Freeze-dried Amorphous Dispersions for Solubility Enhancement of Thermosensitive API Having Low Molecular Lipophilicity

Abstract

The present study focuses on the development of an alternative ‘thermally gentle’ strategy such as freeze-drying to obtain not only solubility enhanced but also physically stabilised amorphous solid dispersions of acetazolamide, which melt with decomposition (M.P.~260°C). The solid dispersions were prepared by freeze-drying an aqueous dispersion of acetazolamide containing a lyoprotectant as sugar alcohol (mannitol) in 1:0.5, 1:1 and 1:2 proportions by weight. All the proportions of solid dispersions reported a marked increase in solubility characteristics compared to those of pure drug; with outstanding performance by 1:1 ratio of about 6 folds rise in saturation solubility and 90% drug release in about initial 30 minutes. This could be attributed to the formation amorphous molecular dispersions, cosolvent effect of mannitol on dispersed acetazolamide as well as its local solubilisation effect at the diffusion layer. During stability study also, 1:1 ratio of solid dispersions reported an insignificant change in solubility characteristics subjected to an unchanged amorphous nature. Such physical stability could be attributed to decreased molecular mobility of the drug molecules in amorphous carrier because of weaker drug-carrier interactions. Thus, it was demonstrated that freeze-drying is an effective method of forming dissolution-enhanced, amorphous solid dispersions of thermally degradable APIs.

Key words

solvent sublimation - acetazolamide - strong crystal lattice - melts with decomposition - accelerated stability study

• References

• 1 Granero GE, Longhi MR, Becker C. Biowaiver monographs for immediate release solid oral dosage form: acetazolamide. J Pharm Sci 2008; 97: 3691-3699
• 2 Myrdal PB, Jozwiakowski MJ. Alteration of the solid state of the drug substances: polymorphs, solvates and amorphous forms. In: Liu R. (ed.) Water – Insoluble Drug Formulation. New York: CRC Press; 2008: 531-566
• 3 Parasrampuria J. Acetazolamide. In: Brittain HG. (ed.) Analytical Profiles of Drug Substances and Excipients. San Diego: Academic Press Inc; 1993: 14-19
• 4 Raje KB, Wesolowski M. Evaluation of usefulness of CA and PCA for incompatibilities in the pharmaceutical phase. Annales 2009; 22: 49-58
• 5 Burnham L, Dollimore D, Alexander KS. Kinetic study of the drug acetazolamide using thermogravimetry. Thermochim Acta 2001; 392: 127-133
• 6 Alhusban F, Elshaer AM, Kansara JH et al. Investigation of formulation and process of lyophilized orally disintegrating tablet (ODT) using novel amino acid combination. Pharmaceutics 2010; 2: 1-17
• 7 Day JG, Stacey G. Cryopreservation and Freeze Drying Protocols. Humana Press; USA: 2007
• 8 Oetjen GW. Freeze Drying. Wiley-VCH; New York, USA: 1999
• 9 Elgindy N, Elkhodairy K, Molokhia A et al. Lyophilisation monophase solution technique for improvement of the physicochemical properties of an anticancer drug, Flutamide. Eur J Pharm Biopharm 2010; 74: 397-405
• 10 Izutsu K, Yomota C, Aoyagi N. Inhibition of mannitol crystallization in frozen solutions by sodium phosphate and citrates. Chem Pharm Bull 2007; 55: 565-570
• 11 Neau S. Prodrugs for Improved Aqueous Solubility. In: Liu R. (ed.) Water-Insoluble Drug Formulation. New York: CRC Press; 2008: 437-466
• 12 Boutonette-Fagegaltier N, Lamure A, Menegotto J. The Use of Thermally Stimulated Current Spectroscopy in the Pharmaceutical Sciences. In: Craig DQM, Reading M. (eds.) Thermal Analysis of Pharmaceuticals. New York: CRC Press; 2007: 359-382
• 13 Vivek K, Reddy H, Murthy RSR. Investigations of the effect of the lipid matrix on drug entrapment, in vitro release and physical stability of Olanzapine-loaded solid lipid nanoparticles. AAPS PharmSciTech 2007; 8: E1-E9
• 14 Kocbek P, Baumgartner S, Kristl J. Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs. Int J Pharm 2006; 312: 179-186
• 15 Waseda Y, Matsubara E, Shinoda K. X-Ray Diffraction Crystallography Introduction. Examples and Solved Problems. Springer; Germany: 2011
• 16 Jadhav NR, Gaikwad VL, Nair KJ et al. Glass transition temperature: Basics and application in pharmaceutical sector. Asian J Pharm 2009; 3: 82-89
• 17 Terakita A, Matsunaga H, Handa T. The influence of water on the stability of lyophilized formulations with inositol and mannitol as excipients. Chem Pharm Bull 2009; 57: 459-463
• 18 Widjaja E, Kanaujia P, Lau G et al. Detection of trace crystallinity in an amorphous system using raman microscopy and chemometric analysis. Eur J Pharm Sci 2011; 42: 45-54