Solution-mediated Transformation Research Articles

Thermodynamic stability relationship of ternary and binary cocrystals of isoniazid: why pH and coformer concentration matter

We explained the thermodynamic behavior of ternary and binary cocrystals of isoniazid, identifying conditions where solution-mediated transformations may take place.

Growth of large norsethite crystals in aqueous ammonium nitrate solutions

Crystallization of norsethite [BaMg(CO3)2] receives considerable attention as a key for solving geological problems, and environmental and resource issues. Noresthite is poorly soluble in water, and is synthesized via witherite [BaCO3] by solution-mediated transformation. In contrast, owing to the difficulties such as tremendous growth time and consideration of multi-step reactions, the shape and size of norsethite were not satisfactory for further investigations so far. Here we tried to increase the solubility of the crystals to overcome these difficulties of the growth by adding NH4NO3. The solubilities of norsethite and witherite in the presence of NH4NO3 were ∼35 and ∼45 times higher than those in the absence of NH4NO3, respectively. At 90 °C, the growth rate of norsethite in NH4NO3 solutions was ∼17 times higher than that in NH4NO3-free solutions, and norsethite in NH4NO3 solutions nucleated immediately after mixing the raw materials. Finally, we succeeded in synthesizing bulky norsethite crystals of 170 μm size only in one month, utilizing 0.1–1 M NH4NO3 solutions of 90 °C. We could explain the appearance of large norsethite, considering that norsethite dominantly consumes the solute by adding NH4NO3 compared with witherite. The findings provide a breakthrough in the growth technique of double carbonates.

Insights into the Role of Na+ on the Transformation of Gypsum into α-Hemihydrate Whiskers in Alcohol-Water Systems.

Alcohol–water solution-mediated transformation of gypsum into α-hemihydrate (α-HH) whiskers provides a green alternative for the high-value-added recycling of flue gas desulfurization (FGD) gypsum. However, the role of non-lattice cations during the transformation is still unclear. We report an evolution from “boosting–retarding” to “boosting–retarding–boosting” and finally to “boosting only” effect of non-lattice Na+ functioned by the concentration of ethylene glycol (EG) in water solutions. The driving force increased almost linearly upon the introduction of Na+ through the formation of ion pairs, and a higher slope was obtained at a higher EG concentration. Adsorption of Na+ ions and solidification of eugsterite on gypsum surfaces blocked the nucleation sites of α-HH. The retarding effect first rapidly increased and gradually approached a limit, following a parabolic trend after Na+ ions were introduced. Pentasalt, with a structure similar to that of α-HH, precipitated on the gypsum surface at higher c(Na+). The interaction of the driving force and the structural evolution of calcium sulfate ionic clusters accounts for the evolution of transformation kinetics. The retardation zone was compressed with the increase in EG volume ratios, and a monotonic boosting effect upon Na+ was observed at a 35.0 vol % of EG. Nucleation kinetics dominates the aspect ratio of α-HH whiskers. This study may provide a significant guidance for the utilization of FGD gypsum.

Solution-mediated transformation of natural zeolite to ANA and CAN topological structures with altered active sites for ethanol conversion

In this study, one-pot syntheses of cancrinite (CAN) and analcime (ANA) frameworks from mordenite (MOR) natural zeolite were performed for the first time. The effects of the synthesis gel composition and alkalinity on the phase formation and crystallinity of the product were investigated. All studied zeolites were evaluated for their catalytic activities in ethanol conversion reactions from 473 K to 673 K and at 1 atm. The results suggested that the formation pathways of CAN and ANA are highly dependent on the alkalinity of the synthesis solution and the type of starting material regardless of synthesis template. The use of natural MOR zeolite (MORNZ) in the synthesis can contribute to highly crystalline ANA structures comparable to the ANA products obtained from fumed silica and sodium aluminate (NaAlO2). The quantity and locations of the acidic-cationic dual active sites of the proton-form product zeolites are suitable for synthesizing acetaldehyde from ethanol with over 90% product selectivity. However, further development of synthesis procedures to enhance the surface area is needed to improve the ethanol conversion of the resulting zeolites. This work provides a new perspective on highly crystalline and pure-phase zeolitic structural formations from natural zeolite and their potential application in ethanol conversion.

