Amorphous pharmaceutical solids: preparation, characterization and stabilization.

The importance of amorphous pharmaceutical solids lies in their useful properties, common occurrence, and physicochemical instability relative to corresponding crystals. Some pharmaceuticals and excipients have a tendency to exist as amorphous solids, while others require deliberate prevention of crystallization to enter and remain in the amorphous state. Amorphous solids can be produced by common pharmaceutical processes, including melt quenching, freeze- and spray-drying, milling, wet granulation, and drying of solvated crystals. The characterization of amorphous solids reveals their structures, thermodynamic properties, and changes (crystallization and structural relaxation) in single- and multi-component systems. Current research in the stabilization of amorphous solids focuses on: (i) the stabilization of labile substances (e.g., proteins and peptides) during processing and storage using additives, (ii) the prevention of crystallization of the excipients that must remain amorphous for their intended functions, and (iii) the selection of appropriate storage conditions under which amorphous solids are stable.

[1]  R. Wasylishen,et al.  Towards understanding 13C-N.M.R. chemical shifts of carbohydrates in the solid state. The spectra of d-mannitol polymorphs and of dl-mannitol , 1990 .

[2]  Ranko Richert,et al.  Dynamics of glass-forming liquids. V. On the link between molecular dynamics and configurational entropy , 1998 .

[3]  C. Lacabanne,et al.  A review of thermo-stimulated current , 1993, IEEE Electrical Insulation Magazine.

[4]  M. Sutton,et al.  Fragility of glass-forming systems and the width of the glass transition , 1996 .

[5]  F. Stillinger,et al.  Packing Structures and Transitions in Liquids and Solids , 1984, Science.

[6]  R. Suryanarayanan,et al.  In Situ Dehydration of Carbamazepine Dihydrate: A Novel Technique to Prepare Amorphous Anhydrous Carbamazepine , 2000, Pharmaceutical development and technology.

[7]  I. Pitkänen,et al.  Thermoanalytical studies on phases of D-mannitol , 1993 .

[8]  R. Hatley Glass fragility and the stability of pharmaceutical preparations--excipient selection. , 1997, Pharmaceutical development and technology.

[9]  D. Mishra,et al.  Existence of a mannitol hydrate during freeze-drying and practical implications. , 1999, Journal of pharmaceutical sciences.

[10]  S. Magazù TRANSPORT PHENOMENA AND ANOMALOUS GLASS-FORMING BEHAVIOUR IN ALPHA , ALPHA-TREHALOSE AQUEOUS SOLUTIONS , 1999 .

[11]  C. Lacabanne,et al.  Thermal analysis of amorphous phase in a pharmaceutical drug , 1997 .

[12]  Cornelius T. Moynihan,et al.  Correlation between the Width of the Glass Transition Region and the Temperature Dependence of the Viscosity of High‐Tg Glasses , 1993 .

[13]  M. Descamps,et al.  Molecular motions in molecular glasses as studied by thermally stimulated depolarisation currents (TSDC) , 2000 .

[14]  S. Yoshioka,et al.  Effect of mannitol crystallinity on the stabilization of enzymes during freeze-drying. , 1994, Chemical & pharmaceutical bulletin.

[15]  P. Claudy,et al.  Etude du comportement thermique des hexitols , 1993 .

[16]  F. Princivalle,et al.  Polymorphic Amorphous and Crystalline Forms of Trehalose , 1998 .

[17]  J. Blair,et al.  Stabilisation and delivery of labile materials by amorphous carbohydrates and their derivatives , 1999 .

[18]  P. Couchman The composition‐dependent glass transition: Relations between temperature pressure, and composition , 1984 .

[19]  E. Topp,et al.  Solid-state chemical stability of proteins and peptides. , 1999, Journal of pharmaceutical sciences.

[20]  S. Magazù,et al.  Anomalous cryoprotective effectiveness of trehalose: Raman scattering evidences , 1999 .

[21]  Bruno C. Hancock,et al.  Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. , 1994, Journal of pharmaceutical sciences.

[22]  P. Royall,et al.  The relevance of the amorphous state to pharmaceutical dosage forms: glassy drugs and freeze dried systems. , 1999, International journal of pharmaceutics.

[23]  W. Mccrone,et al.  Pharmaceutical applications of polymorphism. , 1969, Journal of pharmaceutical sciences.

[24]  John T. Fourkas,et al.  Supercooled liquids : advances and novel applications , 1997 .

