Amorphous drugs

Attempts are often made to formulate poorly water-soluble drugs in their amorphous state. This is because the solubility of amorphous materials is generally higher than that of the same substances in their crystalline state. However, because of the lower free energy of the crystalline state, amorphous substances tend to change to their more thermodynamically stable crystalline state with time. Therefore, crystallization of amorphous drug substances 

The crystallization rate of amorphous frusemide prepared by spray drying depended on the preparation temperature higher temperatures apparently provided a more stable amorphous state with a higher glass-transition temperature (7 ).571 A similar crystallization rate dependency on the spray-drying temperature of macrolide derivatives was seen. Spray 

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Lindfors, L., Forssen, S., Skantze, P, Skantze, U., Zackrisson, A., and Olsson, U. (2006a) Amorphous drug nanosuspensions. 2. Experimental determination of bulk monomer concentrbtiogajuir, 22 911-916. 

Oguchi and coworkers examined the decarboxylation behavior of -aminosalicylic acid (PAS) as a freeze-dried solid under thermal stress conditions (80°C) in the presence of the excipients pullulan (a linear polysaccharide which can not form inclusion complexes with PAS) and a-cyclodextrin (39). The solid-state stability was shown to correlate with the fraction of amorphous PAS. Increasing relative amounts of pullulan resulted in higher fractions of amorphous PAS. Rapid freezing (liquid nitrogen) was shown to result in a greater relative amount of amorphous drug, as expected. 

Babu, N. I., Nangia, A. Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals. Cryst. Growth Des. 2011,11, 2662-2679. 

FIGURE 7 Characterization of amorphous form, (a) DSC thermogram of amorphous substance. Thermogram is characterized by a glass transition temperature (Tg) above which the amorphous form is mobile and recrystallizes (Tcrys) into a crystalline form which finally melts (7m). (b) Amorphous form that does not show any peaks in XRD as it does not have regular arrangement of molecules. Shallow peaks are indicative of an amorphous drug substance. 

Ill, PROBLEMS IHTHE PRIMARY DRYING PROCESS OF amorphous drug ANDTHEiR SOLUTIONS... 

A. General Factors Affecting the Drying Process of Amorphous Drugs... 

E. Optimization of the Freeze-Drying Program for Amorphous Drugs... 

K below Tg, an amorphous drug powder formed compacts that were significantly more brittle than those formed from the crystalline form of the drug although the tensile strengths of the compacts were similar. 

Gupta, M.K. Vanwert, A. Bogner, R.H. Formation of physically stable amorphous drugs by milling with neusilin. J. Pharm. Sci. 2003, 92 (3), 536-551. 

Recent advances in the scientific understanding of the in vivo performance, the role of supersaturation, and advanced manufacturing technologies will likely render solid solutions and solid dispersions more commercially successful. Excipients used in solid solutions and solid dispersions include polyvinylpyrrolidone, PEG 4,000, PEG 8,000, Gelucire 50/13, and Gelucrie 44/14. Solid solutions are molecular mixtures of a drug dissolved in a solid at a concentration below supersaturation and are thus thermodynamically stable, compared to solid dispersions, which are thermodynamically unstable amorphous drug dispersed within a solid matrix susceptible to crystallization. 

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