Abstract
Objective
Amorphous pharmaceuticals, a viable approach to enhancing bioavailability, must be stable against crystallization. An amorphous drug can be stabilized by dispersing it in a polymer matrix. To implement this approach, it is desirable to know the drug’s solubility in the chosen polymer, which defines the maximal drug loading without risk of crystallization. Measuring the solubility of a crystalline drug in a polymer is difficult because the high viscosity of polymers makes achieving solubility equilibrium difficult.
Method
Differential Scanning Calorimetry (DSC) was used to detect dissolution endpoints of solute/polymer mixtures prepared by cryomilling. This method was validated against other solubility-indicating methods.
Results
The solubilities of several small-molecule crystals in polymers were measured for the first time near the glass transition temperature, including d-mannitol (β polymorph) in PVP, indomethacin (γ polymorph) in PVP/VA, and nifedipine (α polymorph) in PVP/VA.
Conclusion
A DSC method was developed for measuring the solubility of crystalline drugs in polymers. Cryomilling the components prior to DSC analysis improved the uniformity of the mixtures and facilitated the determination of dissolution endpoints. This method has the potential of providing useful data for designing physically stable formulations of amorphous drugs.
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References
M. Vasanthavada, W. Tong, Y. Joshi, and M. S. Kislalioglu. Phase behavior of amorphous molecular dispersions I: determination of the degree and mechanism of solid solubility. Pharm. Res. 21:1598–1606 (2004).
M. Vasanthavada, W. Tong, Y. Joshi, and M. S. Kislalioglu. Phase behavior of amorphous molecular dispersions II: role of hydrogen bonding in solid solubility and phase separation kinetics. Pharm. Res. 22:440–448 (2004).
P. J. Marsac, S. L. Shamblin, and L. S. Taylor. Theoretical and practical approaches for prediction of drug–polymer miscibility and solubility. Pharm. Res. 23:2417–2426 (2006).
P. J. Marsac, T. Li, and L. S. Taylor. Estimation of drug–polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm. Res. in press (2008).
R. Mohan, H. Lorenz, and A. S. Myerson. Solubility measurement using differential scanning calorimetry. Ind. Eng. Chem. Res. 41:4854–4862 (2002).
K. Park, J. M. B. Evans, and A. S. Myerson. Determination of solubility of polymorphs using differential scanning calorimetry. Cryst. Growth Des. 3:991–995 (2003).
R. Tamagawa, W. Martins, S. Derenzo, A. Bernardo, M. Rolemberg, P. Carvan, and M. Giulietti. Short-cut method to predict the solubility of organic molecules in aqueous and nonaqueous solutions by differential scanning calorimetry. Cryst. Growth Des. 6:313–320 (2006).
V. Andronis, and G. Zografi. Crystal nucleation and growth of indomethacin polymorphs from the amorphous state. J. Non-Cryst. Solids. 271:236–248 (2000).
V. Andronis, and G. Zografi. Molecular mobility of supercooled amorphous indomethacin, determined by dynamic mechanical analysis. Pharm. Res. 14:410–419 (1997).
M. Yoshioka, B. C. Hancock, and G. Zografi. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J. Pharm. Sci. 83:1700–1705 (1994).
T. Wu, and L. Yu. Origin of enhanced crystal growth kinetics near Tg probed with indomethacin polymorphs. J. Phys. Chem. B. 110:15694–15699 (2006).
S. R. Vippagunta, K. A. Maul, S. Tallavajhala, and D. J. W. Grant. Solid-state characterization of nifedipine solid dispersions. Int. J. Pharm. 236:111–123 (2002).
N. Zajc, A. Obreza, M. Bele, and S. Srcic. Physical properties and dissolution behaviour of nifedipine/mannitol solid dispersions prepared by hot melt method. Int. J. Pharm. 291:51–58 (2005).
I. Sugimoto, A. Kuchiki, and H. Nakagawa. Stability of nifedipine–polyvinylpyrrolidone coprecipitate. Chem. Pharm. Bull. 29:1715–1723 (1981).
H. Ishida, T. Wu, and L. Yu. Sudden rise of crystal growth rate of nifedipine near Tg without and with polyvinylpyrrolidone. J. Pharm. Sci. 96:1131–1138 (2007).
L. S. Taylor, and G. Zografi. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res. 14:1691–1698 (1997).
T. Matsumoto, and G. Zografi. Physical properties of solid molecular dispersions of indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinyl-acetate) in relation to indomethacin crystallization. Pharm. Res. 16:1722–1728 (1999).
T. Miyazaki, S. Yoshioka, Y. Aso, and S. Kojima. Ability of polyvinylpyrrolidone and polyacrylic acid to inhibit the crystallization of amorphous acetaminophen. J. Pharm. Sci. 93:2710–2717 (2004).
K. J. Crowley, and G. Zografi. Cryogenic grinding of indomethacin polymorphs and solvates: assessment of amorphous phase formation and amorphous phase physical stability. J. Pharm. Sci. 91:492–507 (2002).
L. Yu, D. S. Mishra, and D. R. Rigsbee. Determination of the glass properties of d-mannitol using sorbitol as an impurity. J. Pharm. Sci. 87:774–777 (1998).
L. Yu, J. Huang, and K. J. Jones. Measuring free-energy difference between crystal polymorphs through eutectic melting. J. Phys. Chem. B. 109:19915–19922 (2005).
L. Yu. Nucleation of one polymorph by another. J. Am. Chem. Soc. 125:6380–6381 (2003).
J. Tao, and L. Yu. Kinetics of cross-nucleation between polymorphs. J. Phys. Chem. B. 110:7097–7101 (2006).
M. K. Mapes, S. F. Swallen, and M. D. Ediger. Self-diffusion of supercooled o-terphenyl near the glass transition temperature. J. Phys. Chem. B. 110:507–511 (2006).
Acknowledgment
We thank Abbott Laboratories for supporting this work and Dr. Feng Qian of BMS for the helpful discussions about the T end/T g diagrams.
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Tao, J., Sun, Y., Zhang, G.G.Z. et al. Solubility of Small-Molecule Crystals in Polymers: d-Mannitol in PVP, Indomethacin in PVP/VA, and Nifedipine in PVP/VA. Pharm Res 26, 855–864 (2009). https://doi.org/10.1007/s11095-008-9784-z
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DOI: https://doi.org/10.1007/s11095-008-9784-z