Given the potential for formulation flexibility, pharmaceuticists are practicing multiple technologies to produce solid solution/dispersions.
Many methods have been reported and reviewed in the literature, including: spray drying, hot-melt extrusion, melt congelation,
spray freezing into liquid, and nanocrystal technology. These methods impose their own restrictions on polymer selection and
formulation, resulting in different physical properties. Melt-extrusion methods can produce dense compositions. But, due to
the requirement for polymer softening upon heating, the cooled extrudate may be tacky and difficult to pulverize (3). In contrast,
solvent-based spray drying can yield powders of good flowability but of low-bulk density, although new technologies are addressing
this limitation. Additionally, special facilities are required to process and dispose of solvents. Because the amorphous form
eliminates the energy barrier inherent in the crystal lattice, amorphous drug-polymer compositions can enhance aqueous solubility
by fifty-fold or more (8, 9). As a result, water-insoluble NMEs can be formulated and evaluated for enhanced absorption,
and ultimately efficacy. Formulation and process development, however, are needed to optimize final product attributes.
Although solid dispersions are well known to enhance aqueous solubility and bioavailability, their stability must be monitored
to ensure product invariability with time and storage conditions. Crystalline solid dispersions may undergo Ostwald ripening,
a thermodynamically driven process that can occur when the crystalline drug exists with a wide particle-size distribution.
To reach thermodynamic equilibrium, mass is spontaneously transferred from small to large drug crystals to minimize the high
surface energy of the small crystals (10). Proper polymer selection is critical to impede diffusion and inhibit any tendency
for nucleation and crystal growth. Pure drug in the amorphous state often displays a high likelihood to recrystallize (11).
Likewise, amorphous drug-polymer dispersions also may exhibit this solid-state instability. However, drug-polymer solid solutions
can offer unique stability options (1, 9, 12). Understandably, the choice of polymer can strongly influence drug-polymer molecular
interactions and the resulting physicochemical properties. In every case, stability testing of solid solutions/dispersions,
including long-term and accelerated conditions under the International Conference on Harmonization standards is a must for
these formulations. A new, promising approach is to use recrystallization kinetics to model nucleation and crystal growth
rates in order to better understand the effects of formulation and process conditions on stability (13).
The chemical structure and amount of polymer play an important role in drug-polymer solid solutions and solid dispersions,
enabling efficacious drug delivery and stability. Appropriate dispersibility of the dosage form, drug release, and absorption
can be achieved with proper polymer selection. Without doubt, solid solutions and dispersions will provide greater application
and serve as an irreplaceable technology to deliver the ever-increasing number of water-insoluble NMEs.
John Doney, PhD, is a manager of research and development, and Jiao Yang, PhD, is a research chemical engineer, at ISP Pharma
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2. S. Riegelman, and W.L. Chiou, "Increasing the Absorption Rate of Insoluble Drugs," US Patent 4151273, 1978.
3. W. Dong, "Multiparticulate Drug Delivery System for Lipophilic Drugs and Macomolecules," PhD dissertation in Chemistry,
Freie Universität, Berlin, 2005.
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Thermoplastic System-To Improve the Bioavailability of a Novel Microsomal Triglyceride Transfer Protein Inhibitor," J. Pharma. Sci. 93 (5), 1217–1228 (2004).
5. R.J. Pomerantz, "Combining Biomedical Research within Academia and Industry in the 21st Century," presented as the keynote
address, American Association of Pharmaceutical Scientists Annual Meeting, San Diego, CA, 2007.
6. Intelence, Full Prescribing Information, Tibotec, Inc., 2008.
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29 (9), 997–1004 (2003).
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10. J.Yang et al., "Distribution Kinetics of Polymer Crystallization and the Avrami Equation," J. Chem. Phys.
122 (6), 64901–64911 (2005).
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J. Pharm. Sci. 83 (12), 1700–1705 (1994).
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Alcohols," Intl. J. Pharm.
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13. J. Yang et al., "An Improved Kinetics Model to Describe Drug Amorphous Stability," poster presented at the American Association
of Pharmaceutical Scientists Annual Meeting, San Diego, CA, 2007.