Dehydration, hydration behavior, and structural analysis of fenoprofen calcium.

Fenoprofen calcium (FC) is a nonsteroidal, anti-inflammatory, analgesic, and antipyretic agent. The dehydration behavior of FC dihydrate and the rehydration of the dried FC were investigated using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and powder X-ray diffractometry (PXRD). The stoichiometry, the crystal packing arrangement, and water environments in FC dihydrate were determined using single-crystal X-ray diffraction (XRD) analysis. The Arrhenius plot (natural logarithm of the dehydration rate constant versus the reciprocal of absolute temperature) for FC dihydrate from isothermal TGA is not linear. The activation energy of dehydration was 309 kJ/mol in the 50-60 degrees C range and 123 kJ/mol in the 60-80 degrees C range. The difference in activation energy can be explained from the crystal structure data where one water molecule is sandwiched between repeating polar carboxylate groups and the other water is in a slightly less polar region of the crystal. Single-crystal XRD analysis also indicated each calcium ion is coordinated to six oxygens. Two coordinating oxygens are provided by two water molecules and the other four oxygens are provided by the carboxylate group of four separate fenoprofen anions. Each fenoprofen anion, which can provide two oxygens for coordination, is associated with two different calcium ions. Hot-stage PXRD suggested that only a loss of 1 mole of water per mole of FC dihydrate (forming a monohydrate) was required to convert the material to a partially crystalline state. The monohydrate is not completely disordered as evidenced by a strong diffraction peak as well as some weaker peaks in the PXRD pattern. The rehydration of the anhydrous form of FC follows a solution-mediated transformation, prior to crystallizing as the dihydrate.     

Thermal behavior and thermal decarboxylation of 10-hydroxycamptothecin in the solid state

In order to investigate the thermal-related properties and thermal stability of 10-hydroxycamptothecin (10-HCPT) in the solid state, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Fourier transform infrared (FT-IR) microspectroscopy were used. A novel combination of FT-IR microspectroscopy with thermal analyzer was applied simultaneously to monitor the dehydration and rehydration processes of the 10-HCPT sample. The thermal-induced decomposition of the 10-HCPT sample was also determined by using electrospray-ion trap mass spectrometry (ES-ITMS). The results indicated that the 10-HCPT sample used in this study was a monohydrate in structure, this form that can dehydrate to an anhydrate form if the temperature goes beyond 90 degrees C. The 10-HCPT anhydrate was first suggested to have two polymorphs, in which the form I might transform to form II when the 110 degrees C-preheated sample was cooled to 30 degrees C. The polymorphic transformation temperature was shown within 90-120 degrees C with 10.46 kcal/mol of enthalpy. The peak at 1723 cm(-1) found in the IR spectrum of 10-HCPT monohydrate might correspond to the hydrogen-bonded CO stretching vibration of lactone, which shifted to 1750 cm(-1) assigned to a free CO group of lactone after the destruction of hydrogen bonding via dehydration. This suggests that monohydrate seems to interact intramolecularly with 10-HCPT by hydrogen bonding. However, the rehydration process of the 10-HCPT anhydrate might cause it to return to being a monohydrate, depending on the storage condition. In addition, the thermal-induced decarboxylation of the solid-state 10-HCPT when the temperature is beyond 226 degrees C was proven by the appearance of a new IR peak at 1701 cm(-1) and one major mass spectral peak at m/z 321. This unique IR spectral peak at 1701 cm(-1) was due to the conjugated carbonyl group in the degraded product of 10-HCPT. The m/z 321 assigned to the decarboxylation of 10-HCPT was equal to the molecular weight loss of 44 from mass spectra; which was consistent with the weight loss of 11.9% (molecular weight of 43.3) from TGA curve of 10-HCPT anhydrate.     