A Combined Experimental and Theoretical Study of Nitrofuran Antibiotics: Crystal Structures, DFT Computations, Sublimation and Solution Thermodynamics.

Single crystal of furazolidone (FZL) has been successfully obtained, and its crystal structure has been determined. Common and distinctive features of furazolidone and nitrofurantoin (NFT) crystal packing have been discussed. Combined use of QTAIMC and Hirshfeld surface analysis allowed characterizing the non-covalent interactions in both crystals. Thermophysical characteristics and decomposition of NFT and FZL have been studied by differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and mass-spectrometry. The saturated vapor pressures of the compounds have been measured using the transpiration method, and the standard thermodynamic functions of sublimation were calculated. It was revealed that the sublimation enthalpy and Gibbs energy of NFT are both higher than those for FZL, but a gain in the crystal lattice energy of NFT is leveled by an entropy increase. The solubility processes of the studied compounds in buffer solutions with pH 2.0, 7.4 and in 1-octanol was investigated at four temperatures from 298.15 to 313.15 K by the saturation shake-flask method. The thermodynamic functions of the dissolution and solvation processes of the studied compounds have been calculated based on the experimental data. Due to the fact that NFT is unstable in buffer solutions and undergoes a solution-mediated transformation from an anhydrate form to monohydrate in the solid state, the thermophysical characteristics and dissolution thermodynamics of the monohydrate were also investigated. It was demonstrated that a combination of experimental and theoretical methods allows performing an in-depth study of the relationships between the molecular and crystal structure and pharmaceutically relevant properties of nitrofuran antibiotics.

Phase transformation among multiple hydrates of creatine phosphate sodium in solution and in the vapor: A distinction between solution- and solvent- mediated transformation

Understanding transformation pathway and mechanism in multiple-hydrates-system is essential for controlling hydrate forms in the manufacture. In this work, the investigation of thermodynamic stability, transformation pathway and mechanism of creatine phosphate sodium (CPS) hydrates was performed in the water–methanol solvent and vapor environment with different relative humidity (RH) via in-situ Raman, ATR-FTIR, DVS, PXRD, and SEM. Results show that, a novel ternary phase diagram was presented, where seven phase regions are included but without an anhydrate form’s region. The stability of CPS·2H2O, CPS·4.5H2O, and CPS·7H2O depends on the water activity and temperature. Phase transformation can be achieved between any two CPS hydrates in solution, influenced by water content, temperature and solid loading. Meanwhile, phase transformation in the vapor environment was found to carry on via three types of mechanism, solid-state transformation, solvent-mediated transformation, and solution-mediated transformation, the concepts of which were frequently confused before. This work elaborates on the concept and reveals the mechanism of solvent- and solution-mediated transformation, as well as provides guides for controlling hydrate forms in multiple-hydrates-system.

Polymorphs and hydrates of the anticancer drug erlotinib: X-ray crystallography, phase transition and biopharmaceutical studies

The anticancer drug erlotinib revealed two polymorphs and two hydrates. The metastable polymorph and hydrates converted to the stable polymorph, which displayed solution-mediated transformation into the monohydrate at the lowest water activity.

Solution-Mediated Phase Transformation of Aripiprazole: Negating the Effect of Crystalline Forms on Dissolution and Oral Pharmacokinetics

We aimed to evaluate the effect of crystalline forms of aripiprazole, an antipsychotic drug for schizophrenia, on the dissolution rates and oral pharmacokinetics. Solubility, intrinsic dissolution rates, and tablet dissolution rates of the monohydrate (MA) and the anhydrous form (AA) were measured in various aqueous media while monitoring the phase transformation by ATR-FTIR. And their oral pharmacokinetics in dogs were compared. The intrinsic dissolution rate of MA was lower compared to AA, confirming its thermodynamic stability relative to AA in water. Phase transformations during the solubility measurement were media-dependent: In simulated gastric fluid, both AA and MA changed to HCl salt form, whereas AA and HCl salt form transformed to MA in simulated intestinal fluid. In vitro dissolution rates and dog oral pharmacokinetics of AA and MA tablets were similar. The results suggest that the solution-mediated transformation to HCl salt or MA negates the effect of different crystalline forms on dissolution rates in vivo and, consequently, on oral pharmacokinetics. We emphasize the importance of the dissolution tests employing various bio-relevant media for better prediction of in vivo performance and the selection of a solid form for development.

