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AAPS PharmSciTech. 2007 September; 8(3): E52–E60.
Published online 2007 July 20. doi:  10.1208/pt0803058
PMCID: PMC2750554

Rapidly dissolving repaglinide powders produced by the ultra-rapid freezing process

Abstract

The objective of the study was to produce rapidly dissolving formulations of the poorly water-soluble drug repaglinide using an innovative new technology, ultra-rapid freezing (URF), and to investigate the influence of excipient type on repaglinide stability. Repaglinide compositions containing different types and levels of excipients and different drug potencies (50%–86%) were produced by the URF technology. Repaglinide/excipient solutions were frozen on a cryogenic substrate, collected, and lyophilized to form a dry powder. Surfactants, including sodium dodecyl sulfate, and alkalizing agents such as diethanolamine (DEA) and tromethamine (TRIS) were incorporated into the compositions. Forced degradation of repaglinide was conducted under stressed conditions (eg, elevated temperature, exposure to peroxide) to determine the stability of the drug in such environments. The solubility of repaglinide increased as a function of increasing pH; therefore, incorporation of an alkalizing agent into the URF formulations increased the drug's solubility. Drug instability resulted when the drug was exposed to pH values above 9.0. URF formulations containing alkalizing agents showed no degradation or spontaneous recrystallization in the formulation, indicating that increased stability was afforded by processing. URF processing created nanostructured drug/excipient particles with higher dissolution rates than were achieved for unprocessed drug. Alkalizing agents such as TRIS and DEA, present at levels of 25% to 33% wt/wt in the formulations, did not cause degradation of the drug when processed using URF. URF processing, therefore, yielded fast-dissolving formulations that were physically and chemically stable, resistant to alkali degradation or spontaneous recrystallization in the formulation.

Keywords: Ultra-rapid freezing, dissolution enhancement, stability enhancement, repaglinide, alkalizing agents

