Characterization of crystalline and amorphous content in pharmaceutical solids by dielectric thermal analysis

Morphological and thermodynamic transitions in drugs as well as their amorphous and crystalline content in the solid state have been distinguished by thermal analytical techniques, which include dielectric analysis (DEA), differential scanning calorimetry (DSC), and macro-photomicrography. These techniques were used successfully to establish a structure versus property relationship with the United States Pharmacopeia standard set of active pharmaceutical ingredient (API) drugs. A distinguishing method is the DSC determination of the amorphous and crystalline content which is based on the fusion properties of the specific drug and its recrystallization. The DSC technique to determine the crystalline and amorphous content is based on a series of heat and cool cycles to evaluate the drugs ability to recrystallize. To enhance the amorphous portion, the API is heated above its melting temperature and cooled with liquid nitrogen to ?120 °C (153 K). Alternatively a sample is program heated and cooled by DSC at a rate of 10 °C min^?1. DEA measures the crystalline solid and amorphous liquid API electrical ionic conductivity. The DEA ionic conductivity is repeatable and differentiates the solid crystalline drug with a low conductivity level (10^?2 pS cm^?1) and a high conductivity level associated with the amorphous liquid (10⁶ pS cm^?1). The DSC sets the analytical transition temperature range from melting to recrystallization. However, analysis of the DEA ionic conductivity cycle establishes the quantitative amorphous and crystalline content in the solid state at frequencies of 0.10–1.00 Hz and to greater than 30 °C below the melting transition as the peak melting temperature. This describes the “activation energy method.” An Arrhenius plot, log ionic conductivity versus reciprocal temperature (K^?1), of the pre-melt DEA transition yields frequency dependent activation energy (E _a, J mol^?1) for the complex charging in the solid state. The amorphous content is inversely proportional to the E _a where the E _a for the crystalline form is higher and lower for the amorphous form with a standard deviation of ±2%. There was a good agreement between the DSC crystalline melting, recrystallization, and the solid state DEA conductivity method with relevant microscopic evaluation. An alternate technique to determine amorphous and crystalline content has been established for the drugs of interest based on an obvious amorphous and crystalline state identified by macro-photomicrography and compared to the conductivity variations. This second “empirical method” correlates well with the “activation energy” method.     

Kinetics of autocatalytic acid hydrolysis of cellulose with crystalline and amorphous fractions

The acid hydrolysis of cellulose with crystalline and amorphous fractions is analyzed on the basis of autocatalytic model with a positive feedback of acid production from the degraded biopolymer. In the condition of low acid rate production compared with hydrolysis rate, both fraction of cellulose decrease exponentially with linear and cubic time dependence, and the normalized number of scissions per cellulose chain follows a sigmoid behavior with reaction time. The model predicts that self generated acidic compounds from cellulose accelerate the degradation of the biopolymer. However, if the acidic compounds produced are volatile species, then their release under low pressure will reduce the global rate of degradation of cellulose toward its intrinsic rate value determined by the residual acid catalyst present in the starting material.     

Orientation of isotactic polypropylene in crystalline and amorphous phases: IR methods

Two methods based on polarization infrared spectroscopy are described for measurement of polypropylene orientation. One method, for the crystalline phase, allows precise measurement of polypropylene orientation in three orthogonal directions. It is based on the polarization characteristics of two crystallinity bands, those at 841 and 809 cm^?1, which exhibit opposite polarization characteristics. The other method, for the amorphous phase, provides a semiquantitative estimate and is suitable for uniaxially oriented films. It is based on polarization characteristics of the 1155-cm^?1 band. Both methods are applied to the measurement of orientation in polypropylene films uniaxially stretched at various speeds and temperatures.     

