Gannu Praveen Kumar, Bakka Sravan Kumar


Interest  in  amorphous  pharmaceutical  systems  is  steadily growing  over  the  last  10  years.   The  amorphous  state  is  critical  in determining  the  solid  state,  physical  and  chemical  properties  of many pharmaceutical dosage forms. The main reason of the growing interest  toward  amorphous  materials  is  the  need  to  improve  the bioavailability  of  drugs  with  poor  aqueous  solubility.  Many  drugs exist in crystalline solid form due to reasons of stability and ease of handling during the various stages of drug development. Conversion of  the  crystalline  to  amorphous  form  may  occur  during  various pharmaceutical  processes.   This  could  change  the  dissolution  rate and  transport  characteristics  of  the  drug.  The  current  focus  of research  in  this  area  is  to  understand  the  origins  of  amorphous forms.  The  various  thermodynamic  phenomena  such  as  glass transition,  fragility,  molecular  mobility,  devitrification  kinetics, molecular  level  chemical  interactions,  solubility  and  stability  are critically  discussed.  The  aim  of  this  review  is  to  understand  the recent  development  in  the  area  of  amorphous  state  and  to  address the  current  challenges  faced  by  pharmaceutical  formulation  and process  development  scientists  and  thus  is  mandatory  to  anticipate future developments.

Key words:  Crystalline solids, amorphous forms, characterization, stabilization.

Full Text:



Adam, G., and Gibbs, J.H., 1965, On the temperature dependence of cooperative relaxation properties in glass-forming liquids, J. Chem, Phys. 43:139.

Aguiar, A.J., Krc, J., Kinkel, A.W., and Samyn, J.C., 1967, Effect of polymorphism on absorption of chloramphenicol from chloramphenicol palmitate. J. Pharm. Sci. 56:847-853.

Ahlneck, C., and Zografi, G., 1990, The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. Int. J. Pharm. 62: 87-95.

Alig, I., Braun, D., Lagendorf, R., Voigt, M., and Wendorff, J.H., 1997, Simultaneous ageing and crystallization processes within the glassy state of a low molecular weight substance. J. Non-Cryst, Solids. 221:261-264.

Andronis, V., Yoshioka. M., and Zografi, G.,1997, Effect of sorbed water on the crystallization of indomethacin from amorphous state. J. Pharm, Sci. 86(3): 346- 351.

Angell, C.A. 1996, Formation of glasses from liquids and biopolymers. J. Phys, Chem. 100:13200-13212.

Bhugra, C., Shmeis, R.., Krill, S.L., and Pikal, M.J., 2008, Prediction of onset of crystalzation from experimental relaxion times, II, Comparison between predicted and experimental onset times. J. Pharm, Sci. 97:455-472.

Bhugra, C., Shmeis, R., Krill, S.L., and Pikal, M.J., 2006, Predictions of onset of crystal-lization in experimental relaxation times with comparison between predicted and experimental onset times. J. Pharm, Sci. 97:455-472.

Brittain, H.G. 2002, Effects of mechanical processing on phase composition. J. Pharm. Sci. 91: 1573-1580.

Byrn, Pfeiffer, Hoiberg, Ganey, and Poochician., 1995. Pharmaceutical solids: a strategic approach to regulatory considerations Pharm. Res. 12: 945.

Carpenter, J.F., 1994, Interactions of stabilizers with proteins during freezing and drying, in Formulation and Delivery of Proteins and Peptides, ACS, Washington DC. pp. 134-147.

Carpentier, L., Decressain, R., Gusseme, A., Neves, C., dan Descamps, M., 2006, Molecular mobility in glass forming fananserine: A dielectric, NMR, and TMDSC investigation. Pharm. Res. 23:798-805.

Chawla, G., and Bansal, A.K., 2007, A comparative assessment of solubility advantage from glassy and crystalline forms of a water insoluble drug. Eur, J.Pharm, Sci. 32: 45-57.

Chiou, W.L., Riegelman S., 1970, Oral absorption of griseofulvin in dogs: Increased absorption via solid dispersion in polyethylene glycol 6000. J. Pharm. Sci. 59: 937-942.

