“This book, with the historical background information, reviews and original contributions, should be of interest to a wide audience of scientists and technologies concerned with foods and pharmaceuticals. Students in these areas will also be able to browse through the book with profit …”– “Journal of Texture Studies, Vol 34, No 3, p 347-348”

Amorphous Food and Pharmaceutical Systems

By Harry Levine

The Royal Society of Chemistry

Copyright © 2002 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-866-3

Contents

Introduction – Progress in Amorphous Food and Pharmaceutical Systems H. Levine, 1,
Structure and its Significance in the Application Technology of Amorphous Materials,
The Concept of ‘Structure’ in Amorphous Solids from the Perspective of the Pharmaceutical Sciences E. Shalaev and G. Zografi, 11,
Analytical Model for the Prediction of Glass Transition Temperature of Food Systems V. Truong, B.R. Bhandari, T. Howes and B. Adhikari, 31,
Microstructural Domains in Foods: Effect of Constituents on the Dynamics of Water in Dough, as Studied by Magnetic Resonance Spectroscopy Y. Kou, E. W. Ross and I.A. Taub, 48,
Supplemented State Diagram for Sucrose from Dynamic Mechanical Thermal Analysis I. Braga da Cruz, W.M. MacInnes, J.C. Oliveira and F.X. Malcata, 59,
Glassy State Dynamics and its Significance for Stabilization of Labile Bioproducts,
Glassy State Dynamics, its Significance for Biostabilisation and the Role of Carbohydrates R. Parker, Y.M. Gunning, B. Lalloué, T.R. Noel and S.G. Ring, 73,
Influence of Physical Ageing on Physical Properties of Starchy Materials D. Lourdin, P. Colonna, G. Brownsey and S. Ring, 88,
Uptake and Transport of Gas in Microstructured Amorphous Matrices A. Schoonman, J.B. Ubbink, W.M. MacInnes and H.J. Watzke, 98,
Theories of Unstable Aqueous Systems: How Can They Help the Technologist?,
Recent Developments in the Theory of Amorphous Aqueous Systems P.G. Debenedetti and J.R. Errington, 115,
Studies on Raffinose Hydrates K. Kajiwara, A. Motegi, M. Sugie, F. Franks, S. Munekawa, T. Igarashi and A. Kishi, 121,
Comparison between WLF and VTF Expressions and Related Physical Meaning A. Schiraldi, 131,
Progress in Food Processing and Storage,
Progress in Food Processing and Storage, Based on Amorphous Product Technology L. Slade and H. Levine, 139,
The Effect of Microstructure on the Complex Glass Transition Occurring in Frozen Sucrose Model Systems and Foods H.D. Goff, K. Montoya and M.E. Sahagian, 145,
Relationship between the Glass Transition, Molecular Structure and Functional Stability of Hydrolyzed Soy Proteins V. Zylberman and A.M.R. Pilosof, 158,
A Study of Vitrification of Australian Honeys at Different Moisture Contents P.A. Sopade, B. Bhandari, B. D’Arcy, P. Halley and N. Caffin, 169,
Rational Pharmaceutical Formulation of Amorphous Products,
Rational Formulation Design – Can the Regulators be Educated? T. Auffret, 187,
Solid–Liquid State Diagrams in Pharmaceutical Lyophilisation: Crystallization of Solutes E. Shalaev and F. Franks, 200,
Miscibility of Components in Frozen Solutions and Amorphous Freeze-dried Protein Formulations K.-I. Izutsu and S. Kojima, 216,
Investigations into the Amorphous and Crystalline Forms of a Development Compound D. O’Sullivan, G. Steele and T.K. Austin, 220,
Thermophysical Properties of Amorphous Dehydrated and Frozen Sugar Systems, as Affected by Salts M.F. Mazzobre, M.P. Longinotti, H.R. Corti and M.P. Buera, 231,
Glass-forming Ability of Polyphosphate Compounds and Their Stability K. Kawai, T. Suzuki, T. Hagiwara and R. Takai, 244,
Chemistry in Solid Amorphous Matrices,
Chemistry in Solid Amorphous Matrices: Implication for Biostabilization M.J. Pikal, 257,
Residual Water, its Measurement, and its Effects on Product Stability,
Residual Water in Amorphous Solids: Measurement and Effects on Stability D. Lechuga-Ballesteros, D.P. Miller and J. Zhang, 275,
A Decrease in Water Adsorption Ability of Amorphous Starch Subjected to Prolonged Ball-milling is Accompanied by Enthalpy Relaxation T. Suzuki, Y.J. Kim, C. Pradistsuwana and R. Takai, 317,
Novel Experimental Approaches to Studies of Amorphous Aqueous Systems,
Use, Misuse and Abuse of Experimental Approaches to Studies of Amorphous Aqueous Systems D.S. Reid, 325,
Glass Transition and Ice Crystallisation of Water in Polymer Gels, Studied by Oscillation DSC, XRD–DSC Simultaneous Measurements, and Raman Spectroscopy N. Murase, M. Ruike, S. Yoshioka, C. Katagiri and H. Takahashi, 339,
Subject Index, 347,