The glass transition and crystallization of ball milled cellulose

Samples of ball milled cellulose were prepared by ball milling pulps from eucalyptus and softwood (spruce/pine). Water sorption isotherms were obtained by both dynamic vapor sorption and equilibration over saturated salt solutions, in the water content range of 5–42% db (db = dry basis; water as a % age of total solids). Dynamic mechanical analysis using a pocket technique showed a water content dependent thermal transition occurring at the same temperature for the two pulp samples, which was interpreted as a glass transition. Fitting the data to a Couchman–Karasz relationship predicted a value for T _g of the dry cellulose of approximately 478 K, which was similar to values previously reported for other dry polysaccharides. No clear glass transition could be observed calorimetrically, although an endotherm at approximately 333 K was measured, which in polymers is normally attributed to enthalpic relaxation, however the lack of dependence of this endotherm on water content suggests that the melting of some weak associations, such as residual hydrogen bonds, could be a more credible explanation. An exotherm was also observed on heating, which was dependent on water content and which was attributed to partial crystallization of the cellulose. This was confirmed by Wide angle X-ray diffraction and cross polarization magic angle spinning ¹³C NMR (CPMAS NMR). The recrystallisation was predominantly to form I of cellulose. This was thought to be caused by a small amount of residual form I (probably less than 5%) acting as a template for the crystallizing material. Differential scanning calorimetry reheat curves showed the appearance of freezable water for water contents higher than 20%, as a result of a transfer of water to the amorphous phase following crystallization. The increase in cellulose rigidity following crystallization was also confirmed by CPMAS NMR relaxation. Low resolution proton NMR T ₂ relaxation suggested the presence of proton water/cellulose exchange, which was active at water contents of 20% and above.     

Nanocrystalline CaF2 particles obtained by high-energy ball milling

Structural changes in mechanically treated CaF₂ powders have been studied by X-ray diffraction, transmission electron microscopy, thermal analysis, ¹⁹F and ¹H MAS Nuclear Magnetic Resonance and Electron Paramagnetic Resonance methods.Applying the same methods, the results could be compared with those of mechanochemically synthesized CaF₂ samples, prepared for the first time in this study by high-energy ball milling. The applied methods indicate that the mechanically treated samples become, under the applied conditions, nanocrystalline. Unexpectedly, the mechanochemically synthesized samples show the same effects, i.e., nanocrystalline samples were formed. In contrast to many oxide compounds, a weak amorphization takes place only after a strong mechanical impact, and essentially in grain boundaries of spherical particles. Observed effects after the application of mechanical impact like broadening of XRD reflections, broadening of ¹⁹F resonances, or the decreasing ability for H trapping at ambient temperature, are mainly due to decreasing particle sizes as well as very small structural changes in the bulk of the particles. Surprisingly, the spin relaxation of both nuclear spins (¹⁹F) and electron spins (H) appears to be the most sensitive tool for the investigation of mechanically and chemically induced changes indicating the increasing surface to bulk ratio with increasing mechanical impact.     

The role of crystalline, mobile amorphous and rigid amorphous fractions in the performance of recycled poly (ethylene terephthalate) (PET)

The action of thermo-mechanical degradation induced by mechanical recycling of poly(ethylene terephthalate) was simulated by successive injection moulding cycles. Degradation reactions provoked chain scissions and a reduction in molar mass mainly driven by the reduction of diethyleneglycol to ethylene glycol units in the flexible domain of the PET backbone, and the formation of -OH terminated species with shorter chain length. The consequent microstructural changes were quantified taking into account a three-fraction model involving crystalline, mobile amorphous (MAF) and rigid amorphous fractions (RAF). A remarkable increase of RAF, to a detriment of MAF was observed, while the percentage of crystalline fraction remained nearly constant. A deeper analysis of the melting behaviour, the segmental dynamics around the glass-rubber relaxation, and the macroscopic mechanical performance, showed the role of each fraction leading to a loss of thermal, viscoelastic and mechanical features, particularly remarkable after the first processing cycle.     

Quantification of amorphous content in maltitol by

A method was developed for the quantification of low levels of amorphous content in maltitol with StepScan DSC. The method was based on the fact that the change of specific heat at the glass transition is linearly proportional to the amorphous content. The influence of different measurement parameters of StepScan DSC was evaluated and two different calibration heating rates were tested. Synthetic mixtures with various proportions of crystalline and amorphous maltitol were prepared. Two different measurement methods were compared and the linear regression between ΔC_p and amorphous content was obtained. The limit of detection (LOD) and the limit of quantification (LOQ) values were for the fictive temperature 0.24% (amorphous content) and 0.81% and for the half point temperature 0.27 and 0.92%, respectively, (method 1) and for the fictive temperature 0.18 (amorphous content) and 0.61% and for the half point temperature 0.16 and 0.52%, respectively (method 2). Very low determination limits for the quantification of amorphous content could be attained with the StepScan DSC method. However, the realistic limit of quantification was somewhat higher (about 3%) because of noise in the StepScan measurement. The main advantage of the StepScan DSC method for quantification of amorphous content was that the glass transition and relaxation peaks are separated into different curves and the interpretation becomes easier.     

