soc Jpn 28:555-559.
247. Pennings FH, Kwee BLS, Vromans H. 2006. Influence of enzymes and surfactants on the disintegration behavior of cross-linked hard gelatin capsules during dissolution. Drug Dev Ind Pharm 32:33-37.
248. Onesippe C, Lagerge S. 2009. Study of the complex formation between sodium dodecyl sulphate and gelatin. Colloids Surf A: Physicochem Eng Aspects 337:61-66.
249. Ofner CM, Schott H. 1987. Swelling studies of gelatin II: Effect of additives. J Pharm Sci 76:715-723.
250. Woolfrey SG, Banzon GM, Groves MJ. 1986. The effect of sodium chloride on the dynamic surface tension of sodium dodecyl sulfate solutions. J Colloid Interface Sci 112:583-587.
251. Crison JR, Weiner ND, Amidon GL. 1997. Dissolution media for in vitro testing of water-insoluble drugs: Effect of surfactant purity and electrolyte on in vitro dissolution of carbamazepine in aqueous solutions of sodium lauryl sulfate. J Pharm Sci 86:384-388.
252. Cao Y, Marra M, Anderson BD. 2004. Predictive relationships for the effects of triglyceride ester concentration and water uptake on solubility and partitioning of small molecules into lipid vehicles. J Pharm Sci 93:2768-2779.
253. Land LM, Li P, Bummer PM. 2005. The influence of water content of triglyceride oils on the solubility of steroids. Pharm Res 22:784-788.
254. Rane SS, Anderson BD. 2008. What determines drug solubility in lipid vehicles: Is it predictable? Adv Drug Deliv Rev 60:638-656.
255. Shah NH, Stiel D, Infeld MH, Railkar AS, Malick AW, Patrawala M. 1992. Elasticity of soft gelatin capsules containing polyethylene glycol 400-quantitation and resolution. Pharm Technol 3:126-131.
256. Jun HW, Whitworth CW, Luzzi LA. 1972. Decomposition of aspirin in polyethylene glycols. J Pharm Sci 61:1160-1162.
257. Whitworth CW, Jun HW, Luzzi LA. 1973. Stability of aspirin in liquid and semisolid bases I. Substituted and nonsubstituted polyethylene glycols. J Pharm Sci 62:1184-1185.
258. Wei Y, Shelley RS. 1998. Comparison of lipophilic and hydrophilic ketoprofen solution softgel formulations. AAPS Annual Meeting, Poster 2134.
259. Greenwald RB, Conover CD, Choe YH. 2000. Poly(ethylene glycol) conjugated drugs and prodrugs: A comprehensive review. Crit Rev Ther Drug Carrier Syst 17:101-161.
260. Kochling JD, Miao H, Young CR, Looker AR, Shannon M, Montgomery ER. 2007. Understanding the degradation pathway of a poorly water-soluble drug formulated in PEG-400. J Pharm Biomed Anal 43:1638-1646.
261. Ranucci E, Sartore L, Peroni I, Latini R, Bernasconi R, Ferruti P. 1994. Pharmacokinetic results on naproxen prodrugs based on poly(ethyleneglycol)s. J Biomat Sci Polymer Edn 6:141-147.
262. Sartore L, Perone I, Ferruti P, Latini R, Barnasconi R. 1997. Synthesis and pharmacokinetic behaviour of ester derivatives of 4-isobutylphenyl-2- propionic acid (Ibuprofen) with end-hydroxylated poly(N-vinyl pyrrolidinone) and poly(N-acryloyl morpholine) oligomers. J Biomater Sci Polym Ed 8:741-754.
263. Whitworth CW, Asker AF. 1974. Stability of aspirin in liquid and semisolid bases IV: Polyethylene glycol 400 diacetate and triethylene glycol diacetate. J Pharm Sci 63:1790-1792.