CHAPTER 1

The Concept of ‘Structure’ in Amorphous Solids from the Perspective of the Pharmaceutical Sciences

Evgenyi Shalaev and George Zografi

1 Introduction

Partially or completely amorphous pharmaceutical materials are often created during the manufacture of dosage forms, when an initially highly crystalline bulk drug is processed by standard methods, such as milling, compaction, wet granulation, freeze-drying and spray-drying. The importance of amorphous materials in pharmaceutical research and development has been highlighted in a number of reviews. Formation of a disordered solid may be intentional, when higher solubility and bioavailability are desired, or it may be accidental, during the processing of crystalline materials. In both cases, the physical and chemical stability of such a disordered solid drug must be considered to have possibly been compromised. Because of the very strict regulatory requirements for maintaining the stability of pharmaceuticals, an understanding of amorphous/crystal relationships is an essential part of the drug development process.

In the pharmaceutically related literature on amorphous solids, the main focus has been on studies of the relationships between molecular mobility and chemical and physical stability. In particular, many efforts have been devoted to identifying a ‘critical’ temperature, below which an amorphous material will be completely stable on practical time scales. Candidates for such a critical stability temperature include the glass transition temperature (Tg) a ‘chemical reaction glass transition temperature’ and the Kauzmann temperature (TK or T0) (see refs. 4–7 for examples). It has been recognized, however, that although molecular mobility is important, it is not the only factor that determines the stability of amorphous solids. For example, it has been suggested recently that effects (e.g. polarity) of the medium can be important in controlling the chemical stability of amorphous solids. In particular, the role of ‘solid-state pH’ in amorphous systems is attracting increasing attention in the pharmaceutical literature.

Another critical factor that is expected to have a significant impact on the stability of amorphous solids is the structural nature of molecules in the solid state. Indeed, there are well-established relationships between crystal structure and chemical reactivity in crystalline solids. However, studies on amorphous structure/stability relationships are still under-represented in the pharmaceutical literature. In the present paper, we review different aspects of the structural features of amorphous solids, in relation to their chemical and physical stability. The paper includes five following sections. In the first, we ask the following question, ‘is there more than one amorphous state of the same material?’ In particular, the issue of ‘polyamorphism’ is considered. Both true polyamorphism (i.e. involving a phase transition between two amorphous phases) and relaxation ‘polyamorphism’, where there is a continuous space of dynamic amorphous states, are discussed. The second section is devoted to the microscopic heterogeneity of amorphous materials, and in particular, how this might relate to chemical reactivity. The third part of this review considers the (dis)similarity between local structures of amorphous and crystalline states of the same material. Several examples, such as indomethacin and polyhydroxy compounds, are considered and possible relationships between differences in the local structures of amorphous solids vs crystals and crystallization potential of amorphous solids are highlighted. The topic of crystalline mesophases is considered in the fourth section. Such mesophases include liquid crystals, plastic crystals/orientationally disordered crystals and conformationally disordered crystals, all of which combine the properties of both crystalline (i.e. long-range order) and amorphous (i.e. glass transition) materials and are considered to be intermediate between crystalline and amorphous states. The last part of this review deals with the glass transition of material in small or confined spaces. Examples of ‘confined glasses’ in pharmaceutical systems include slightly disordered crystalline materials, liposome/drug complexes, and frozen aqueous solutions of carbohydrates or proteins.