Dehydration of trehalose dihydrate at low relative humidity and ambient temperature

The physico-chemical behaviour of trehalose dihydrate during storage at low relative humidity and ambient temperature was investigated, using a combination of techniques commonly employed in pharmaceutical research. Weight loss, water content determinations, differential scanning calorimetry and X-ray powder diffraction showed that at low relative humidity (0.1% RH) and ambient temperature (25 degrees C) trehalose dihydrate dehydrates forming the alpha-polymorph. Physical examination of trehalose particles by scanning electron microscopy and of the dominant growth faces of trehalose crystals by environmentally controlled atomic force microscopy revealed significant changes in surface morphology upon partial dehydration, in particular the formation of cracks. These changes were not fully reversible upon complete rehydration at 50% RH. These findings should be considered when trehalose dihydrate is used as a pharmaceutical excipient in situations where surface properties are key to behaviour, for example as a carrier in a dry powder inhalation formulations, as morphological changes under common processing or storage conditions may lead to variations in formulation performance.     

Multivariate chemometric approach to thermal solid-state FT-IR monitoring of pharmaceutical drug compound

The study of thermal-related solid-state reaction monitored by spectroscopic method needs the use of advanced multivariate chemometric approach. It is because visual inspection of spectral data on particular functional groups or spectral bands is difficult to reveal the complete physical and chemical information. The spectral contributions from various species involved in the solid-state changes are generally highly overlapping and the spectral differences between reactant and product are usually quite minute. In this article, we demonstrate the use of multivariate chemometric approach to resolve the in situ thermal-dependent Fourier-transform infrared (FT-IR) mixture spectra of lisinopril dihydrate when it was heated from 24 to 170 degrees C. The collected FT-IR mixture spectra were first subjected to singular value decomposition (SVD) to obtain the right singular vectors. The right singular vectors were rotated into a set of pure component spectral estimates based on entropy minimization and spectral dissimilarity objective functions. The resulting pure component spectral estimates were then further refined using alternating least squares (ALS). In current study, four pure component spectra, that is, lisinopril dihydrate, monohydrate, anhydrate, and diketopiperazine (DKP) were all resolved and the relative thermal-dependent contributions of each component were also obtained. These relative contributions revealed the critical temperature for each transformation and degradation. This novel approach provides better interpretation of the pathway of dehydration and intramolecular cyclization of lisinopril dihydrate in the solid state. In addition, it can be used to complement the information obtained from differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).     

Intramolecular cyclization of diketopiperazine formation in solid-state enalapril maleate studied by thermal FT-IR microscopic system.

The pathway of diketopiperazine (DKP) formation of solid-state enalapril maleate has been studied by using a novel Fourier transform infrared microspectroscope equipped with a thermal analyzer (thermal FT-IR microscopic system). The thermogram of the conventional differential scanning calorimetry (DSC) method was also compared. The results show new evidence of IR peaks at 3250 cm(-1) (the broad O-H stretching mode of water), and at 1738 and 1672 cm(-1) (the carbonyl band of DKP), indicating DKP formation in enalapril maleate via intramolecular cyclization. Moreover, the disappearance of IR peaks from enalapril maleate at 3215 cm(-1) (the secondary amine), 1728 cm(-1) (the carbonyl group of carboxylic acid), and 1649 cm(-1) (the carbonyl stretching of tertiary amide) also confirmed the DKP formation. The thermal FT-IR microscopic system clearly evidenced that the DKP formation in enalapril maleate started from 129 degrees C, and reached a maximum at 137 degrees C. This result was also confirmed by the conventional DSC thermogram of the compressed mixture of KBr powder and enalapril maleate, in which an endothermic peak at 144 degrees C with an extrapolated onset temperature at 137 degrees C was observed. This strongly suggests that the thermal FT-IR microscopic system was able to qualitatively detect the formation of DKP derivatives in solid-state enalapril maleate via intramolecular cyclization.     

Dehydration behavior of eprosartan mesylate dihydrate.

