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AAPS PharmSciTech. 2002 March; 3(1): 23–31.
Published online 2002 February 8. doi:  10.1208/pt030103
PMCID: PMC2750250

Response surface methodology for the optimization of ubiquinone self-nanoemulsified drug delivery system


The aim of the present study was to prepare and evaluate an optimized, self-nanoemulsified drug delivery system of ubiquinone. A 3-factor, 3-level Box-Behnken design was used for the optimization procedure with the amounts of Polyoxyl 35 castor oil (X1), medium-chain mono- and diglyceride (X2), and lemon oil (X3) as the independent variables. The response variable was the cumulative percentage of ubiquinone emulsified in 10 minutes. Different ubiquinone release rates were obtained. The amount released ranged from 11% to 102.3%. Turbidity profile revealed 3 regions that were used to describe the progress of emulsion formation: lag phase, pseudolinear phase, and plateau turbidity. An increase in the amount of surfactant decreased turbidity values and caused a delay in lag time. Addition of cosurfactant enhanced the release rates. Increasing the amount of the eutectic agent was necessary to overcome drug precipitation especially at higher loading of surfactants and cosurfactants. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the cumulative percentage emulsified in 10 minutes was Y1=90.9–22.1X1+5.03X2+13.95X3+12.13X1X2+15.13X1X3-14.40X12-6.25X32. The optimization model predicted a 93.4% release with X1, X2, and X3 levels of 35, 35, and 30 respectively.

The observed responses were in close agreement with the predicted values of the optimized formulation. This demonstrated the reliability of the optimization procedure in predicting the dissolution behavior of a self-emulsified drug delivery system.

Key words: Self-nanoemulsified drug delivery, Coenzyme Q10, Optimization, Response surface methodology, Turbidimetry

