Variable Temperature X-ray Powder Diffractometry Research Articles

Pressure and Temperature Induced Dual Responsive Molecular Crystals: Effect of Polymorphism

The rapid conversion of energy into mechanical motion is a crucial requirement in the design of advanced flexible sensors and optoelectronic devices. Responsive materials that show mechanical movement when exposed to different external stimuli such as heat, pressure, humidity, or light can serve as technomimetics in smart actuator and microrobotic devices. However, it is quite challenging to design molecular crystals which can respond to two or more external stimuli. Herein, we report dimorphic forms (1a and 1b) of 2-hydroxy-3,5-dibromobenzylidine-4-fluoro-3-nitroaniline (Crystal 1) where form 1a is brittle and form 1b is elastically bendable. Both polymorphs exhibit progressive thermosalient responses which are seemingly different in nature. One polymorph (1a) shows jumping, while the other (1b) shows bending. The property difference is solely attributed to the inherent crystal packing and linked to the differences in the molecular conformations, structural packing, and intermolecular interactions. 2-Hydroxy-3-bromo-5-chlorobenzylidine-4-fluoro-3-nitroaniline (Crystal 2) was nonthermosalient but was mechanically flexible. Variable temperature powder X-ray diffractometry revealed anisotropic crystallographic face expansion─a possible explanation for the different thermosalient behaviors of the dimorphs.

A high-temperature multiaxial precision time-delayed dielectric switch crystal triggered by linear/propeller/ball three-form motion

The new crystal motor with extraordinary thermal hysteresis turns out to be a multiaxial precision time-delayed dielectric switch.

Drug-Excipient Interactions: Effect on Molecular Mobility and Physical Stability of Ketoconazole–Organic Acid Coamorphous Systems

The use of excipients other than polymers for enhancing the physical stability of amorphous active pharmaceutical ingredients (APIs) has largely been unexplored. We investigated several organic acids (oxalic, tartaric, citric, and succinic acid) for the purpose of stabilizing a weakly basic API, ketoconazole (KTZ), in the amorphous state. Coamorphous systems with each acid, in 1:1 KTZ-acid molar ratio, were prepared by spray drying. The interaction of KTZ with each acid was investigated by FT-IR, solid-state NMR, and quantum chemical calculations. Each acid exhibited ionic and/or hydrogen-bonding interactions with KTZ, and quantum chemical calculations provided a measure of the strength of this interaction. The α-relaxation times, a measure of molecular mobility, were determined by dielectric spectroscopy, and their crystallization propensity by variable temperature X-ray powder diffractometry. Crystallization was observed only in two systems, KTZ-oxalic salt and KTZ-succinic as a cocrystal. An increase in the strength of KTZ-acid interaction translated to a decrease in molecular mobility. When the two systems prepared with structurally similar dicarboxylic acids (succinic and oxalic acid) were compared, the physical stability enhancement of KTZ-oxalic coamorphous system could be attributed to its lower mobility. However, the exceptional stability of KTZ-tartaric and KTZ-citric could not be explained by mobility alone, indicating that structural factors may also contribute to stabilization. The interaction between KTZ and acid may alter the system sufficiently so that the crystallization propensity of the KTZ-acid complex (salt or cocrystal) becomes relevant. We conclude that small molecule excipients have the potential to improve the physical stability of amorphous APIs.

Unusual Sequential Reversible Phase Transitions Containing Switchable Dielectric Behaviors in Cyclopentyl Ammonium 18-Crown-6 Perchlorate

Multisequential reversible phase transitions based on molecular materials have important applications in ferroelastic materials, ferroeletric materials, switchable dielectric materials, and temperature-controlling materials. Here, we report that a new compound, [Hcpa-(18-crown-6)]+[ClO4]− (1) (where Hcpa represents protonated cyclopentylamine cations) displays unusual multisequential reversible phase transitions accompanied by switchable dielectric behaviors. The stepwise synergistic disordering of Hcpa cations and ClO4– anions leads to the sequential reversible phase transitions and symmetry breaking. These unusual reversible phase transitions were further confirmed by the variable-temperature powder X-ray diffractometry (PXRD), thermal anomalies of differential scanning calorimetry (DSC) measurements, and abrupt dielectric anomalies in the heating and cooling processes.