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Selected References

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1. Amidon GL. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:413–420. doi: 10.1023/A:1016212804288. [PubMed] [Cross Ref]
2. Dressman JB, Reppas C. In vitro-in vivo correlations for lipophilic, poorly water soluble drugs. Eur J Pharm Sci. 2000;11:S73–S80. doi: 10.1016/S0928-0987(00)00181-0. [PubMed] [Cross Ref]
3. Hu JH, Johnston KP, Williams RO. Nanoparticle engineering processes for enhancing the dissolution rates of poorly water soluble drugs. Drug Dev Ind Pharm. 2004;30:233–245. doi: 10.1081/DDC-120030422. [PubMed] [Cross Ref]
4. Hu JH, Johnston KP, Williams RO. Spray-freezing into liquid (SFL) particle engineering technology to enhance dissolution of poorly water soluble drugs: organic solvent versus organic/aqueous co-solvent systems. Eur J Pharm Sci. 2003;20:295–303. doi: 10.1016/S0928-0987(03)00203-3. [PubMed] [Cross Ref]
5. Hu JH, Johnston KP, Williams RO. Rapid dissolving high potency danazol powders produced by spray freezing into liquid process. Int J Pharm. 2004;271:145–154. doi: 10.1016/j.ijpharm.2003.11.003. [PubMed] [Cross Ref]
6. Yu ZS, Rogers TL, Hu JH, Johnston KP, Williams RO. Preparation and characterization of microparticles containing peptide produced by a novel process: spray-freezing into liquid. Eur J Pharm Biopharm. 2002;54:221–228. doi: 10.1016/S0939-6411(02)00050-4. [PubMed] [Cross Ref]
7. Rogers TL, Nelson AC, Hu JH, et al. A novel particle engineering technology to enhance dissolution of poorly water soluble drugs: spray-freezing into liquid. Eur J Pharm Biopharm. 2002;54:271–280. doi: 10.1016/S0939-6411(02)00063-2. [PubMed] [Cross Ref]
8. Rogers TL, Johnston KP, Williams RO. Solution-based particle formation of pharmaceutical powders by supercritical or compressed fluid carbon dioxide and cryogenic spray-freezing technologies. Drug Dev Ind Pharm. 2001;27:1003–1015. doi: 10.1081/DDC-100108363. [PubMed] [Cross Ref]
9. Vaughn JM, Gao X, Yacaman JM, Johnston KP, Williams RO. Comparison of powder produced by evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) technologies using Z-contrast STEM and complimentary techniques. Eur J Pharm Biopharm. 2005;60:81–89. doi: 10.1016/j.ejpb.2005.01.002. [PubMed] [Cross Ref]
10. Etzler FM, Sanderson MS. Particle size analysis: a comparative study of various methods. Part Part Syst Charact. 1995;12:217–224. doi: 10.1002/ppsc.19950120503. [Cross Ref]
11. Waltersson JO, Lundgren P. The effect of mechanical comminution on drug stability. Acta Pharm Suec. 1985;22:291–300. [PubMed]
12. Leuenberger H. Spray freeze drying: the process of choice for low water soluble drugs? J Nanoparticle Res. 2002;4:111–119. doi: 10.1023/A:1020135603052. [Cross Ref]
13. Maa YF, Nguyen PA, Sweeney T, Shire SJ, Hsu CC. Protein inhalation powders: spray drying vs. spray freeze drying. Pharm Res. 1999;16:249–254. doi: 10.1023/A:1018828425184. [PubMed] [Cross Ref]
14. Costantino HR, Firouzabadian L, Hogeland K, et al. Protein spray freeze drying. Effect of atomization conditions on particle size and stability. Pharm Res. 2000;17:1374–1383. doi: 10.1023/A:1007570030368. [PubMed] [Cross Ref]
15. Evans JC, Scherzer BD, Tocco CD. Preparation of nanostructured particles of poorly water soluble drugs via a novel ultra-rapid freezing technology. In: Svenson S, editor. Polymeric Drug Delivery Volume II—Polymeric Matrices and Drug Particle Engineering. New York, NY: American Chemical Society; 2004. pp. 2048–2057.
16. Hall RS, Board SJ, Clare AJ, Duffey RB, Playle TS, Poole DH. Inverse Leidenfrost phenomenon. Nature. 1969;224:266–267. doi: 10.1038/224266a0. [Cross Ref]
17. Gottfried BS, Lee CJ, Bell KJ. The Leidenfrost phenomenon: film boiling of liquid droplets. Int J Heat Mass Transfer. 1966;9:1167–1187. doi: 10.1016/0017-9310(66)90112-8. [Cross Ref]
18. Culy C, Jarvis B. Repaglinide, a review of its therapeutic use in Type 2 diabetes mellitus. Drugs. 2001;61:1625–1660. doi: 10.2165/00003495-200161110-00008. [PubMed] [Cross Ref]
19. Malaisse W. Repaglinide, a new oral antidiabetic agent: a review of recent preclinical studies. Eur J Clin Invest. 1999;29:21–29. doi: 10.1046/j.1365-2362.1999.00001.x. [PubMed] [Cross Ref]
20. Landgraf R, Frank M, Bauer C, Dieken M. Prandial glucose regulation with repaglinide: its clinical and lifestyle impact in a large cohort of patients with Type II diabetes. Int J Obes. 2000;24:S38–S44. doi: 10.1038/sj/ijo/0801424. [PubMed] [Cross Ref]
21. Wang FEI. Focus on repaglinide: an oral hypoglycemic agent with a more rapid onset and shorter duration of action than the sulfonylureas. Formulary. 1998;33:5–5.
22. Higuchi T, Connors K. Phase solubility diagram. Adv Anal Chem Instrum. 1965;4:117–212.
23. Gandhimathi M, Ravi T, Renu S. Determination of repaglinide in pharmaceutical formulations by HPLC and UV detection. Anal Sci. 2003;19:1675–1677. doi: 10.2116/analsci.19.1675. [PubMed] [Cross Ref]
24. Krishna Reddy KVSR, Babu J, Mathad V, et al. Impurity profile study of repaglinide. J Pharm Biomed Anal. 2003;32:461–467. doi: 10.1016/S0731-7085(03)00216-4. [PubMed] [Cross Ref]
25. US Food and Drug Administration. Stability Testing: Drug substance stress testing. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; February, 6, 2003; Rockville, MD, Rockville, MD: US Food and Drug Administration; 2003.
26. Yamashita K, Nakate T, Okimoto K, et al. Establishment of new preparation method for solid dispersion formulation of tacrolimus. Int J Pharm. 2003;267:79–91. doi: 10.1016/j.ijpharm.2003.07.010. [PubMed] [Cross Ref]
27. Grell W, Hurnaus R, Griss G, et al. Repaglinide and related hypoglycemic benzoic acid derivatives. J Med Chem. 1998;41:5219–5246. doi: 10.1021/jm9810349. [PubMed] [Cross Ref]
28. Nakagaki M, Yokoyama S. Acid catalyzed hydrolysis of sodium dodecyl sulfate. J Pharm Sci. 1985;74:1047–1052. doi: 10.1002/jps.2600741005. [PubMed] [Cross Ref]
29. Patel KC, Banker GS, DeKay HG. Anionic and cationic wetting agents in a hydrophilic ointment-base, I: choice of wetting agents. J Pharm Sci. 1961;50:294–300. doi: 10.1002/jps.2600500404. [PubMed] [Cross Ref]
30. Newton JM, Rowley G, Tornblom JFV. Effect of additives on the release of drug from hard gelatin capsules. J Pharm Pharmacol. 1971;23:452–453. [PubMed]
31. Newton JM, Razzo FN. Interaction of formulation factors and dissolution fluid and the in vitro release of drug from hard gelatin capsules.J Pharm Pharmacol. 1975;27:78P. [PubMed]
32. Valsami G, Dokoumetzidis A, Macheras P. Modeling of supersaturated dissolution data. Int J Pharm. 1999;181:153–157. doi: 10.1016/S0378-5173(99)00020-4. [PubMed] [Cross Ref]
33. Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17:397–404. doi: 10.1023/A:1007516718048. [PubMed] [Cross Ref]
34. Hancock BC, Zograffi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86:1–12. doi: 10.1021/js9601896. [PubMed] [Cross Ref]
35. Raghavan SL, Trividic A, Davis AF, Hadgraft J. Effect of cellulose polymers on supersaturation and in vitro membrane transport of hydrocortisone acetate. Int J Pharm. 2000;193:231–237. doi: 10.1016/S0378-5173(99)00345-2. [PubMed] [Cross Ref]
36. Gilbert JC, Hadgraft J, Bye A, Brookes LG. Drug release from Pluronic F-127 gels. Int J Pharm. 1986;32:223–228. doi: 10.1016/0378-5173(86)90182-1. [Cross Ref]
37. Couarraze G, Leclere B, Conrath G, Falson-Rieg F, Puisieux F. Diffusion of a dispersed solute in a polymeric matrix. Int J Pharm. 1989;56:197–206. doi: 10.1016/0378-5173(89)90015-X. [Cross Ref]

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