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Selected References

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1. Perng CH, Kearney AS, Patel K, Palepu NR, Zuber G. Investigation of formulation approaches to improve the disolution of SB-210661, a poorly water soluble 5-lipoxygenase inhibitor. Int J Pharm. 1998;176:31–38. doi: 10.1016/S0378-5173(98)00296-8. [Cross Ref]
2. Nazzal S, Guven N, Reddy IK, Khan MA. Preparation and characterization of Coenzyme Q10-Eudragit© solid dispersion. Drug Dev Ind Pharm. 2002;28(1):49–57. doi: 10.1081/DDC-120001485. [PubMed] [Cross Ref]
3. Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and “selfmicroemulsifying” drug delivery systems. Eur J Pharm Sci. 2000;2(Suppl):93–8. doi: 10.1016/S0928-0987(00)00167-6. [PubMed] [Cross Ref]
4. Charman SA, Charman WN, Rogge MC, Wilson TD, Dutko FJ, Pouton CW. Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharm Res. 1992;9(1):87–93. doi: 10.1023/A:1018987928936. [PubMed] [Cross Ref]
5. Craig DQM, Lievens HSR, Pitt KG, Storey DE. An investigation into the physico-chemical properties of self-emulsifying systems using low frequency dielectric spectroscopy, surface tension measurements and article size analysis. Int J Pharm. 1993;96:147–155. doi: 10.1016/0378-5173(93)90222-2. [Cross Ref]
6. Gao ZG, Choi HG, Shin HJ, Park KM, Lim SJ, Hwang KJ, Kim CK. Physicochemical characterization and evaluation of a microemulsion system for oral delivery of cyclosporin A. Int J Pharm. 1998;161:75–86. doi: 10.1016/S0378-5173(97)00325-6. [Cross Ref]
7. Groves MJ, de Galindez DA. Rheological characterization of self-emulsifying oil/surfactant systems. Acta Pharm Suecica. 1976;13:353–360. [PubMed]
8. Yalabik-Kas HS, Groves MJ. Zeta potential of droplets prepared from a self-emulsifying oil. Drug Dev Ind Pharm. 1984;10(2):211–223. doi: 10.3109/03639048409064646. [Cross Ref]
9. Craig DQ, Barker SA, Banning D, Booth SW. Investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy. Int J Pharm. 1995;114:103–110. doi: 10.1016/0378-5173(94)00222-Q. [Cross Ref]
10. Kim CK, Ryuu SA, Park KM, Lim SJ, Hwang SJ. Preparation and physicochemical characterization of phase inverted water/oil microemulsion containing cyclosporin A. Int J Pharm. 1997;147:131–134. doi: 10.1016/S0378-5173(96)04791-6. [Cross Ref]
11. Cortesi R, Esposito E, Maietti A, Menegatti E, Nastruzzi C. Formulation study for the antitumor drug camptothecin: ilposomes, micellar solutions and a microemulsion. Int J Pharm. 1997;159:95–103. doi: 10.1016/S0378-5173(97)00275-5. [Cross Ref]
12. Prinderre P, Piccerelle P, Cauture E, Kalantzis G, Joachim J. Formulation and evaluation of o/w emulsions using experimental design. Int J Pharm. 1998;163:73–79. doi: 10.1016/S0378-5173(97)00368-2. [Cross Ref]
13. Gullapalli RP, Sheth BB. Influence of an optimized nonionic emulsifier blend on properties of oil in water emulsions. Eur J Pharm Biopharm. 1999;48(3):233–238. doi: 10.1016/S0939-6411(99)00048-X. [PubMed] [Cross Ref]
14. Kommuru TR, Gurley B, Khan MA, Reddy IK. Selfemulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. Int J Pharm. 2001;212:233–46. doi: 10.1016/S0378-5173(00)00614-1. [PubMed] [Cross Ref]
15. Karachi AA, Khan MA. Box-Behnken design for the optimization of formulation variables of indomethacin coprecipitates with polymer mixtures. Int J Pharm. 1996;131:9–17. doi: 10.1016/0378-5173(95)04216-4. [Cross Ref]
16. Singh SK, Reddy IK, Khan MA. Optimization and characterization of controlled release pellets coated with an experimental latex: II. Cationic drug. Int J Pharm. 1996;141:179–195. doi: 10.1016/0378-5173(96)04635-2. [Cross Ref]
17. Sastry SV, Reddy IK, Khan MA. Atenolol gastrointestinal therapeutic system: optimization of formulation variables using response surface methodology. J Cont Rel. 1997;45:121–130. doi: 10.1016/S0168-3659(96)01553-2. [Cross Ref]
18. Wehrle P, Korner D, Benita S. Sequential statistical optimization of a positively charged submicron emulsion of miconazole. Pharm Dev Tech. 1996;1(1):97–111. doi: 10.3109/10837459609031423. [PubMed] [Cross Ref]
19. Box GEP, Behnken DW. Some new three level designs for the study of quantitative variables. Technometrics. 1960;2:455–475. doi: 10.2307/1266454. [Cross Ref]
20. Nazzal S, Smalyukh II, Lavrentovich OD, Khan MA. Preparation and in vitro characterization of a eutectic based semisolid self-nanoemulsified drug delivery system (SNEDDS) of Ubiquinone: Mechanism and progress of emulsion formation. Int J Pharm. In press. [PubMed]
21. Groves MJ, Mustafa RAM. Measurement of the “spontaneity” of self-emulsifiable oils. J Pharm Pharmac. 1974;26:671–681. [PubMed]
22. Pouton CW. Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. Int J Pharm. 1974;26:671–681.
23. Nazzal S, Zaghloul AA, Reddy IK, Khan MA. Analysis of ubidecarenone (CoQ10) aqueous samples using reversed phase liquid chromatography. Pharmazie. 2001;56(5):394–396. [PubMed]
24. Reiss H. Entropy-induced dispersion of bulk liquids. J Colloid Interface Sci. 1975;53(1):61–70. doi: 10.1016/0021-9797(75)90035-1. [Cross Ref]
25. Iranloye TA, Pilpel N, Groves MJ. Some factors affecting the droplet size and charge of dilute oil-in-water emulsions prepared by self-emulsification. J Disp Sci and Technology. 1983;4(2):109–121. doi: 10.1080/01932698308943358. [Cross Ref]
26. Constantinides PP, Scalart JP. Formulation and physical characterization of water-in-oil microemulsions containing long- versus medium-chain glycerides. Int J Pharm. 1997;158:57–68. doi: 10.1016/S0378-5173(97)00248-2. [Cross Ref]
27. Halbaut L, Berbe C, del Pozo A. An investigation into physical and chemical properties of semi-solid selfemulsifying systems for hard gelatin capsules. Int J Pharm. 1996;130:203–212. doi: 10.1016/0378-5173(95)04296-2. [Cross Ref]
28. Bachynsky MO, Shah NH, Patel CI, Malick AW. Factors affecting the efficiency of a self-emulsifying oral delivery system. Drug Dev Ind Pharm. 1997;23(8):809–816. doi: 10.3109/03639049709150551. [Cross Ref]
29. Shah NH, Carvajal MT, Patel I, Infeld MH, Malick AW. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int J Pharm. 1994;106:15–23. doi: 10.1016/0378-5173(94)90271-2. [Cross Ref]

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