Solid-State Characterization of Novel Propylene Glycol Ester Solvates Isolated from Lipid Formulations.

The purpose of this study was to identify and characterize precipitates obtained from a liquid formulation of GNE068.HCl, a Genentech developmental compound, and lipophilic excipients, such as propylene glycol monocaprylate, and monolaurate. Precipitates were characterized using powder X-ray diffractometry (PXRD), differential scanning calorimetry, thermogravimetry, microscopy, nuclear magnetic resonance spectroscopy (NMR; solution and solid-state) and water sorption analysis. PXRD and NMR revealed the precipitates to be crystalline solvates of propylene glycol esters. The solvates (capryolate and lauroglycolate) were isomorphic and stable up to 70 °C, beyond which melting of the lattice occurred with subsequent dissolution of the active ingredient in the melt (microscopy and variable temperature PXRD). They were found to be mechanically stable (no change in PXRD pattern upon compression) and were nonhygroscopic up to ∼70% RH (25 °C). Our results highlight the outcome of inadvertent drug-excipient interactions in two separate lipid solution formulations with good solid-state properties and, thus, potential for further development.

Solid-state characterization of an NR2B selective N-methyl d-aspartate (NMDA) antagonist polymorphs

(−)-6-{2-[4-(3-Fluorophenyl)-4-hydroxy-piperidin-1-yl]-1-hydroxyethyl}-3,4-dihydro-quinolin-2(1H)-one (compound A) is an NR2B selective N-methyl d-aspartate (NMDA) antagonist that has shown at least two polymorphs, forms I and II. In this report, we prepared two polymorphs, forms I and II and their crystal forms were identified and characterized by single crystal X-ray diffractometry, differential scanning calorimetry (DSC) and variable temperature powder X-ray diffractometry (VT-PXRD). The results of DSC and VT-PXRD suggested that compound A has at least three polymorphic forms: I, II and a new form III, and that forms II and III showed an enantiotropic relationship. We also performed single crystal X-ray analyses of specific conditions based on the results of VT-PXRD. The unit cell dimensions in crystallographic parameter and molecular arrangements of form I were quite different from forms II and III. Whereas, the crystal structures of forms II and III were similar with the exception of the C58–C59–C61–C62 torsion angle.

Investigating Dehydration from Compacts Using Terahertz Pulsed, Raman, and Near-Infrared Spectroscopy

The purpose of this study was to investigate the dehydration of piroxicam monohydrate (PRXMH) in compacts using terahertz pulsed spectroscopy (TPS), Raman spectroscopy, and reflectance near-infrared (NIR) spectroscopy. Compacts were prepared by using PRXMH and poly(tetrafluoro)ethylene powders and combining them in three different manners before compression to produce compacts in which the PRXMH was dispersed throughout the compact, deposited on one face of the compact, or included as a layer within the compact. TPS was a suitable technique to assess the effect of sample preparation on dehydration, whereas Raman and NIR spectroscopy were limited by their sampling depth and the interference of the polymer matrix. TPS revealed that the dehydration behavior depended largely on the compact preparation method. Non-isothermal dehydration was investigated with all three spectroscopic techniques, combined with principal component analysis (PCA) on samples where the PRXMH was deposited on one face of the compact. In addition, variable temperature X-ray powder diffractometry (VT-XRPD) was used to verify the transformation from PRXMH to anhydrous PRX form I, while thermogravimetric analysis (TGA) was used to monitor the water loss. All three spectroscopic techniques allowed in situ monitoring of the dehydration from the surface layers of the compacts. TPS and Raman spectroscopy detected structural changes of the crystal, while NIR spectroscopy was more sensitive to water loss. PCA of the TPS, Raman spectroscopy, and XRPD data revealed similar dehydration profiles. In contrast, the NIR spectroscopy profile was more similar to the TGA results. The spectroscopic techniques were more suitable than slower techniques such as VT-XRPD for monitoring rapid structural changes that occurred during the dehydration.