A readily monitored and controllable hydrothermal system for the facile, cost-effective transformation of FGD gypsum to calcium sulfate hemihydrate whiskers

The controllable transformation of flue gas desulfurization (FGD) gypsum to calcium sulfate hemihydrate (HH) whiskers under facile, readily monitored, and cost-effective hydrothermal conditions could play a vital role in the preparation of high quality HH whiskers and improve our understanding of the transformation process. This work assessed the conversion of FGD gypsum to HH whiskers in 5×10–4 mol/L H2SO4 and 1.5 wt% CuCl2 at 120 °C while determining the effects of temperature as well as H2SO4 and CuCl2 concentrations on transformation kinetics. The preparation of HH whiskers was found to involve a solution-mediated transformation from the dihydrate (DH) to the α-HH. This transition was determined to proceed via a dissolution crystallization mechanism, the rate of which was controlled by nucleation and growth of the HH whiskers. An autocatalytic kinetic model was established based on variations in the HH whiskers mole fraction over time, and this model accurately fit the experimental data with R2 = 0.990. Increasing the temperature or H2SO4 concentration accelerated the transformation by modifying the super-saturation and water activity in the reaction solution, while increasing the CuCl2 concentration had the opposite effect. The hydrothermal conditions had an important effect on the transformation from FGD gypsum to HH whiskers.

Exploring the Complexity of Processing-Induced Dehydration during Hot Melt Extrusion Using In-Line Raman Spectroscopy

The specific aim in this study was to understand the effect of critical process parameters on the solid form composition of model drug compounds during hot melt extrusion using in-line Raman spectroscopy combined with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) modeling for semi-quantitative kinetic profiling. It was observed that the hydrate and anhydrate solid forms of two model drugs in the melts of nitrofurantoin (NF):polyethylene oxide (PEO) and piroxicam (PRX):PEO could be resolved from a MCR-ALS model without an external calibration dataset. Based on this model, the influence of two critical process parameters (shear and temperature) on the solid form composition could be evaluated in a real-time mode and the kinetics of complex transformation pathways could be explored. Additionally, the dehydration pathways of NF monohydrate and PRX monohydrate in molten PEO could be derived. It can be concluded that dehydration of both hydrates in PEO occurs via competing mechanisms—a solution-mediated transformation pathway and a solid–solid transformation, and that the balance between these mechanisms is determined by the combined effect of both temperature and shear. Another important observation was that the water released from these hydrate compounds has a detectable effect on the rheological characteristics of this mixture.

Identification of novel adefovir dipivoxil-saccharin cocrystal polymorphs and their thermodynamic polymorphic transformations

In this paper, two novel polymorphs of adefovir dipivoxil-saccharin (AD-SAC) cocrystals, forms II and III, were prepared and characterized by PXRD, DSC, FT-IR and SEM. Polymorphic transformations of these two forms and the known form (form I) were also investigated. In comparison to form I, forms II and III of AD-SAC cocrystals showed different thermal behaviors on DSC, characteristic diffraction peaks on PXRD and absorption spectra on FT-IR. In addition, form I exhibited an irregular plate-like shape, while forms II and III showed as needle-like shape and stubby columnar shape, respectively. During the heating process on DSC, forms I and II underwent solid-solid transformations to form III with endothermic transition peaks, suggesting that forms I and II were enantiotropically related to form III. Furthermore, slurry conversion experiments in ethanol showed forms II and III would quickly convert to form I by solution-mediated transformation, indicating that form I was the most stable form among three forms of AD-SAC cocrystal from 15 to 50 °C.