2 Polyamorphism

It is well-established that the properties of amorphous glasses can be different for the same material, depending on the previous history of treatment and time of storage. Thus, from a kinetic perspective, we can speak of an amorphous glass as existing in different states with different glass properties, e.g. Tg, relaxation time. For those interested in the stability of amorphous states, the differentiation of such states is of great interest. Such differences can be depicted in the form of a Gibbs free energy plot, as shown in Figure 1. In contrast to behavior based on kinetic properties, which is described by curves ‘glass 2’ and ‘glass 2”, we can also encounter true polyamorphic systems, where a first-order phase transition occurs between two amorphous phases in the supercooled or equilibrium liquid state, as depicted by curves ‘liquid 1’ and ‘liquid 2’ (Figure 1). In addition, Figure 1 illustrates that liquid/liquid phase transitions may be hindered, if Tg1 happens to be higher than the temperature of liquid/liquid phase transition, T11. Such phase transitions between two liquids with different structures and densities have been predicted theoretically. A first-order transition between two liquid phases of the same composition, for example, has been described by a potential energy hypersurface with megabasins that show local minima of potential energy in a glassy state. Angell has suggested that ‘polyamorphs’ differ in their strength, with a low-density form acting as a ‘strong glass-former’ and a high-density form as a ‘fragile glass-former’. Experimental examples of materials showing such phase transitions between amorphous phases with different densities include water, silica, carbon, and the melt of Y2O3-Al2O3.

For organic materials, there are fewer documented examples of polyamorphism than for inorganic substances. For several polymers, e.g. atactic poly(styrene) (at-PS), atactic poly(methylmethacrytate) (at-PMMA), atactic poly(propylene oxide) (at-PPO), isotactic poly(methylmethacrylate) (it-PMMA) and isotactic poly(vinyl chloride) (it-PVC), a liquid/liquid phase transition has been observed at T between Tg and the melting temperature, Tm. This liquid/liquid phase transition usually occurs at a temperature approximately equal to 1.2Tg (in Kelvin). The transition is considered to be highly cooperative (involving the entire polymer chain), corresponding to a transition from a polymer melt with local order to a completely disordered polymer melt. A special case of polyamorphism in biological polymers might be associated with native vs denatured proteins, which can form glassy states with very different packing of the structural elements, i.e. coils or helices.

Triphenyl phosphite has been suggested as a small organic molecule that undergoes a liquid/liquid phase transition from a supercooled liquid to a new amorphous ‘glacial phase’ at temperatures of 227 to 213 K, which are between Tg (176 K) and Tm (295 K). This ‘glacial phase’ is X-ray amorphous, has a higher viscosity, longer spin-lattice relaxation times and a higher density than does its regular amorphous form. In addition, non-isothermal crystallization of the ‘glacial phase’ occurs at a higher temperature, with a lower enthalpy than that observed with an ordinary supercooled liquid. Evidence that the formation of the glacial phase from the supercooled liquid involves a first-order transition is supported by the observations of an induction period and the appearance of opacity (a characteristic of phase boundaries), which accompany the conversion. It has also been suggested that the apparently amorphous ‘glacial phase’ may in fact be a crystalline phase with a lower degree of order than that found in a three-dimensional crystal, e.g. a liquid crystalline phase. To prove if this is so would require additional experiments using, for example, small-angle X-ray diffraction. If the ‘glacial phase’ of triphenyl phosphite is indeed a liquid crystalline phase, it would be an example of a group of solid states known as ‘crystalline mesophases’, to be discussed later, rather than a true liquid ‘polyamorph’.

Another example of a possible liquid/liquid phase transition in the amorphous state is the thermal transition observed for fructose at 100 °C by Slade and Levine. A similar thermal event for fructose at ~ 65 °C has been observed when it was mixed with a phospholipid. Presently, it is not clear whether these thermal events observed for fructose correspond to first-order liquid/liquid transformations and, hence, true polyamorphism. However, if this is so, it would be the first example of polyamorphism in a system of practical interest in the food and pharmaceutical sciences.

There is a lack of discussion in the literature on the possible nature of polyamorphism in small organic molecules. A possible reason for liquid/liquid polyamorphism in such systems may be the distinctly different states of molecular conformation which can occur. If this is the case, polyamorphism in general may be characteristic of many glassy carbohydrates under certain sets of conditions, because carbohydrates are known to be able to exist in different conformations.

With regard to the second type of ‘polyamorphism’, involving kinetic states of amorphous systems, there are numerous examples that arise from different types of processing, such as milling, freeze-drying or spray-drying. For example, it has been shown that freeze-dried and spray-dried cefamandole nafate have very different X-ray diffraction patterns. While both materials exhibit typical amorphous diffraction patterns, i.e. a broad halo without sharp crystalline peaks, the spray-dried material has a weak and relatively narrow line at 5 degrees 2Φ, suggesting that it is more ordered than the freeze-dried material. This suggestion is supported by the fact that the heat of dissolution for the spray-dried sample was closer to that of the crystalline material. Moreover, when the freeze-dried material was annealed below Tg, both its X-ray diffraction pattern and its heat of solution were shifted closer to that of the spray-dried material. Therefore, according to these results for this system, we would conclude that amorphous forms arise in different kinetic states, rather than in thermodynamic states, when the process used to produce them is altered and that this represents the result of thermal and processing history, rather than two distinct liquid phases.