Multivariate data analysis as a fast tool in evaluation of solid state phenomena

A thorough understanding of solid state properties is of growing importance. It is often necessary to apply multiple techniques offering complementary information to fully understand the solid state behavior of a given compound and the relations between various polymorphic forms. The vast amount of information generated can be overwhelming and the need for more effective data analysis tools is well recognized. The aim of this study was to investigate the use of multivariate data analysis, in particular principal component analysis (PCA), for fast analysis of solid state information. The data sets analyzed covered dehydration phenomena of a set of hydrates followed by variable temperature X-ray powder diffractometry and Raman spectroscopy and the crystallization of amorphous lactose monitored by Raman spectroscopy. Identification of different transitional states upon the dehydration enabled the molecular level interpretation of the structural changes related to the loss of water, as well as interpretation of the phenomena related to the crystallization. The critical temperatures or critical time points were identified easily using the principal component analysis. The variables (diffraction angles or wavenumbers) that changed could be identified by the careful interpretation of the loadings plots. The PCA approach provides an effective tool for fast screening of solid state information.

Insight into Thermally Induced Phase Transformations of Erythromycin A Dihydrate

Thermal stress that pharmaceutical solids are exposed to during manufacturing can induce various phase transitions in bulk drug substances or excipients, resulting in altered dosage form performance. This paper reports on the thermally induced transformations of a macrolide antibiotic, erythromycin A dihydrate, investigated in situ by variable temperature powder X-ray diffractometry and hot-stage Raman spectroscopy. Erythromycin A dihydrate undergoes dehydration to isomorphic dehydrate, which then melts and recrystallizes to anhydrate. Raman spectroscopy was able to distinguish the two isomorphs of erythromycin A, the dihydrate and the dehydrate, thus offering a potential tool for in-process control of the drying process. The model fitting approach did not provide insight into the solid-state dehydration mechanism. However, the reaction mechanism was presented on the basis of crystal chemistry.

Physical changes of β-sitosterol crystals in oily suspensions during heating

The aim of this research was to describe the thermal behavior of beta-sitosterol crystals in oil-suspensions with a focus on the role of water during heating. The suspensions were prepared by recrystallization in order to achieve a microcrystalline particle size. The structural changes together with the mechanical properties of the suspensions during heating were studied by using variable temperature X-ray powder diffractometry (VT-XRPD), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA). Hydrated beta-sitosterol crystals in an oil-suspension dehydrated, despite the composition of the suspensions, at low temperatures. At high beta-sitosterol concentration, the monohydrate crystal form changed partially to a hemihydrated form, and when only a small amount of water was initially incorporated, the hemihydrate crystal form dehydrated to a mostly anhydrate crystal form. The released water, which was immiscible in the surrounding oil, caused the recrystallization of hydrated beta-sitosterol during cooling. This procedure indicated a reversible dehydration process. Structural and thermal analysis of beta-sitosterol crystals in suspensions, together with mechanical analysis made it possible to understand various physical changes during heating.

Partially Crystalline Systems in Lyophilization: II. Withstanding Collapse at High Primary Drying Temperatures and Impact on Protein Activity Recovery

In an accompanying article we have described the construction of the water-rich sections of raffinose-glycine-water and trehalose-glycine-water state diagrams. In this study, we use the information obtained from the state diagrams to identify the minimum weight fraction of the crystalline component in glycine-carbohydrate systems necessary to withstand collapse at high primary drying temperatures. We also determine the impact of primary drying, substantially above T'g, on the recovery of lactate dehydrogenase (LDH) activity. Ambient and variable temperature X-ray powder diffractometry and differential scanning calorimetry were used to characterize the frozen and freeze-dried systems. Aqueous solutions with glycine to carbohydrate (raffinose pentahydrate or trehalose dihydrate) weight ratios ranging from 0.2 to 2.0 were freeze dried. The protein formulations contained 20 mM citrate buffer (pH 6.0) and LDH (20 microg/mL). A glycine to anhydrous raffinose weight ratio >or=1.18 and a glycine to anhydrous trehalose weight ratio >or=1.56 were necessary to withstand macroscopic collapse in the system, when the primary drying was carried out at a product temperature at least 10 degrees C above the T'g. The recovery of LDH activity was almost complete in the reconstituted lyophile whether the primary drying was carried out above T'g (-10 degrees C) or below T'g (-32 degrees C). Thus, by judiciously combining crystalline and amorphous components, it was possible to primary dry at temperatures substantially above the T'g.