[25]  P. Mehl Calorimetric investigation of the glass transition and relaxation in 60:40 ethylene glycol: water: Part 1. Isothermal annealing experiments , 1993 .

[26]  D. Law,et al.  Nucleation and crystallization kinetics of hydrated amorphous lactose above the glass transition temperature. , 1999, Journal of pharmaceutical sciences.

[27]  Andrew Streitwieser,et al.  Introduction to organic chemistry , 1976 .

[28]  D. Craig,et al.  Characterisation of spray-dried lactose using modulated differential scanning calorimetry , 1998 .

[29]  P. Darcy,et al.  Assessment of disorder in crystalline powders--a review of analytical techniques and their application. , 1999, International journal of pharmaceutics.

[30]  S. Nail,et al.  The physical state of mannitol after freeze-drying: effects of mannitol concentration, freezing rate, and a noncrystallizing cosolute. , 1998, Journal of pharmaceutical sciences.

[31]  J. Rollinger,et al.  Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol. , 2000, Journal of pharmaceutical sciences.

[32]  S. Riegelman,et al.  Pharmaceutical applications of solid dispersion systems. , 1971, Journal of pharmaceutical sciences.

[33]  G. A. Jeffrey,et al.  The crystal structure of the K form of d‐mannitol , 1968 .

[34]  C. Angell,et al.  One- and two-step calorimetric studies of crystallization kinetics in simple ionic glass-forming liquids. 1. Calcium nitrate-potassium nitrate system , 1991 .

[35]  T A Jennings,et al.  The effects of cooling rate on solid phase transitions and associated vial breakage occurring in frozen mannitol solutions. , 1986, Journal of parenteral science and technology : a publication of the Parenteral Drug Association.

[36]  J. Carpenter,et al.  The role of vitrification in anhydrobiosis. , 1998, Annual review of physiology.

[37]  J. Christian,et al.  The theory of transformations in metals and alloys , 2003 .

[38]  G. Zografi,et al.  Crystal nucleation and growth of indomethacin polymorphs from the amorphous state , 2000 .

[39]  T. Fox Influence of Diluent and of Copolymer Composition on the Glass Temperature of a Poly-mer System , 1956 .

[40]  G. A. Jeffrey,et al.  Conformations of the alditols , 1970 .

[41]  G Zografi,et al.  How does residual water affect the solid-state degradation of drugs in the amorphous state? , 1996, Journal of pharmaceutical sciences.

[42]  Kang Xu,et al.  Fragility in Liquids and Polymers: New, Simple Quantifications and Interpretations , 1999 .

[43]  Michael J. Pikal,et al.  Freeze‐Drying of Proteins. Process, Formulation, and Stability. , 1995 .

[44]  C. Lefebvre,et al.  Study of Different Crystalline forms of Mannitol: Comparative Behaviour under Compression , 1987 .

[45]  S. Srčič,et al.  Thermal analysis of glassy pharmaceuticals , 1995 .

[46]  R. Niven,et al.  Delivery of biotherapeutics by inhalation aerosol. , 1995, Critical reviews in therapeutic drug carrier systems.

[47]  T. Arakawa,et al.  Interactions of Stabilizers with Proteins During Freezing and Drying. , 1995 .

[48]  G. Höhne,et al.  Temperature calibration on cooling using liquid crystal phase transitions , 1993 .

[49]  Martin Goldstein,et al.  Viscous Liquids and the Glass Transition. II. Secondary Relaxations in Glasses of Rigid Molecules , 1970 .

[50]  C. Angell,et al.  Nonexponential relaxations in strong and fragile glass formers , 1993 .

[51]  G. P. Johari,et al.  Characterizing amorphous and microcrystalline solids by calorimetry , 1990 .

[52]  G. A. Jeffrey,et al.  The crystal structure of xylitol , 1969 .

[53]  C. T. Moynihan,et al.  Estimation of activation energies for structural relaxation and viscous flow from DTA and DSC experiments , 1996 .

[54]  S. Nagel,et al.  Supercooled Liquids and Glasses , 1996 .

[55]  Hajime Tanaka Two-order-parameter description of liquids. I. A general model of glass transition covering its strong to fragile limit , 1999 .

[56]  D. Mishra,et al.  Determination of the glass properties of D-mannitol using sorbitol as an impurity. , 1998, Journal of pharmaceutical sciences.

[57]  C. Lacabanne,et al.  Dielectric relaxations of collagen and elastin in the dehydrated state , 2000 .