264. Bergh M, Shao LP, Hagelthorn G, Gafvert E, Lars J, Nilsson G, Karlberg AT. 1998. Contact allergens from surfactants. Atmospheric oxidation of polyethylene alcohols, formation of ethoxylated aldehydes, and their allergenic activity. J Pharm Sci 87:276-282.
265. Ha E, Wang W, Wang YJ. 2002. Peroxide formation in polysorbate 80 and protein stability. J Pharm Sci 91:2252-2264.
266. Kumar V, Kalonia DS. 2006. Removal of peroxides in polyethylene glycols by vacuum drying: Implications in the stability of biotech and pharmaceutical formulations. AAPS PharmSciTech 7:E1-E7.
267. Li Z, Kozlowski BM, Chang EP. 2007. Analysis of aldehydes in excipients used in liquid/semi-solid formulations by gas chromatography - Negative chemical ionization mass spectrometry. J Chromatography A 1160:299-305.
268. Wasylaschuk WR, Harmon PA, Wagner G, Harman AB, Templeton AC, Xu H, Reed RA. 2007. Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci 96:106.
269. Frontini R, Mielck JB. 1995. Formation of formaldehyde in polyethylene glycol and in poloxamer under stress conditions. Int J Pharm 114:121-123.
270. Barrio MD, Hu J, Zhou P, Cauchon N. 2006. Simultaneous determination of formic acid and formaldehyde in pharmaceutical excipients using headspace GC/MS. J Pharm Biomed Anal 41:738-743.
271. Nassar MN, Nesarikar VN, Lozano R, Parker WL, Huang Y, Palaniswamy V, Xu W, Khaselev N. 2004. Influence of formaldehyde impurity in Polysorbate 80 and PEG-300 on the stability of a parenteral formulation of BMS-204352: Identification and control of the degradation product. Pharm Dev Tech 9:189-195.
272. McGhee JD, Von Hippel PH. 1975. Formaldehyde as a probe of DNA structure. I. Reaction with exocyclic amino groups of DNA bases. Biochemistry 14:1281-1296.
273. Chaw YFM, Crane LE, Lange P, Shapiro R. 1980. Isolation and identification of cross-links from formaldehyde-treated nucleic acids. Biochemistry 19:5525-5531.
274. Huang H, Solomon MS, Hopkins PB. 1992. Formaldehyde preferentially interstrand cross-links duplex DNA through deoxyadenosine residues at the sequence 5′-d(AT). J Am Chem Soc 114:9240-9241.
275. Laicher A, Junger H, Klemm FH. 1997. Stability behaviour of molsidomine-containing pellet formulations. J Pharm Pharmacol 49:131-134.
276. Stephenson SA, Bryant DK, Thomson CM, Walsgrove TC, Webb ML. 1998. An analytical study of the interaction of low levels of formaldehyde with active pharmaceuticals. J Pharm Pharmacol 50:122.
277. Hartauer KJ, Arbuthnot GN, Baertschi SW, Johnson RA, Luke WD, Pearson NG, Rickard EC, Tingle CA, Tsang PK, Wiens RE. 2000. Influence of peroxide impurities in povidone and crospovidone on the stability of raloxifene hydrochloride in tablets: Identification and control of an oxidative degradation product. Pharm Dev Technol 5:303-310.
278. Huang T, Garceau ME, Gao P. 2003. Liquid chromatographic determination of residual hydrogen peroxide in pharmaceutical excipients using platinum and wired enzyme electrodes. J Pharm Bio Anal 31:1203-1210.
279. Buhler V. 2008. Kollidon® - Polyvinylpyrrolidone excipients for the pharmaceutical industry. 9th edition. Ludwigshafen, Germany: BASF SE Pharma Ingredients & Services. pp. 45-48.
280. Patel K, Kearney AS, Palepu NR. 1997. Investigation of new degradation products arising from the encapsulation of an oil-based suspension formulation of topotecan. Int J Pharm 151:7-13.
