Characterization of the amorphous state

A wide selection of techniques is available for the physical characterization of amorphous solids, though they do not all provide the same information (Table 2.3). Basic characterization can be conducted by X-ray diffractometry (XRD) techniques and differential scanning calorimetry (DSC). The specificity and accurate quantitative nature of XRD in detecting long-range molecular order has made it a standard method for studying amorphous/crystalline systems. Temperature and environmental control makes it possible to follow the kinetics of phase transformations (e.g. crystallization) (Byrn et al.

1999d). DSC is widely used for studying fundamental thermodynamic properties, such as glass transitions, heat capacities and enthalpy changes of the amorphous state. However, the influences of several experimental variables (e.g. sample size, heating and cooling rate) can effect the type and quality of the data obtained (Bhugra et al. 2006, Vyazovkin and Dranca 2006, Bhugra et al. 2008).

If one wishes to study pharmaceutical systems containing a few weight percent of amorphous material, then isothermal microcalorimetry (IMC), solution calorimetry and water vapour sorption techniques are the preferred means (Saleki-Gerhardt 1994, Mackin et al. 2002, Ramos et al. 2005). If one wishes to quantify of the degree of crystallinity, also solid state nuclear magnetic resonance spectroscopy (ssNMR) can be used. Instead of recognizing long-range molecular order (like XRD), ssNMR is more sensitive to local or “short-range” order, thus differences between the results obtained with XRD and ssNMR are to be expected (Stephenson et al. 2001). In addition to quantifying the degree of crystallinity, Fourier-transform infrared spectroscopy (FTIR), near-infrared spectroscopy (NIR) and Raman spectroscopy have been used for determining the glass transition temperature and mean molecular relaxation times (IJ) as a function of temperature (Oksanen and Zografi 1993, Taylor and Zografi 1998, Stephenson et al.

2001, Lubach et al. 2007, Imamura et al. 2008). Due to enhanced sensitivity of FT-Raman spectroscopy and its advantages, such as minimum sample preparation and greater specificity relative to NIR, its application in quantitative analysis is predicted to increase in the future (Stephenson et al. 2001). However, interpretation of spectral data is often quite complex and thus supporting information obtained by other techniques may

Table 2.3. Techniques for physical characterization of amorphous solids. MethodObservationsSpecific informationReferences X-ray Diffraction (XRD)Sharp diffraction peaks are visible in the case of crystalline material. Amorphous material shows a halo pattern. Suitable for detecting and quantifying molecular order down to levels of about 5%.

Conventional (with temperature and environmental control, wide-angle and small-angle techniques (SAXS) are applicable. Nondestructive.

Hancock and Zografi 1997, Men et al. 2005, Pluta and Galeski 2007, Roe and Curro 1983, Saleki-Gerhardt et al. 1994 Vibrational spectroscopy (FTIR, NIR and Raman)

Sharp vibrational bands observed in the case of crystalline material. For amorphous samples, the bands are broader.

Non-destructive. Often the spectral features of different solid-state forms overlap in which case special approaches are needed in order to obtain a calibration curve to quantify the degree of crystallinity.

Bugay 2001, Stephenson 2001, Taylor and Zografi 1998 Solid-state Nuclear Magnetic Resonance Spectroscopy (ssNMR)

Peaks are sharp for crystalline solids and broad for amorphous solids. Quantitative analysis of crystalline/amorphous mixtures can be achieved without the need for standard curve preparation.

Non-destructive. Even whole tablets can be studied without disrupting the tablet structure and the physical state of its contents.

Lubach et al. 2007, Tiscmack et al. 2003 Differential Scanning Calorimetry (DSC)

Sharp fusion endotherm is observed for crystalline solids. Amorphous/partially amorphous samples show glass transition (Tg) with/without recrystallization endotherm and fusion endotherm.

Difficult to quantify low levels of amorphous content (i.e. below 10%) with conventional DSC. By using high speed DSC (Hyper-DSC) amorphous contents as low as 1.5% can be detected.

Hancock and Zografi 1997, Saleki-Gerhardt et al. 1994, Saunders et al. 2004 Modulated temperature DSC (MTDSC)

The heat flow signal is separated into reversing (showing Tg) and non-reversing (showing relaxation endotherm, recrystallization exotherm and fusion endotherm) components.

Enables the detection of hidden phenomena, such as overlapping Tg and crystallization. Able to detect and quantify low amorphous contents.

Coleman and Craig 1996, Guinot and Leveiller 1999, Saklatvala et al. 1999 Isothermal Microcalorimetry (IMC)

No response for crystalline sample, for amorphous material a recrystallization exotherm is observed.

Measurements in constant relative humidity (RH) or linearly ramping the RH from 0 to 100% are possible. Amorphous contents as small as 0.5% can be detected.

Lechuga-Ballesteros et al. 2003, Mackin et al. 2002, Samra and Buckton 2004

Solution calorimetry High heat of solution for crystalline materials and low heat of solution for amorphous materials.

Amorphous contents as small as 0.5% can be detected. For example, for lactose solution calorimetry has been reported to give more precise results than IMC.

Hogan and Buckton 2000, Ramos et al. 2005 Dielectric Analysis (DEA)No response for crystalline sample, dielectric loss at Tg for amorphous materials.Possible to monitor a range of low temperature transitions associated with changes in molecular mobility.

Craig 1996, Duddu and Sokoloski 1995 Dynamical Mechanic Analysis (DMA)

The mechanical properties of a sample are measured as a function of temperature. Amorphous sample shows a large change in these properties at Tg.

Very sensitive technique for the identification and characterization of glass transitions, usually with polymers.

Royall et al. 2005 ViscometryDecrease in viscosity is continuous for crystalline materials, while a sudden decrease in viscosity is seen above Tg for amorphous samples.

Experimental difficulties have restricted the use of the method.Andronis and Zografi 1997, Hancock and Zografi 1997 DensityDensity of a crystalline material is higher than that of the corresponding amorphous form.Yu 2001 Gravimetric water absorption

An overall mass loss is observed as a clear hump in the sorption diagram in the case of crystallization.

Crystallization process can be studied by monitoring the mass change of the material as a function of time at given conditions, since amorphous material adsorbs relatively large amounts of water vapor and, when crystallizing, gives up the extra moisture due to decreased sorption capacity of the crystalline material.

Burnett et al. 2004, Newman et al. 2008 Polarized light microscopeBirefringency in the case of crystalline material under polarized light.Polarized light is refracted from the crystal planes and is seen as bright areas in the inspection under the microscope.

Byrn et al. 1999c

be needed (Bugay 2001). Raman spectroscopy is sensitive to changes in intramolecular conformations and intermolecular interactions arising from changes in solid state structure. The changes in the spectra between the different solid-state forms are often very small, but when combined with suitable data-analysis method (e.g. partial least squares discriminant analysis, PLS-DA, and partial least squares regression analysis, PLS), Raman spectroscopy can be used for monitoring and quantifying the solid-phase transition occurring during the dissolution of amorphous drugs (Savolainen et al. 2009).

Thus, there are many suitable methods available for the characterization of amorphous materials. However, none of these methods is sufficient per se, instead a detailed characterization of an amorphous material should always involve the combination of spectroscopic, X-ray diffraction and thermal methods.