Eprosartan mesylate (SKF 108566-J; EM) is an antihypertensive agent approved for marketing in the USA. EM dihydrate was prepared by three methods, one of which included suspending the anhydrous drug in an aqueous solution of 1.0 M methanesulfonic acid to form a slurry, followed by filtration. The dehydration kinetics of EM dihydrate were derived by analyzing the fit of the isothermal thermogravimetric analytical (TGA) data to numerous kinetic models. EM dihydrate undergoes dehydration in two distinct steps, each involving the loss of 1 mol of water at 25-70 degrees C and 70-120 degrees C, respectively. Recrystallization of EM occurs at approximately 120-140 degrees C after dehydration to the anhydrous phase. This explanation is supported by variable temperature powder X-ray diffractometry. The mechanism of the dehydration reaction is complex, the dependence of the reaction rate on temperature varying as a function of the particles size. For the dihydrate of sieve fraction <125 microm, the kinetics of the first and second dehydration steps are consistent with the Avrami-Erofeev equation (A3, n = 1/3) over the temperature range studied, corresponding to three-dimensional growth of nuclei. In contrast, for the 125-180-microm and 180-250-microm sieve fractions, the kinetics are best described by the two-dimensional phase boundary reaction (R2) at a lower dehydration temperature (i.e., 28.3 degrees C), and by the Avrami-Erofeev equation (A3, n = 1/3) at a higher dehydration temperature (i.e., 93.7 degrees C). The activation energies (15-40 kcal/mol) and frequency factors of the dehydration of EM dihydrate were determined both by Arrhenius plots of the isothermal rates determined by TGA and by Kissinger plots of the nonisothermal differential scanning calorimetric data. Hot stage microscopy of single crystals of EM dihydrate showed random nucleation at the surface and dehydration with the growth of microcrystals along the needle a axis. Cerius(2) molecular modeling software showed the existence of water channels along the a axis and enabled the observed dehydration behavior of EM dihydrate crystals to be explained in terms of the bonding environment of water molecules in the crystal structure.     

Characterization of azithromycin hydrates.

Azithromycin (AZI) is a macrolide antibiotic with an expanded spectrum of activity that is commercially available as a dihydrate. This study was carried out to characterize hydrates of azithromycin. A commercial dihydrate sample was used to prepare monohydrate from water/ethanol (1:1) mixture. Hydrates were characterized using DSC, TGA, KFT, XRD, HSM, SEM and FT-IR. TGA showed that the commercial samples are dihydrate and the sample prepared from water/ethanol (1:1) was a monohydrate. Solubility studies revealed that monohydrate converted to dihydrate during solubility studies and as a result there was no significant difference in the equilibrium solubility of MH and DH. Thermal analysis under various conditions revealed that dehydration and melting took place simultaneously. Anhydrous AZI was found to be hygroscopic and converted to DH on storing at room temperature. Molecular modeling studies revealed the probable sites of attachment of water molecules to AZI.     

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

ABSTRACT

The 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.     

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 (I alpha to I epsilon), 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, I alpha, 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 > or = 7.6 and 84% respectively. Heating II and III to 130 degrees C in the variable temperature XRD resulted in the formation of I beta and I gamma respectively. On the other hand, I delta and I epsilon were obtained when II and III were respectively stored at 60 degrees 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 degrees C and 200-250 degrees 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.     

Physical characterization of picotamide monohydrate and anhydrous picotamide

Picotamide is an antiplatelet agent given by mouth as monohydrate (PICOW) (Plactidil) in thrombo-embolic disorders. This study deals with physical characterization of PICOW recrystallized from various solvents and the respective dehydration products using X-ray powder diffractometry (XRD), infrared spectroscopy (IR), and thermal analytical techniques (differential scanning calorimetry, DSC; thermogravimetric analysis, TGA; simultaneous TGA/DSC; hot stage microscopy, HSM). Monophasic and biphasic DSC and TGA profiles of water loss were recorded under open conditions for PICOW samples which showed the same monoclinic crystal structure. Biphasic profiles became monophasic for gently ground samples which were, however, structurally identical to the intact samples. Morphological factors, the various degree of "perfection" of the PICOW crystal lattice, and/or cluster aggregation of PICOW crystals were assumed to be responsible for the differing dehydration patterns. Polymorphism in anhydrous picotamide, i.e., nucleation of crystal forms A, mp 135.5 +/- 0.4 degrees C, and B, mp 152.9 +/- 0.3 degrees C after dehydration of PICOW, was detected by DSC and HSM. The dehydration product of PICOW under isothermal conditions (115 degrees C, 20 mmHg), PICOA, was mainly composed of the lower melting polymorph A (fusion enthalpy 74.4 +/- 2.2 J g(-1)), which gradually reverted to the starting hydrate by storing in an ambient atmosphere. Dissolution tests of PICOW and PICOA in water at 37 degrees C as both powders and compressed disks reflected to some extent the higher solubility of the metastable form (by 24% at 37 degrees C) in terms of both higher dissolution efficiency and percent of active ingredient dissolved (by 28%) and intrinsic dissolution rate (by 32%).     