281. Armstrong NA, James KC, Pugh KL. 1984. Drug migration into soft gelatin capsule shells and its effect on in-vitro availability. J Pharm Pharmacol 36:361-365.
282. Armstrong NA, James KC, Collett D, Thomas M. 1985. Solute migration from oily solutions into glycerin-gelatin mixtures. Drug Dev Ind Pharm 11:1859-1868.
283. Hauer B, Meinzer A, Posanski U, Richter F. 1994. Pharmaceutical compositions comprising cyclosporins. US Patent 5,342,625.
284. Gursoy RN, Benita S. 2004. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother 58:173-182.
285. Marriott C, Kellaway IW. 1978. The release of antibacterial agents from glycerolgelatin gels. Drug Dev Ind Pharm 4:195-208.
286. Hong CI, Kim JW, Choi NH, Shin HJ, Yang SG. 2000. Cyclosporin-containing microemulsion preconcentrate composition. US Patent 6,063,762.
287. Hauer B, Meinzer A, Posanski U, Richter F. 2007. Pharmaceutical compositions comprising cyclosporins. US Patent 7,235,248.
288. Woo JS. 1997. Cyclosporin-containing soft capsule compositions. US Patent 5,603,951.
289. Cole ET, Cade D, Benameur H. 2008. Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration. Adv Drug Deliv Rev 60:747-756.
290. Walker SE, Ganley JA, Bedford K, Eaves T. 1980. The filling of molten and thixotropic formulations into hard gelatin capsules. J Pharm Pharmacol 32:389-393.
291. Cade D, Cole ET, Mayer JPH, Wittwer F. 1986. Liquid filled and sealed hard gelatin capsules. Drug Dev Ind Pharm 12:2289-2300.
292. Cole ET. 1999. Liquid filled and sealed hard gelatin capsules. In: Recent advances in the formulation & development of poorly-soluble drugs, B.T. Gattefossé No 92. Saint-Priest, Cedex, France: Gattefossé Corporation. pp. 67-77.
293. El Massik MA, Abdallah OY, Galal S, Daabis NA. 2003. Semisolid matrix filled capsules: An approach to improve dissolution stability of phenytoin sodium formulation. Drug Dev Ind Pharm 29:531-543.
294. Barakat NS. 2006. Etodolac-liquid-filled dispersion into hard gelatin capsules: An approach to improve dissolution and stability of etodolac formulation. Drug Dev Ind Pharm 32:865-876.
295. Smith T. 2006. The hard capsule with the soft center: The reemergence of liquid-filled hard capsules. Tablets & Capsules May: 5-9.
296. Stein D, Bindra DS. 2007. Stabilization of hard gelatin capsule shells filled with polyethylene glycol matrices. Pharm Dev Tech 12:71-77.
297. Hariharan M, Ganorkar LD, Amidon GE, Cavallo A, Gatti P, Hageman MJ, Choo I, Miller JL, Shah UJ. 2003. Reducing the time to develop and manufacture formulations for first oral dose in humans. Pharm Technol 27: 68-84.
298. Koon RC. 2006. How softgels are made and how to select a manufacturer. Tablets & Capsules May: 42-46.
299. Kontny MJ, Mulski CA. 1989. Gelatin capsule brittleness as a function of relative humidity at room temperature. Int J Pharm 54:79-85.
300. Jones BE. 2004. Manufacture and properties of two-piece hard capsules. In: Podczeck F, Jones BE, editors. Pharmaceutical capsules. 2nd edition. London: Pharmaceutical Press. pp. 93-94.
301. Fulper D, Wang H, Downey D. 2010. Influence of mechanical stress on the formation of cracks in two-piece capsules. Tablets & Capsules January: 8-15.
302. Richardson M, Stegemann S. 2007. Filling two-piece hard gelatin capsules with liquids. Tablets & Capsules January: 97-110.