Miscibility of crystalline and amorphous polymers: Poly-ethylene/polyisobutylene blends

Blends were prepared from a linear low density polyethylene and a polyisobutylene in the entire composition range. Flory-Huggins interaction parameters were determined from DMTA and DSC measurements. The usual technique had to be modified in the case of DSC data, since the T_g of PE cannot be determined by this technique. The two methods yielded identical results and indicated good interaction of the components, which was supported also by a SEM study and the mechanical properties of the blends.     

PVT of amorphous and crystalline polymers and their nanocomposites

The Pressure-Volume-Temperature (PVT) of polystyrene (PS), polyamide-6 (PA-6) and their clay-containing polymeric nanocomposites (CPNC) were determined at T = 300-600 K and P = 0.1-190 MPa, thus in the molten, glassy and semicrystalline phase. The melt and glass behavior was interpreted following the Simha-Somcynsky (S-S) cell-hole free volume theory while that of the semicrystalline phase using S-S and the Midha-Nanda-Simha-Jain (MNSJ) cell theory describing crystalline quantum interactions. The theoretical analysis yielded two sets of the interaction parameters, one from the S-S and the other from the MNSJ model. The derivative properties: the compressibility, κ, and thermal expansion coefficient, α, were computed as functions of T, P and clay content, w. These functions, crossing several transition regions, were significantly different for the amorphous PS than for the semicrystalline PA-6. The isobaric PS plots of κ and α vs. T detected secondary transitions at T_β/T_g ≈ 0.9 ± 0.1 and at T_c/T_g = 1.2 ± 0.1. Addition of clay severely affected the vitreous phase (physical aging). In PA-6 systems the behavior was distinctly different than in PS, viz. κ = κ(T) followed a similar function across the melting zone, while α = α(T) dependencies were dramatically different for the solid and molten phase. The theoretical functions in reduced variables provided good basis for explanation of the observed dependencies.     

Quantification of amorphous content in mixed systems: amorphous trehalose with lactose

There has been a lot of interest in quantification of the amorphous content of materials, especially when the amorphous content is a small percentage of the total mass. Whilst there has been success in studies on single materials, there has been little work showing how quantification of the amorphous content of one material can be undertaken in the presence of another. In this work isothermal microcalorimetry was used to measure the content of amorphous trehalose following mixing with crystalline lactose. Gravimetric water sorption studies revealed that trehalose did not form a complete dihydrate when exposed to 75% RH, presumably due to the rapid crystallisation of the outer regions of the particles. At 53% RH, the gravimetric studies showed dihydrate formation. The calorimetry data revealed that the crystallisation response was directly related to the mass of amorphous material in the mixture and was not affected by the mass of non-crystallising sample. It was shown that as long as there was a minimum mass of amorphous material (in this case 4 mg), it was possible to measure a crystallisation response with sufficient accuracy to allow quantification. Lower masses of amorphous content allowed detection, but less accurate quantification, as the response was superimposed on the initial calorimetric heat flow response. It was also found that the response at 53% RH in the TAM was less accurate due to the low peak height and long duration (compared to that seen at 75% RH). It can be concluded that the TAM method is well suited to both detection and quantification of amorphous content when there is one amorphous sample mixed with another (and thus presumably more than one) non-crystallising material.     