[58]  G. A. Jeffrey,et al.  The crystal structures of the a' and forms of D-mannitol , 1968 .

[59]  C. Angell Relaxation in liquids, polymers and plastic crystals — strong/fragile patterns and problems☆ , 1991 .

[60]  N. A. Williams,et al.  Vial breakage by frozen mannitol solutions: correlation with thermal characteristics and effect of stereoisomerism, additives, and vial configuration. , 1991, Journal of parenteral science and technology : a publication of the Parenteral Drug Association.

[61]  R. Langer,et al.  Formulation and delivery of proteins and peptides , 1994 .

[62]  P. Mehl Determination of enthalpy relaxation times using traditional differential scanning calorimetry for glycerol and for propylene glycol , 1996 .

[63]  G. Desiraju Organic solid state chemistry , 1987 .

[64]  C. A. Mitchell,et al.  Crystallization and Polymorphism of Conformationally Flexible Molecules: Problems, Patterns, and Strategies , 2000 .

[65]  I. Hodge Strong and fragile liquids — a brief critique , 1996 .

[66]  Å. Fransson,et al.  Accurate temperature calibration of differential scanning calorimeters , 1996 .

[67]  D. Wallace,et al.  Thermodynamics of Crystals , 1972 .

[68]  Hajime Tanaka Two-order-parameter description of liquids. II. Criteria for vitrification and predictions of our model , 1999 .

[69]  M. Hanaya,et al.  Microscopic observation of a peculiar crystallization in the glass transition region and β-process as potentially controlling the growth rate in triphenylethylene , 1999 .

[70]  H. Zimmermann,et al.  Structural relaxation of the fragile glass-former propylene carbonate studied by nuclear magnetic resonance , 2000 .

[71]  M. Pikal,et al.  Quantitative crystallinity determinations for beta-lactam antibiotics by solution calorimetry: correlations with stability. , 1978, Journal of pharmaceutical sciences.

[72]  I. Hodge Enthalpy relaxation and recovery in amorphous materials , 1994 .

[73]  Kaori Ito,et al.  Thermodynamic determination of fragility in liquids and a fragile-to-strong liquid transition in water , 1999, Nature.

[74]  M. Descamps,et al.  Slow structural relaxations of glass-forming Maltitol by modulated DSC calorimetry , 1999 .

[75]  G. P. Johari Effect of annealing on the secondary relaxations in glasses , 1982 .

[76]  D S Reid,et al.  Is trehalose special for preserving dry biomaterials? , 1996, Biophysical journal.

[77]  Christopher T. Rhodes,et al.  The spray drying of pharmaceuticals , 1992 .

[78]  Bruno C. Hancock,et al.  Characteristics and significance of the amorphous state in pharmaceutical systems. , 1997, Journal of pharmaceutical sciences.

[79]  Paul F. McMillan,et al.  Polymorphic Phase Transitions in Liquids and Glasses , 1997, Science.

[80]  J. C. Tucker,et al.  Dependence of the glass transition temperature on heating and cooling rate , 1974 .

[81]  J. Létoffé,et al.  Study of the respective binary phase diagrams of sorbitol with mannitol, maltitol and water , 1999 .

[82]  T. Threlfall Analysis of organic polymorphs. A review , 1995 .

[83]  H. Brittain Polymorphism in Pharmaceutical Solids , 1999 .

[84]  C. Angell,et al.  The protein-glass analogy: New insight from homopeptide comparisons , 1994 .

[85]  N. B. Olsen Scaling of β-relaxation in the equilibrium liquid state of sorbitol , 1998 .

[86]  C. Angell,et al.  Formation of Glasses from Liquids and Biopolymers , 1995, Science.

[87]  Wendell Q. Sun,et al.  Protein stability in the amorphous carbohydrate matrix: relevance to anhydrobiosis. , 1998, Biochimica et biophysica acta.

[88]  G. Adam,et al.  On the Temperature Dependence of Cooperative Relaxation Properties in Glass‐Forming Liquids , 1965 .

[89]  H. Wagner,et al.  Spatial uniformity of the β-relaxation in D-sorbitol , 1998 .

[90]  G. Stephenson,et al.  Physical characterization of polymorphic drugs: an integrated characterization strategy , 1998 .

[91]  A. Saleki-Gerhardt,et al.  Hydration and dehydration of crystalline and amorphous forms of raffinose. , 1995, Journal of pharmaceutical sciences.

[92]  C. Angell,et al.  Glass transition temperatures for simple molecular liquids and their binary solutions , 1978 .