Structure in Dehydrated Trehalose Dihydrate—Evaluation of the Concept of Partial Crystallinity

Purpose (i) To use trehalose as a model compound to evaluate the concept of crystallinity in pharmaceuticals. (ii) To understand the structural nature of dehydrated trehalose dihydrate.Materials and Methods Trehalose dihydrate was dehydrated isothermally at several temperatures below 100°C and the anhydrous product was characterized by XRD, DSC and water vapor sorption.Results XRD and DSC suggested that the dehydration product was a partially crystalline α-polymorphic form of anhydrous trehalose . An increase in the temperature of dehydration resulted in a decrease in lattice order. In agreement with earlier findings, the ordered regions in the dehydrated lattice converted to the dihydrate at much lower RH values than amorphous trehalose. However, the lattice order in the dehydrated product dictated the RH at which this conversion was initiated—the higher the lattice order the lower this RH. The structural nature of these samples can be explained based on the one-state model of crystallinity. In dehydrated trehalose, there is a continuum in lattice order ranging from highly crystalline to a completely disordered (i.e., amorphous) state.Conclusion The extent of lattice order in anhydrous trehalose was dictated by the kinetics of water removal from trehalose dihydrate. The partially crystalline nature of anhydrous trehalose produced by dehydration could be described on a continuous scale of lattice order based on the one-state model of crystallinity.     

In situ dehydration of carbamazepine dihydrate: a novel technique to prepare amorphous anhydrous carbamazepine

The purposes of this project were to prepare amorphous carbamazepine by dehydration of crystalline carbamazepine dihydrate, and to study the kinetics of crystallization of the prepared amorphous phase. Amorphous carbamazepine was formed and characterized in situ in the sample chamber of a differential scanning calorimeter (DSC), a thermogravimetric analyzer (TGA), and a variable temperature x-ray powder diffractometer (VTXRD). It has a glass transition temperature of 56 degrees C and it is a relatively strong glass with a strength parameter of 37. The kinetics of its crystallization were followed by isothermal XRD, under a controlled water vapor pressure of 23 Torr. The crystallization kinetics are best described by the three-dimensional nuclear growth model with rate constants of 0.014, 0.021, and 0.032 min-1 at 45, 50, and 55 degrees C, respectively. When the Arrhenius equation was used, the activation energy of crystallization was calculated to be 74 kJ/mol in the presence of water vapor (23 Torr). On the basis of the Kissinger plot, the activation energy of crystallization in the absence of water vapor (0 Torr water vapor pressure) was determined to be 157 kJ/mol. Dehydration of the dihydrate is a novel method to prepare amorphous carbamazepine; in comparison with other methods, it is a relatively gentle and effective technique.     

Dehydration kinetics of neotame monohydrate

The dehydration of neotame monohydrate was monitored at various temperatures by differential scanning calorimetry (DSC), thermogravimetry (TGA), hot-stage microscopy (HSM), powder X-ray diffractometry (PXRD), and (13)C solid-state nuclear magnetic resonance (SSNMR) spectroscopy. This work emphasizes kinetic analysis of isothermal TGA data by fitting to various solid-state reaction models and by model-free kinetic treatment. The dehydration of neotame monohydrate follows the kinetics of a two-dimensional phase boundary reaction (R2) at 40-50 degrees C with an activation energy of 75 +/- 9 kJ/mol, agreeing well with 60-80 kJ/mol from model-free kinetics. At a low heating rate in DSC and TGA, neotame monohydrate undergoes dehydration to produce anhydrate Form E, which then converts to anhydrate Form A, followed by the melting of A. Neotame monohydrate under dry nitrogen purge at 50 mL/min undergoes partial isothermal dehydration at 50 degrees C to produce neotame anhydrate Form A. When neotame monohydrate is heated very slowly from 50 to 65-70 degrees C over 24 h, pure Form A is obtained.     