Another example of process-induced differences is amorphous tri-O-methyl-β -cyclodextrin produced by milling and quenching of the melt by rapid cooling. In these systems, first of all, the enthalpy relaxation rate was shown to be faster for the milled sample. Indeed, the milled material, which tended to relax more quickly, also showed a stronger tendency to crystallize upon standing. One other possible reason for greater crystallization rates in the milled samples, however, may have been the presence of residual seed crystals not present in the quench-cooled melt. Caution in concluding that different processes always lead to different amorphous states in the glass can be prompted from the observation that the Tg and heat capacity values for the milled sample and the quench-cooled melt of tri-O-methyl-β-cyclodextrin were quite similar, despite differences in enthalpy relaxation rates. Also, two amorphous forms of raffinose, produced by freeze-drying and by dehydration of its crystalline pentahydrate, exhibited the same Tg and similar water sorption profiles and rates of recrystallization when equilibrated at relative humidities greater than 45%.

One of the first examples of a possible influence of thermal history and processing on chemical stability of pharmaceuticals in the amorphous state was that of the antibiotic moxalactam. Here, two samples prepared by freeze-drying were subjected to identical conditions except that one underwent secondary drying at 40 °C, while the other was so treated at 60 °C for the same length of time. Both samples had the same residual water content, but were characterized by different rates of decarboxylation. The rate of decarboxylation was slower for the sample dried at the higher temperature, presumably because it was in a more relaxed state and hence in a state of greater order.

2.1 Significance in the Pharmaceutical Sciences

To date, the existence of any true polyamorphism in pharmaceutical materials has not been established, thus calling for more careful examination of amorphous drugs and excipients in this regard. Unambiguous proof of such polyamorphism would be the observation of a discontinuity in the Gibbs free energy curve for two amorphous forms, as shown schematically in Figure 1. If such polyamorphism is detected and understood, it may be possible to take advantage of a particular ‘liquid’ polymorph in the formulation process. Clearly, of more current significance is the very strong possibility that the kinetic properties of an amorphous material can be affected by the process used to produce it. Consequently, characterization of an amorphous material must involve careful attention to thermal history, as well as to the production process to be used.

3 Heterogeneity in Amorphous Solids

Amorphous solids that contain single components have been shown to exhibit dynamic properties that affect molecular mobility and, hence, the translational and rotational motions that affect their physical and chemical stability. Strong evidence exists to suggest that in most cases of interest, the relaxation times for such materials, particularly in the vicinity of Tg, exist as a distribution of relaxation times, most likely due to spatial heterogeneity. This is reflected in the non-exponential behavior for the rate of structural relaxation, X(t), as expressed in the well-known Kohlrausch–Williams–Watts (KWW) equation:

X(t) = exp (- t/τKWW)βKWW (1)

where X(t) is a property of the material, τKWW is the average relaxation time and βKWW measures the extent of non-exponentiality and the distribution of relaxation times. Values of βKWW vary from 0 to 1, with 1 representing a single-exponential relaxation process. Typically, many organic amorphous materials have values of β from 0.3 to 0.8, indicating a broad distribution of relaxation times. An alternative view, which attributes non-exponentiality to homogeneous relaxation that is intrinsically non-exponential due to certain types of cooperativity, has also been proposed, but with less experimental support.

Recent experiments and simulations have provided strong support for the role of spatial heterogeneity in the vicinity of Tg. Such support, for example, has been obtained in single molecule experiments that allow a direct answer concerning the distribution of relaxation times of exponentially relaxing elements. The rotational motion of Rhodamine G molecules in a film of poly(methylmethacrylate) was monitored using transient fluorescence intensity. Experiments were performed at 5 to 15 K above Tg. On a shorter time scale (e.g. ~ 103), at Tg + 5 K, single molecule relaxation obeyed a single-exponential law, whereas non-exponentiality increased, wherein βKWW in Equation 1 decreased from 1.0 to 0.4 as the time scale was extended from 103 to 104. In addition, it has been shown that the change from one environment to another occurred in an instantaneous ‘jump’ manner on the time scale of the experiment. Such a ‘jump’ was believed to originate from large-scale collective motions. Such heterogeneity of amorphous materials can be visualized from the Adam–Gibbs theory of cooperatively rearranging clusters, with heterogeneity in the size of such clusters. Evidence for clusters and density fluctuations in amorphous materials near Tg has been confirmed by light scattering experiments.

(Continues…)Excerpted from Amorphous Food and Pharmaceutical Systems by Harry Levine. Copyright © 2002 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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