Solid‐state Properties of Creatine Monohydrate

Creatine monohydrate (CM) is a nutritional supplement and an ergogenic aid for athletes. It appears to increase lean body mass, high‐intensity power output and strength in healthy humans. The crystal structure of creatine monohydrate has previously been reported. However, little information is available on its solid‐state properties. In this investigation, creatine monohydrate was subjected to Thermal Analyses, Karl‐Fisccher Titrimetry (KFT), Scanning Electron Microscopy (SEM), and Variable Temperature X‐ray Powder Diffractometry (VTXRD) to characterize its solid‐state properties. The results of this study suggested that commercially available creatine monohydrate dehydrates at about 97–125°C. A phase transition after dehydration was confirmed by X‐ray diffraction studies. This dehydrated phase at a temperature above 230°C undergoes intramolecular cyclization with a loss of an additional mole of water to form creatinine. Creatinine finally melts with decomposition at about 290°C. VTXRD, confirmed that the above solid‐state thermal transformation was kinetically driven, and occurred within a narrow temperature range. Mass Spectrometric (MS) studies further indicated a possible dimerization of creatinine formed during the solid‐state transformation. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:708–718, 2002

Investigation of solid-state reactions using variable temperature X-ray powder diffractometry. II. Aminophylline monohydrate.

The object of this investigation was to demonstrate the utility of X-ray powder diffractometry (XRD) to study the kinetics of a complex pharmaceutical solid-state reaction wherein the reactant, product and intermediate phases were all simultaneously quantified. Aminophylline monohydrate (I) decomposed to anhydrous theophylline (III) either directly or through an intermediate (anhydrous aminophylline, II). The reaction kinetics were studied isothermally at several temperatures ranging from 65 to 100 degrees C. By measuring the intensities of the XRD peaks unique to I, II and III, it was possible to simultaneously quantify the 3 phases during the entire reaction. Assuming that all the reaction steps follow first-order kinetics. the three equations describing the concentrations of I, II and III as a function of time, were derived. By fitting the experimental data to these equations, it was possible to obtain the rate constants for the three reaction steps. The rate constants were obtained at different temperatures and were used to draw Arrhenius type plots from which the activation energies were determined. At lower temperatures (< 80 degrees C). the concentration of the intermediate phase, i.e., II, was low throughout the reaction while at higher temperatures (> 90 degrees C), there was rapid formation and accumulation of II during the early stages of the reaction. These differences could be attributed to the fact that k1 (I --> II) had a more pronounced temperature dependence than k2 (I --> III) and k3 (II --> II). The XRD results were confirmed with isothermal thermogravimetry. Variable temperature XRD is a powerful tool to probe reaction kinetics in crystalline pharmaceuticals since it permits simultaneous quantification of multiple solid phases.

Physico-chemical Characterization of Hydrated and Anhydrous Crystal Forms of Amlodipine Besylate

The antihypertensive drug substance amlodipine besylate crystallizes in two stable crystal forms, an anhydrate and a hitherto unknown monohydrate. Both forms have been characterized by thermal analysis, X-ray powder diffractometry, FTIR- and FT Raman spectroscopy. Moisture sorption- and desorption investigations reveal their unusual physical stability in a broad range of relative humidities. The monohydrate forms an isomorphic dehydrate upon dehydration, which was elucidated by variable temperature X-ray powder diffractometry. Physico-chemical properties as well as relative stabilities of the crystal forms are described and discussed based on a comprehensive analytical identification, and enable an estimation of practical relevance for manufacturing of amlodipine besylate solid dosage forms.