Unusual Effect of Water Vapor Pressure on Dehydration of Dibasic Calcium Phosphate Dihydrate

Dibasic calcium phosphate occurs as an anhydrate (DCPA; CaHPO₄) and as a dihydrate (DCPD; CaHPO₄?2H₂O). Our objective was to investigate the unusual behavior of these phases. Dibasic calcium phosphate dihydrate was dehydrated in a (i) differential scanning calorimeter (DSC) in different pan configurations; (ii) variable-temperature X-ray diffractometer (XRD) at atmospheric and under reduced pressure, and in sealed capillaries; and (iii) water vapor sorption analyzer at varying temperature and humidity conditions. Dehydration was complete by 210°C in an open DSC pan and under atmospheric pressure in the XRD. Unlike “conventional” hydrates, the dehydration of DCPD was facilitated in the presence of water vapor. Variable-temperature XRD in a sealed capillary and DSC in a hermetic pan with pinhole caused complete dehydration by 100°C and 140°C, respectively. Under reduced pressure, conversion to the anhydrate was incomplete even at 300°C. The increase in dehydration rate with increase in water vapor pressure has been explained by the Smith–Topley effect. Under “dry” conditions, a coating of poorly crystalline product is believed to form on the surface of particles and act as a barrier to further dehydration. However, in the presence of water vapor, recrystallization occurs, creating cracks and channels and facilitating continued dehydration.     

Thermodynamic and kinetic characterization of polymorphic transformation of famotidine during grinding

Two polymorphs of famotidine were prepared by recrystallization from acetonitrile for form A and methanol for form B, respectively. The effect of grinding process on the polymorphic transformation of famotidine was investigated. Each famotidine sample ground for various grinding times in a ceramic mortar was determined by differential scanning calorimetry (DSC), conventional and thermal Fourier transform infrared (FT-IR) microspectroscopy. The results indicate that the raw material of famotidine was proved to be a form B. A unique IR absorption band at 3505 cm(-1) for famotidine form B gradually decreased its intensity with the grinding time, while two newer IR absorption bands at 3451 and 1671 cm(-1) for famotidine form A slowly appeared. The peak intensity ratio of 3451/350 5 cm(-1) was linearly (r=0.9901) increased with the grinding time, suggesting that the grinding process could induce the polymorphic transformation of famotidine from form B to form A by a zero-order process. The DSC endothermic peaks also confirmed this polymorphic transformation from famotidine form B (167 degrees C, DeltaH: 165J/g) to famotidine form A (174 degrees C, DeltaH: 148J/g) in which the values of enthalpy were linearly reduced with the increase of grinding time (r=0.9943). The phase transition temperature of the different ground famotidine samples could be easily and only evidenced by using thermal FT-IR microspectroscopy, rather than by DSC analysis. These phase transition temperatures of the famotidine form B ground for 5-20 min quickly reduced from 144 to 134 degrees C and maintained a constant at 134 degrees C even after 20-30 min grinding. The grinding process not only decreased the crystallinity of famotidine form B but also reduced the particle size of famotidine form B, resulting in easy induction of the polymorphic transformation of famotidine from form B to form A in ground famotidine sample.     

Trehalose and hyaluronic acid coordinately stabilized freeze-dried pancreatic kininogenase.

The ability and mechanisms of stabilization of freeze-dried formulations of pancreatic kininogenase (PKase) by carbohydrates were evaluated. Activity and structure of PKase were examined after freeze-drying and rehydration in presence with or without a carbohydrate. Addition of trehalose, lactose, sucrose, hyaluronic acid (HA) or a combination of trehalose and HA to PKase formulations prior to freeze-drying step increases the stability of PKase during freeze-drying, storage and rehydration as measured by activity preservation. The combination of trehalose and HA is the most effective for the stabilization of PKase. Addition of HA alone to a formulation does not affect protein structure, but it increases glass-transition temperature (Tg) and stability of lyophilized PKase in presence of trehalose during dehydration, storage and rehydration processes. Therefore, trehalose and HA offer complementary properties that improve the stability of PKase during dehydration, storage and rehydration.     