303. Rowley G. 2004. Filling of liquids and semi-solids into hard two-piece capsules. In: Podczeck F, Jones BE, editors. Pharmaceutical capsules. 2nd edition. London: Pharmaceutical Press. pp. 169-194.
304. Tindal S, Asgarzadeh F. 2006. Laboratory scale softgel encapsulation (Minicap). AAPS Annual Meeting and Exposition, San Antonio, TX. http://www.aapsj.org/abstracts/AM-2006/AAPS2006-001526.pdf
305. Fatouros DG, Karpf DM, Nielsen FS, Mullertz A. 2007. Clinical studies with oral lipid based formulations of poorly soluble compounds. Ther Clin Risk Manage 3:591-604.
306. Garg R, Bhhatarai B. 2004. A mechanistic study of 3-aminoindazole cyclic urea HIV-1 protease inhibitors using comparative QSAR. Bioorg Med Chem 12:5819-5831.
307. Heimbach T, Fleisher D, Kaddoumi A. 2007. Overcoming poor aqueous solubility of drugs for oral delivery. In: Stella VJ, Borchardt RT, Hageman MJ, Oliyai R, Maag H, Tilley JW, editors. Prodrugs: Challenges and rewards, part 1. New York: AAPS Press, Springer. p. 175.
308. Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennerna1s H, Hussain AS, Junginger HE, Stavchansky SA, Midha KK, Shah VP, Amidon GL. 2004. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm 1:85-96.
309. Lindenberg M, Kopp S, Dressman JB. 2004. Classification of orally administered drugs on the World Health Organization model list of essential medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm 58:265-278.
310. Darwish IA, Florence AT, Saleh AM. 1989. Effects of hydrotropic agents on the solubility, precipitation, and protein binding of etoposide. J Pharm Sci 78:577-581.
311. Branchu S, Rogueda PG, Plumb AP, Cook WG. 2007. A decision-support tool for the formulation of orally active, poorly soluble compounds. Eur J Pharm Sci 32:128-139.
312. Yunzhe S, Rui Y, Wenliang Z, Xing T. 2008. Nimodipine semi-solid capsules containing solid dispersion for improving dissolution. Int J Pharm 359:144-149.
313. O'Driscoll CM, Griffin BT. 2008. Biopharmaceutical challenges associated with drugs with low aqueous solubility - The potential impact of lipid-based formulations. Adv Drug Deliv Rev 60:617-624.
314. Akhlaghi F, Trull AK. 2002. Distribution of cyclosporin in organ transplant recipients. Clin Pharmacokinet 41:615-637.
315. Sharma P, Varma MVS, Chawla HPS, Panchagnula R. 2005. Absorption enhancement, mechanistic and toxicity studies of medium chain fatty acids, cyclodextrins and bile salts as peroral absorption enhancers. Il Farmaco 60:884-893.
316. Agarwal S, Boddu SHS, Jain R, Samanta S, Pal D, Mitra AK. 2008. Peptide prodrugs: Improved oral absorption of lopinavir, a HIV protease inhibitor. Int J Pharm 359:7-14.
317. Price JC. 2006. Polyethylene glycol. In: Rowe RC, Sheskey PJ, Owen SC, editors. Handbook of pharmaceutical excipients. 5th edition. London: Pharmaceutical Press and Washington, DC: American Pharmacists Association. pp. 545-550.
318. Lawrence MJ. 2006. Medium-chain triglycerides. In: Rowe RC, Sheskey PJ, Owen SC, editors. Handbook of pharmaceutical excipients. 5th edition. London: Pharmaceutical Press and Washington, DC: American Pharmacists Association. pp. 454-456.
319. Cable CG. 2006. Soybean oil. In: Rowe RC, Sheskey PJ, Owen SC, editors. Handbook of pharmaceutical excipients. 5th edition. London: Pharmaceutical Press and Washington, DC: American Pharmacists Association. pp. 722-724.