Miscibility in crystalline/amorphous blends of poly(3-hydroxybutyrate)/DGEBA

A differential scanning calorimetry (DSC) and small-angle X-ray scattering (SAXS) study of miscibility in blends of the semicrystalline polyester poly(3-hydroxybutyrate) (PHB) and amorphous monomer epoxy DGEBA (diglycidyl ether of bisphenol A) was performed. Evidence of the miscibility of PHB/DGEBA in the molten state was found from a DSC study of the dependence of glass transition temperature (T_g) as a function of the blend composition and isothermal crystallization, analyzing the melting point (T_m) as a function of blend composition. A negative value of Flory–Huggins interaction parameter χ_PD was obtained. Furthermore, the lamellar crystallinity in the blend was studied by SAXS as a function of the PHB content. Evidence of the segregation of the amorphous material out of the lamellar structure was obtained. © 2013 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2013     

Relaxations of selenium in crystalline and amorphous states

Complex shear modulus at 33 kc./sec. is measured at temperatures of ?150–150°C. for amorphous selenium and crystalline selenium with different crystallinities. The dielectric relaxation at 10 kc./sec. to 3 kc./sec. to 3 Mc./sec. is observed at temperatures of ?32–25°C. for iodine-doped crystalline selenium. It is concluded from the results of this study and of others' that selenium exhibits four relaxations, α, β γ, and δ, in order of descending temperature. The β relaxation is observed only in the amorphous sample above the glass temperature and is assigned to the primary relaxation. The α, γ, and δ relaxations are found in the crystalline selenium. The α relaxation, which is prominent in a highly crystalline sample, is assigned to the crystalline relaxation. The γ and δ relaxations increase in peak height with decreasing crystallinity and are attributed to the disordered region in the crystalline selenium. The dispersion map (logarithm of frequency versus reciprocal absolute temperature of loss maximum) of selenium is presented.     

Quantification of drug amorphous fraction by DSC

The processes of production of drugs and dosage forms in the solid state often cause unwanted transformation of portions of the substances into amorphous state, with significant changes of properties such as stability and bio-availability. When this amorphous fraction is of the order of a few percent, it usually goes unnoticed, but it should be accurately determined within a quality control system. In this work, we consider a model drug, perphenazine, where partial amorphisation may be induced by standard mechanical treatments. We show that Differential Scanning Calorimetry (DSC) leads to consistent estimations of the amorphous fractions induced by the treatment. Furthermore, DSC also yields the expected amounts of amorphous perphenazine when analysing known mixtures of perfectly crystalline samples (untreated) and partially amorphous samples (treated). We show that even amorphous fractions of the order of 1% are accurately estimated by our method.     

Surface hydration of crystalline and amorphous silicas

The surface properties of three SiO₂ samples, one crystalline (quartz) and two amorphous, with a large difference in particle size, have been investigated by thermal analysis, adsorption calorimetry and infrared spectroscopy. The variation in the silanol group population upon thermal treatment has been followed via the evolution of the i.r. bands at 3745–3750 cm^–1 (free hydroxyl groups) and 3650-3550 cm^–1 (adjacent pairs of SiOH) and the evolution of the heat of adsorption of water with coverage on the outgassed samples.The adsorption capacities increase in the sequence high surface area amorphous sample T=673 K) brings about dehydroxylation leaving only isolated silanols on the high surface area amorphous silica, and partial dehydroxylation of the low surface area material. Quartz is totally hydrophilic, as its regular structure probably stabilizes the hydroxyl layers at the surface.

---

Zusammenfassung Die Oberflächeneigenschaften von einer kristallinen (Quarz) und zwei amorphen SiO₂-Proben mit großen Unterschieden in der Partikelgröße wurden durch thermische Analyse, Adsorptionskalorimetrie und Infrarotspektroskopie untersucht. Bei thermischer Behandlung eintretende Veränderungen in der Silanolgruppenpopulation wurden durch Messung der IR-Banden bei 3745–3750 cm^–1 (freie Hydroxylgruppen) und 3650–3550 cm^–1 (benachbarte SiOH-Paare) und der Adsorptionswärme von Wasser an ausgeheitzten Proben untersucht. Die Adsorptionskapazitäten nehmen in folgender Reihenfolge ab: amorphe Probe mit großer Oberfläche > amorphe Probe mit geringer Oberfläche > Quarz. Dehydroxylierung der Oberfläche hat zunehmenden hydrophoben Charakter (Gestalt der Isothermen, Adsorptionswärme kleiner als Kondensationswärme von Wasser) zur Folge. Bei der gleichen thermischen Behandlung (673 K) werden bei amorphen Siliciumdioxid mit großer Oberfläche eine nur isolierte Hydroxylgruppen zurücklassende Dehydroxylierung und bei Material mit kleiner Oberfläche eine teilweise Dehydroxylierung beobachtet. Quarz ist vollkommen hydrophyl, da die reguläre Struktur wahrscheinlich die Hydroxylschichten an der Oberfläche stabilisiert.