Thermal Behavior of Ursodeoxycholic Acid in Urea: Identification of Anomalous Peak in the Thermal Analysis

The objective of this study was to clarify the thermal behavior of ursodeoxycholic acid (UDCA) in mixtures with urea. Physical mixtures of UDCA and urea in various ratios were prepared, and the thermal analysis of these sample mixtures was investigated using conventional differential scanning calorimetry (DSC) and variable-temperature powder X-ray diffractometry (VTXRD). The hot-stage microscopy (HSM) and powder X-ray diffractometry (PXRD) were used as complementary techniques. From the DSC results of all sample mixtures, it was found that there was no endothermic peak at the melting temperature of intact UDCA crystals. The DSC thermograms of each ratio showed only the endothermic peak at about 136°C due to the melt of urea and the anomalous endothermic peak at about 155°C–157°C. The VTXRD study revealed that the crystals of urea completely disappeared at a temperature of 140°C. At this temperature, it was identified that the VTXRD pattern obtained was of UDCA crystals. The crystalline peaks gradually decreased in intensity at a temperature of 150°C. When the temperature was up to 160°C, the identical crystalline peaks of UDCA crystals completely disappeared. It was concluded that the anomalous endothermic peak at 155°C–157°C was the peak due to the dissolution of UDCA crystals in the surrounding melted urea.

Investigation of solid-state reactions using variable temperature X-ray powder diffractrometry. I. Aspartame hemihydrate.

The object of this study was to demonstrate the applicability of variable temperature X-ray powder diffractometry (XRD) to investigate solid-state reactions using aspartame as a model compound. Aspartame exists as a hemihydrate (ASH) under ambient conditions and converts to aspartame anhydrate (ASA) at approximately 130 degrees C. ASA on further heating to approximately 180 degrees C undergoes decomposition (intramolecular cyclization) to form a diketopiperazine derivative (DKP). The dehydration as well as the decomposition kinetics were studied isothermally at several temperatures. The unique feature of this technique is that it permits simultaneous quantification of the reactant as well as the product. While the dehydration of ASH appeared to follow first-order kinetics, the cyclization of ASA was a nucleation controlled process. The rate constants were obtained at various temperatures, which permitted the calculation of the activation energies of dehydration and cyclization from the Arrhenius plots. The activation energy of dehydration was also calculated according to the method described by Ng (Aust. J. Chem., 28:1169-1178, 1975) and the two values were in good agreement. The study demonstrates that XRD is an excellent complement to thermal analysis and provides direct information about the solid-states of various reaction phases.

Solid-State Phase Transitions of AG337, an Antitumor Agent

The object of this investigation was to perform detailed solid-state characterization studies on the different solid forms of AG337 and to determine the conditions of their interconversions. Solid-state characterization was done using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy, Karl Fischer titrimetry, ambient and variable temperature X-ray powder diffractometry (XRD) and TGA coupled with FTIR (TGA/FTIR). In addition to five polymorphic forms of the anhydrate (Iαto Iε), a hemihydrate (C14H12N4OS· 2HCl · 0.5H2O, II), a monohydrate (C14H12N4OS · 2HCl · H2O; III), as well as a dihydrate (C14H12N4OS · 2HCl · 2H2O; IV) were identified. The ‘as is’ anhydrate, Iα, resisted water uptake until stored at 98% RH (room temperature), where it transformed directly to IV. II and III transformed to IV at RH values ≥ 7.6 and 84% respectively. Heating II and III to 130°C in the variable temperature XRD resulted in the formation of Iβ and Iγ respectively. On the other hand, Iδ and Iε were obtained when II and III were respectively stored at 60°C under vacuum. Variable temperature XRD, by providing information about the solid-state as a function of temperature, assisted in the interpretation of the DSC and TGA results. TGA/FTIR provided direct evidence that the thermal events observed in the temperature ranges of 25–150°C and 200–250°C were due to loss of water and loss of hydrogen chloride respectively. In addition to the conventional analytical techniques such as XRD, DSC, TGA and KFT, two other techniques, (variable temperature XRD and TGA/FTIR), were very useful in these solid-state characterization studies.