Non-isothermal dehydration kinetic study of aspartame hemihydrate using DSC,TGA and DSC-FTIR microspectroscopy

Three thermal analytical techniques such as differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) using five heating rates, and DSC-Fourier Transform Infrared (DSC-FTIR) microspectroscopy using one heating rate, were used to determine the thermal characteristics and the dehydration process of aspartame (APM) hemihydrate in the solid state. The intramolecular cyclization process of APM anhydrate was also examined. One exothermic and four endothermic peaks were observed in the DSC thermogram of APM hemihydrate, in which the exothermic peak was due to the crystallization of some amorphous APM caused by dehydration process from hemihydrate to anhydride. While four endothermic peaks were corresponded to the evaporation of absorbed water, the dehydration of hemihydrate, the diketopiperazines (DKP) formation via intramolecular cyclization, and the melting of DKP, respectively. The weight loss measured in TGA curve of APM hemihydrate was associated with these endothermic peaks in the DSC thermogram. According to the Flynn–Wall–Ozawa (FWO) model, the activation energy of dehydration process within 100–150 °C was about 218 ± 11 kJ/mol determined by TGA technique. Both the dehydration and DKP formation processes for solid-state APM hemihydrate were markedly evidenced from the thermal-responsive changes in several specific FTIR bands by a single-step DSC-FTIR microspectroscopy.     

Dehydration Study of Piracetam Co-Crystal Hydrates

A hydrate of co-crystal of piracetam and 3,5-dihydroxybenzoic acid was obtained via crystallization from water. Single-crystal X-ray data show that piracetam/3,5-dihydroxybenzoic acid tetrahydrate (P35TH) crystallizes in the triclinic system with a P1 space group. The physicochemical properties of co-crystal hydrate were characterized using powder X-ray diffractometry, differential scanning calorimetry (DSC), thermogravimetric analyzer (TGA), and FTIR spectroscopy. The dehydration kinetics of P35TH was monitored at various temperatures and heating rates by DSC and TGA. Activation energy of P35TH dehydration was obtained using temperature ramp DSC, isothermal and nonisothermal TGA methods. Kinetic analysis of isothermal TGA data was fitted to various solid-state reaction models. Mechanistic models derived from isothermal dehydration kinetic data are best described as a 2-dimensional diffusion mechanism. A correlation was noted between the dehydration behavior and the bonding environment of the water molecules in the crystal structure. This study is a good demonstration of complexity of co-crystal hydrate and their dehydration behavior.     

In Situ Dehydration of Carbamazepine Dihydrate: A Novel Technique to Prepare Amorphous Anhydrous Carbamazepine

The purposes of this project were to prepare amorphous carbamazepine by dehydration of crystalline carbamazepine dihydrate, and to study the kinetics of crystallization of the prepared amorphous phase. Amorphous carbamazepine was formed and characterized in situ in the sample chamber of a differential scanning calorimeter (DSC), a thermogravimetric analyzer (TGA), and a variable temperature x-ray powder diffractometer (VTXRD). It has a glass transition temperature of 56°C and it is a relatively strong glass with a strength parameter of 37. The kinetics of its crystallization were followed by isothermal XRD, under a controlled water vapor pressure of 23 Torr. The crystallization kinetics are best described by the three-dimensional nuclear growth model with rate constants of 0.014, 0.021, and 0.032 min¹ at 45, 50, and 55°C, respectively. When the Arrhenius equation was used, the activation energy of crystallization was calculated to be 74 kJ/mol in the presence of water vapor (23 Torr). On the basis of the Kissinger plot, the activation energy of crystallization in the absence of water vapor (0 Torr water vapor pressure) was determined to be 157 kJ/mol. Dehydration of the dihydrate is a novel method to prepare amorphous carbamazepine; in comparison with other methods, it is a relatively gentle and effective technique.     

Oiling out or molten hydrate-liquid-liquid phase separation in the system vanillin-water

Vanillin crystals in a saturated aqueous solution disappear and a second liquid phase emerges when the temperature is raised above 51 degrees C. The phenomenon has been investigated with crystallization and equilibration experiments, using DSC, TGA, XRD and hot-stage microscopy for analysis. The new liquid solidifies on cooling, appears to melt at 51 degrees C, and has a composition corresponding to a dihydrate. However, no solid hydrate can be detected by XRD, and it is shown that the true explanation is that a liquid-liquid phase separation occurs above 51 degrees C where the vanillin-rich phase has a composition close to a dihydrate. To our knowledge, liquid-liquid phase separation has not previously been reported for the system vanillin-water, even though thousands of tonnes of vanillin are produced globally every year.