Kinetics of the Aqueous-Ethanol Solution Mediated Transformation between the Beta and Alpha Polymorphs of p-Aminobenzoic Acid

A quantitative kinetics analysis of the solution-mediated phase transformations in aqueous-ethanol between the enantiotropically related alpha and beta polymorphs of p-aminobenzoic acid (PABA) is presented. A new temperature-controlled transmission flow-cell design for use with a laboratory X-ray source which can be utilized for diffraction or scattering experiments is described. This transmission cell in combination with in situ slurry X-ray diffraction is utilized to provide a quantitative analysis of the percentage by mass of respective solid phases in flowing suspensions, coupled with solution concentration as measured with UV–vis spectroscopy. The separate phases are identified through individual fingerprint peaks, the (1 0 3) reflection at 2θ = 15.6° relating to the alpha phase and the (0 2 2) reflection at 2θ = 25.3° for the beta phase. Examination of the conversion of a slurry of beta PABA in a 70:30 water/ethanol solvent mixture to the alpha polymorph, at a temperature range of 24–30 °C reveals t...

Inhibition of the solid state transformation of carbamazepine in aqueous solution: impact of polymeric properties

The effects of polymers on the anhydrate-to-hydrate transformation of carbamazepine (CBZ) was investigated. The three types of polymers studied were polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and substituted celluloses which included hydroxypropyl methylcellulose (HPMC) and methylcellulose (MC). Anhydrous CBZ was added to dilute aqueous polymer solutions and Raman spectroscopy measurements were collected to monitor the kinetics of the solution-mediated transformation to CBZ dihydrate. Polymers exhibiting the greatest inhibition were able to reduce the growth phase of the solution-mediated transformation and change the habit of the hydrate crystal indicating polymer adsorption to the hydrate crystal surface as the mechanism of inhibition. The results of the various polymers showed that short chain substituted celluloses (HPMC and MC) inhibited the CBZ transformation to a much greater extent than longer chains. The same trend was observed for PVP and PVA, but to a lesser extent. These chain length effects were attributed to changes in polymer confirmation when adsorbed on the crystal surface. Additionally, decreasing the percentage of hydroxyl groups on the PVA polymer backbone reduced the ability of the polymer to inhibit the transformation and changing the degree of substitutions of methyl and hydroxypropyl groups on the cellulosic polymer backbone had no effect on the transformation.

Solution-Mediated Polymorphic Transformation: From Amorphous to Crystals of Disodium Guanosine 5′-Monophosphate in Ethanol

Solvent-mediated transformation of disodium guanosine 5′-monophosphate (5′-GMPNa2) from amorphous to hydrated crystal phases was studied. The SMT process is dominated by the dissolution of the amorphous form and nucleation and growth of the crystal polymorph. The kinetic estimation based on population balance equation was carried out according to experimental data, including polymorphic fraction in the solid phase, solute concentration, and crystal size distribution. Furthermore, independent seeded batch experiments were carried out to estimate the kinetic parameters. The experimental data showed that the nucleation and growth of the crystal polymorph occurred shortly after the dissolution of the amorphous form. The estimated growth, nucleation, and dissolution rates indicated that the solution-mediated transformation was governed by the nucleation and growth of crystal polymorph. We believe that the results hold great importance toward understanding the transformation process of 5′-GMPNa2, which provides...

Dehydration of Nitrofurantoin Monohydrate during Melt Extrusion

Hot melt extrusion is important for the development of advanced pharmaceutical dosage forms. In this study, the dehydration of nitrofurantoin monohydrate during melt extrusion below the expected dehydration temperature has been investigated. The influence of process time, temperature, and drug/polymer ratio on the solid form of the drug compound was studied using drug/polymer physical mixtures with thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction, rheometry, and hot-stage microscopy and compared with data generated from the extruded products. Extensive dehydration of nitrofurantoin monohydrate was surprisingly observed at extrusion temperatures as low as 70 °C in contrast with TGA and DSC analysis of the pure drug indicating dehydration onset at around 90 °C. This was related to shear induced solution-mediated transformation, where nitrofurantoin dissolved into the molten polymer and rapidly recrystallized as nitrofurantoin anhydrate, as well as simultane...