Crocker, L.S., and McCauley, J.A., 1997,Comparison of the crystallinity of imipenem samples by X ray diffraction of amorphous material. J. Pharm, Sci. 84(2): 226-227.

Crowe, J.H., Carpenter, J.F., dan Crowe, L.M. 1998, The role of vitrification in anhydrobiosis. Annu. Rev. Physiol. 60:73-103.

Dmitri, V., and Louzguine-Luzgin., 2007,A glance on glass-transition phenomenon from the view point of devitrification. J. Alloys and Comp. 434-435 121-125.

Elliot, S.R., Rao, N.R., and Thomas, J.M., 1986, The chemistry of the non-crystalline state. Chem. Int. Ed. Engl. 25: 31-46.

Fang Z., Jaakko A., 2009, Influence of particle size and preparation methods on the physical and chemical stability of amorphous simvastatin. Eur. J.Pharm. and Biop. 71:64-70.

Fulcher, G.S., 1925, Analysis of recent measurements of the viscosity of glasses.J. Am. Ceram. Soc. 8: 339-355.

Garima C, Arvind B.K. 2009. Molecular Mobility and Physical Stability of Amorphous Irbesartan. Sci Pharm. 7:695-709.

Grant, D., Higuchi, T., 1990, Solubility Behaviour of Organic Compounds, 1st ed. John Wiley & Sons, New York.

Gupta, P., and Arvind B. K., 2005, Devitrification of Amorphous Celecoxib. AAPS. Pharm. Sci. Tech. 6(2)

Gupta, P., Kakumanu, V.K., and Bansal, A.K., 2004, Stability and solubility of celecoxib–PVP amorphous dispersions: A molecular perspective. Pharm Res. 21: 1762-1769.

Hancock, B.C., Carlson, G.T., Ladipo, D.D., Langdon, B.A., and Mullarney, M.P., 2002, Comparison of the mechanical properties of the crystalline and amorphous forms of a drug substance.Int, J. Pharm. 241(1): 73-85.

Hancock, B.C., Dupuis, Y., and Thibert, R.,1999, Determination of the viscosity of an amorphous drug using thermo mecha-nical analysis (TMA). Pharm. Res. 16:672-675.

Hancock, B.C., Parks, M., 2000, What is the true solubility advantage for amorphous pharmaceuticals?. Pharm. Res. 17:397-404.

Hancock, B.C., Shamblin, S.L., and Zografi, G., 1995, Molecular mobility of amorphous pharmaceutical solids below their glasstransition temperatures. Pharm. Res. 12: 799-806.

Hancock, B.C., Zografti, G., 1997, Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 86:1-12

Hancock, B.C. 2002, Disordered drug delivery: destiny, dynamics and the Deborah number. J. Pharm. Pharmacol. 54 (6):737-746

Hilden, L.R., Morris, K.R. 2004, Physics of amorphous solids. J. Pharm, Sci. 93:3-12.

Hodge, I.M., 1996, Strong and fragile liquids-A brief critique. J. Non-Cryst, Sol. 202:164-172.

Indrajit G., Jennifer Sr, Radha V., Marilyn A., Ronak V., Wei-Qin (Tony) T., and Sudha V., 2011, Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder. Int. J. Phar. 419:12-19

Jacob, S., Nair, A. B., Patil, P. N., and Panda B. P., 2011, Solid state crystallinity, amorphous state, and its implications in the Pharmaceutical process., Ind. J. Pharm. Sci. Rres. 2(3):472-482.

Jared, A., Baird, Lynne, S., and Taylor, 2011, Evaluation of Amorphous Solid Dispersion Properties using Thermal Analysis Techniques. S0169-409 X (11):00203-1.

Jeong-Soo, Ki., 2008, Physico-chemical properties and oral bioavailability of amorphous atorvastatin hemi-calcium using spray-drying and SAS. Int. J. Pharm. 359: 211-219.