Applications of pressure differential scanning calorimetry in the study of pharmaceutical hydrates. II. Ampicillin trihydrate

The dehydration of ampicillin trihydrate (C 16H 19N 3O 4S·3H 2O) was studied by both conventional differential scanning calorimetry (DSC) and by pressure differential scanning calorimetry (PDSC). The solid state of the anhydrous phase formed was influenced by the DSC conditions. At ambient pressure, dehydration resulted in the formation of X-ray amorphous anhydrous ampicillin, while at elevated pressures a crystalline anhydrate was obtained. These conclusions were based on variable temperature X-ray powder diffractometry (VTXRD) which was used as a complementary technique. PDSC was a reliable technique to quantify the relative amounts of ampicillin trihydrate and anhydrous ampicillin when they occur as a mixture. Grinding-induced alterations in the degree of crystallinity of ampicillin trihydrate were also quantified by PDSC. The changes in crystallinity induced after milling for just 1 min were detected and quantified with a high degree of precision. PDSC appears to be an excellent technique not only for the characterization but also for obtaining quantitative information about the solid state of pharmaceutical hydrates.

Influence of Environmental Conditions on the Kinetics and Mechanism of Dehydration of Carbamazepine Dihydrate

ABSTRACTThe object of this project was to study the influence of temperature and water vapor pressure on the kinetics and mechanism of dehydration of carbamazepine dihydrate and to establish the relationship between the dehydration mechanism and the solid-state of the anhydrous phase formed, Three experimental techniques were utilized to study the kinetics of dehydration of carbamazepine dihydrate (C15H12N2O·2H2O)-thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and variable temperature powder X-ray diffractometry (VYXRD). These techniques respectively provide information about the changes in weight, heat flow and solid-state (phase) during the dehydration process. The instrumental setup was modified so that simultaneous control of both the temperature and the water vapor pressure was possible. The experiments were carried out at different temperatures, ranging from 26 to 64°C. In the absence of water vapor, the dehydration followed the 2-dimen-sional phase boundary controlled model at all the temperatures studied. In the next stage, the water vapor pressure was altered while the studies were carried out at a single temperature of 44°C. The dehydration was 2-dimensional phase boundary controlled at water vapor pressures ≤5.1 torr while the Avrami-Erofeev kinetics (3-dimensional nucleation) was followed at water vapor pressures ≥ 12.0 torr. In the former case, the anhydrous phase formed was X-ray amorphous while it was the crystalline anhydrous γ-carbamazepine in the latter. Thus a relationship between the mechanism of dehydration and the solid-state of the product phase was evident. The dehydration conditions influence not only the mechanism but also the solid-state of the anhydrous phase formed. While the techniques of TGA and DSC have found extensive use in studying dehydration reactions, VTXRD proved to be an excellent complement in characterizing the solid-states of the reactant and product phases.

Polymorphism in Anhydrous Theophylline—Implications on the Dissolution Rate of Theophylline Tablets

The objects of this investigation were (i) to prepare and characterize a new anhydrous theophylline phase that is metastable under ambient conditions, and (ii) to prepare model tablet formulations containing either this metastable anhydrate (I*) or stable anhydrous theophylline (I), store them under different relative humidity (RH) conditions, and compare their dissolution behavior. I* was prepared by dehydration of theophylline monohydrate (II). Variable temperature X-ray powder diffractometry of II revealed the following series of transitions: II→I*→I. The metastable anhydrate, I*, which has not yet been reported in the literature, appears to be related monotropically to I. it was characterized by ambient and variable temperature X-ray powder diffractometry, Karl Fischer titrimetry, and thermoanalytical techniques (differential scanning calorimetry and thermogravimetric analysis). Tablet formulations containing either I* or I were prepared and stored at 33 and 52% RH (room temperature). The solid state of the drug was monitored by X-ray powder diffractometry and the tablets were subjected to the USP dissolution test. In tablets, I* completely converted to I in ≤10 days when stored at either 33 or 52% RH. Scanning electron microscopy provided direct visual evidence of recrystallization. This recrystallization was accompanied by a decrease in the dissolution rate of the stored formulations that was so pronounced in the formulations stored at 52% RH that they failed the USP dissolution test. The in situ solid-state transition appears to be responsible for the decrease in dissolution rate observed following storage. Stored tablets containing I showed neither a phase transition nor an alteration in their dissolution behavior.