---

, , (), — . 3745–3750 ^–1 ( ) 3650–3550 ^–1 ( SiOH), . < < . ( , ). (T=673 K) . , , , .

---

---

This research was supported by the Ministry of Public Education within a national programme relating to the structure and reactivity of surfaces.     

Predicting shelf-lives of pharmaceutical products

The computer simulation package SIMAN^® is used to carry out Monte Carlo simulations with a view to estimating and predicting the shelf-lives of pharmaceutical products. The input data take account of assay variance and low extents of decomposition typical of data sets submitted by pharmaceutical companies in support of their product licence applications. It is shown that Monte Carlo methods provide estimates of the predicted shelf-life with a narrower and more symmetrical distribution than obtainable with integral methods. The results indicate that the median may be a more reliable estimate of shelf-life than the mean particularly if assay variance is high. Despite its usefulness SIMAN is a difficult package to use and is not generally recommended.     

Thermal analysis of amorphous phase in a pharmaceutical drug

Thermally Stimulated Current (TSC) spectroscopy and Differential Scanning Calorimetry (DSC) have been applied to the characterization of the microstructure of a pharmaceutical drug.The dielectric relaxation spectrum shows two modes located in the temperature range of the glass transition. They have been attributed to the molecular mobility in the true amorphous phase and in the rigid amorphous region.     

Molecular dynamics of amorphous/crystalline polymer blends studied by broadband dielectric spectroscopy

The molecular dynamics of poly(vinyl acetate), PVAc, and poly(hydroxy butyrate), PHB, as an amorphous/crystalline polymer blend has been investigated using broadband dielectric spectroscopy over wide ranges of frequency (10⁻² to 10⁵ Hz), temperature, and blend composition. Two dielectric relaxation processes were detected for pure PHB at high and low frequency ranges at a given constant temperature above the T_g. These two relaxation peaks are related to the α and α′ of the amorphous and rigid amorphous regions in the sample, respectively. The α′-relaxation process was found to be temperature and composition dependent and related to the constrained amorphous region located between adjacent lamellae inside the lamellar stacks. In addition, the α′-relaxation process behaves as a typical glass relaxation process, i.e., originated from the micro-Brownian cooperative reorientation of highly constraints polymeric segments. The α-relaxation process is related to the amorphous regions located between the lamellar crystals stacks. In the PHB/PVAc blends, only one α-relaxation process has been observed for all measured blends located in the temperature ranges between the T_g’s of the pure components. This last finding suggested that the relaxation processes of the two components are coupled together due to the small difference in the T_g’s (ΔT_g = 35 °C) and the favorable thermodynamics interaction between the two polymer components and consequently less dynamic heterogeneity in the blends. The T_g’s of the blends measured by DSC were followed a linear behavior with composition indicating that the two components are miscible over the entire range of composition. The α′-relaxation process was also observed in the blends of rich PHB content up to 30 wt% PHB. The molecular dynamics of α and α′-relaxation processes were found to be greatly influenced by blending, i.e., the dielectric strength, the peak broadness, and the dielectric loss peak maximum were found to be composition dependent. The dielectric measurements also confirmed the slowing down of the crystallization process of PHB in the blends.     

Comparison of HPLC and UV spectrophotometric methods for the determination of cefuroxime sodium in pharmaceutical products

This paper describes the development and evaluation of a HPLC and UV spectrophotometric methods to quantify cefuroxime sodium in injectables. HPLC analysis were carried out using a C18 Wat 054275 column and a mobile phase composed of methanol and water (70:30), with a flow rate of 0.8 mL/min and UV detection at 280 nm. For the spectrophotometric analysis, water was used as solvent and the wavelength of 280 nm was selected for the detection. Both methods were found to quantify cefuroxime sodium in injectables accurately. Therefore HPLC and UV methods presented the most reliable results for the analyses of injectables.