Kawakami, K., Pikal, M.J., 2005, Calorimetric investigation of the structural relaxation of amorphous materials: Evaluating validity of the methodologies. J. Pharm. Sci. 94: 948-965.

Lian, Y., 2001, Amorphous pharmaceutical solids: preparation characterization and stabilization. Adv. Drug Del. Rev. 48: 27-42.

Longley, W., 1948. The Collected Works of J. Willard Gibbs. Yale University Press, New Haven.

Marsac, P.J., Konno, H., Rumondor , A.C.F., and Taylor, L.S., 2008, Recrystallization of nifedipine and felodipine from amorphous molecular level solid dispersions containing poly (vinylpyrrolidone) and sorbed water. Pharm, Res. 25:647-656.

Marsac, P.J., Konno, H., and Taylor, L.S., 2006, A comparison of the physical stability of amorphous felodipine and nifedipine systems. Pharm. Res. 23: 2306-2316.

Morris, K.R., Griesser, U.J., Eckhardt, C.J., and Stowell, J.G., 2001, Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes. Adv. Drug Deliv.Rev. 48:91-114.

Nagapudi, K., and Jona, J., 2008, Amorphous Active Pharmaceutical Ingredients in preclinical Studies: Preparation, Characterization, and Formulation Current Bioactive Compounds. 4:213-224

Onoue, S., Sato, H., Kawabata, Y., Mizumoto, T., Hashimoto, N., Yamada., S., 2009, In vitro and in vivo characterization on amorphous solid dispersion of cyclosporine A for inhalation therapy. J.

Contr. Rele. 138:16-23

Onoue, S., Sato, H., Ogawa, K., Kawabata, Y., Mizumoto, T., Yuminoki, K., Hashimoto, N., and Yamada, S., 2010,

Improved dissolution and pharmacokinetic behavior of cyclosporine, A using high-energy amorphous solid dispersion approach. Int. J. Pharm. 399:94-101.

Parks, G.S., Huffman, S.W., and Cattoir, F.R., 1928, Studies on glass II, The transition between the glassy and liquid states in the case of glucose. J. Phys. Chem. 32:1366-1379.

Parks, G.S., Snyder, L.J., and Cattoir, F.R. 1934, Studies on glass XI, Some thermo dynamic relations of glassy and alphacrystalline glucose. J. Chem. Phys. 2:595.

Pikal, M., 1994, Freeze-drying of proteins: process, formulation and stability, in Formulation and Delivery of Proteins and peptides, by Cleland, L.J., Langer, R., ACS, Washington DC. pp 20-133.

Pjohari, G., 2001, On extrapolating a supercooled liquid‟s excess entropy, the vibrational component, and reinterpreting the configurational entropy theory. J. Phys, Chem. B105:3600-3604.

Privalko, V.P., 1980, Excess entropies and related quantities in glass-forming liquids. J. Phys. Chem. 84:3307-3312.

Richard Z., 1998, The physics of amorphous solids 1st Edition. Wiley, John & Sons, New York.

Robertson, C.G., Santangelo, P.G., and Roland, C.M., 2000, Comparison of Glass Formation Kinetics and Segmental Relaxation in Polymers. J. of Non-Cryst. Solid. 275: 153-159.

Rodrıguez-Hornedo, N., Murphy, D., 1999. Significance of controlling crystallization mechanisms and kinetics in pharmaceutical systems. J. Pharm. Sci. 88:651-660.

Saleki-Gerhardt, A., Stowell, J.G., Byrn, S.R., and Zografi, G., 1995, Hydration and dehydration of crystalline and amorphous forms of raffinose. J. Pharm, Sci. 84:318-323

Savolainen, M., Kogermann, K., Heinz, A., Aaltonen, J., Peltonen, L., Strachan, C., and Liruusi, J.Y., 2009, Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy. Eur, J. Pharm. Biopharm. 71:7179

Schmelzer, J., 2008, Crystal nucleation and growth in glass-forming melts: Experiment and theory. J. Non-Cryst. Sol. 354:269-278.

Shamblin, S.L., Tang, X., Chang, L., Hancock, B.C., and Jpikal, M., 1999, Characterization of the time scales of molecular motion in pharmaceutically important glasses. J Phys Chem. B 103: 4113-4121.

Shmeis, R.A., Wang, Z., and Krill, S.L., 2004, A mechanistic investigation of an amorphous pharmaceutical and its solid dispersions, Part II: Molecular mobility and activation thermodynamic parameters. Pharm. Res. 21:2031-2039.

Sun, W.Q., Davidson, P., and Chan, H.S.O., 1998, Protein stability in amorphous carbohydrate matrix: Relavance to anhydrobio-sis,Biochim. Biophys. Acta. 1425:245- 254.

Takeuchi, H., Nagira, S., Yamamoto, H., and Kawashima, Y., 2005, Solid dispersion particles of amorphous in dome thacin with fine porous silica particles by using spray-drying method. Int. J. Phar. 293:155-164.

Tammann, G., Hesse, W., 1926. The dependency of viscosity on temperature in hypothermic liquids. Z. Anorg. Allg. Chem. 4:156.

Tang, X.C., Pikal, M.J., and Taylor, L.J. 2002, A spectroscopic investigation of hydrogen bond patterns in crystalline

and amorphous phases in dihydropyridine calcium channel blockers. Pharm Res. 19:477-483

Tombari, E., Ferrari, C., Johari, G.P., and Shanker, RM., 2008, Calorimetric relaxation in pharmaceutical molecular glasses and its utility in understanding their stability against crystallization. J. Phys. Chem. B. 112:10806-10814

Vogel, H., 1921, The temperature dependence law of the viscosity of fluids. Physikal Zeitschr. 22:645-646

Vyazovkin, S., Dranca, I., 2007, Effect of physical aging on nucleation of amorphous indomethacin. J. Phys. Chem. B. 111: 7283-7287

Vyazovkin, S., Dranca, I., 2006, Probing beta relaxation in pharmaceutically relevant glasses by using DSC. Pharm. Res. 23:422-428.

Weuts, I., Kempen, D., and Six, K., 2003, Evaluation of different calorimetric methods to determine the glass transition temperature and molecular mobility below Tg for amorphous drugs.

Int. J. Phar. 17-25.

Williams, G., Watts, D.C., 1970, Nonsymmetrical dielectric relaxation be haviour arising from a simple empirical decay function. Trans. Faraday Soc. 66-80.

Yoshioka, M., 1994, Crystallization of in domethacin from the amorphous state below and above its glass-transition temperature. J. Pharm. Sci. 83:1700-1705.

Yoshioka, S., Aso, Y., 2007, Correlations between molecular mobility and chemical stability during storage of amorphous pharmaceuticals. J. Pharm, Sci. 96:960-981.

Yoshioka, Y., Kojima, S., 2004, Molecular mobility-based estimation of the crystallization rates of amorphous nifedipine and phenobarbital in poly (vinylpyrrolidone) solid dispersions. J. Pharm. Sci. 93:384-391 .

Yoshioka, Y.S., Kojima, S., 2001, Explanation of the crystallization rate of amorphous nifedipine and phenobarbital from their molecular mobility as measured by 13C nuclear magnetic resonance relaxation time and the relaxation time obtained from the heating rate dependence of the glass transition temperature. J. Pharm. Sci.90:798-806.

Yu, L., 2001, Amorphous pharmaceutical solids, preparation, characterization and stabilization. Adv. Drug Del. Rev. 48:27-42.

Zhou, D., Zhang, G.G.Z., Law, D., Grant, D.L.W., and Schmitt, E.A., 2002, Physical stability of amorphous pharmaceuticals, importance of configurationnally thermodynamic quantities and molecular mobility. J. Pharm. Sci.91:1863-1872.

Zografi, G., and Hancock, B.C., 1994, Water solid interactions in pharmaceutical systems. Proceedings of the International Pharmaceutical Federation Conference. Tokyo, Japan. pp. 405-419



  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

Indonesian J Pharm indexed by:


analytics View My Stats