Thermodynamic Investigation of Carbamazepine-Saccharin Co-Crystal Polymorphs

Polymorphism in active pharmaceutical ingredients can be regarded as critical for the potential that crystal form can have on the quality, efficacy, and safety of the final drug product. The current contribution aims to characterize thermodynamic interrelationship of a dimorphic co-crystal, FI and FII, involving carbamazepine (CBZ) and saccharin (SAC) molecules. Supramolecular synthesis of CBZ-SAC FI and FII has been performed using thermokinetic methods and systematically characterized by differential scanning calorimetry, powder X-ray diffraction, solubility, and slurry measurements. According to the heat of fusion rule by Burger and Ramberger, FI (ΔHfus = 121.1 J/g; melting point, 172.5°C) and FII (ΔHfus = 110.3 J/g; melting point, 164.7°C) are monotropically related. The solubility and van't Hoff plot results suggest FI stable and FII metastable forms. This study reveals that CBZ-SAC co-crystal phases, FI or FII, could be stable to heat-induced stresses; however, FII converts to FI during solution-mediated transformation.

The improved dissolution performance of a post processing treated spray-dried crystalline solid dispersion of poorly soluble drugs

Context: Solution-mediated transformation has been cited as one of the main problems that deteriorate dissolution performances of solid dispersion (SD). This is mainly attributed by the recrystallization tendency of poorly soluble drug. Eventually, it will lead to extensive agglomeration which is a key process in reducing the dissolution performance of SD and offsets the true benefit of SD system. Here, a post-processing treatment is suggested in order to reduce the recrystallization tendency and hence bring forth the dissolution advantage of SD system.Objectives: The current study investigates the effect of a post processing treatment on dissolution performance of SD in comparison to their performances upon production.Methods: Two poorly soluble drugs were spray dried into SD using polyvinyl alcohol (PVA) as hydrophilic carrier. The obtained samples were post processing treated by exposure to high humidity, i.e. 75% RH at room temperature. The physical properties and release rate of the SD system were characterized upon production and after the post-processing treatment.Results and discussion: XRPD, Infrared and DSC results showed partial crystallinity of the fresh SD systems. Crystallinity of these products was further increased after the post-processing treatment at 75% RH. This may be attributed to the high moisture absorption of the SD system that promotes recrystallization process of the drug. However, dissolution efficiencies of the post-treated systems were higher and more consistent than the fresh SD. The unexpected dissolution trend was further supported by the results intrinsic dissolution and solubility studies.Conclusions: An increase of crystallinity in a post humidity treated SD did not exert detrimental effect to their dissolution profiles. A more stabilized system with a preferable enhanced dissolution rate was obtained by exposing the SD to a post processing humidity treatment.

Pharmaceutical Salts of Biologically Active Hydrazone Compound Salinazid: Crystallographic, Solubility, and Thermodynamic Aspects

The crystal structures of salts of the active pharmaceutical ingredient (API) called salinazid with dicarboxylic acids and acesulfame were determined by single-crystal X-ray diffraction method. The crystals contain hydrogen bond motifs of different structure and complexity, the energies of which were estimated by using the quantum theory of atoms in molecules and crystals (QTAIMC) methodology. It was found that the driving force for facile the oxalate and malate salts formation is the bifurcated N+–H···O– and N+–H···O hydrogen bond synthon, while salinazid malonate is mainly stabilized via a “classic” pyridinium-carboxylate heterosynthon. The oxalate and acesulfame salts of salinazid were found to be stable during aqueous dissolution experiments, providing a substantial solubility improvement compared to pure API (33 and 18 times, respectively). However, the malonate and malate salts dissolved incongruently and rapidly underwent a solution-mediated transformation to form pure salinazid. Based on the solub...

Understanding metastable phase transformation during crystallization of RDX, HMX and CL-20: experimental and DFT studies.

Multiphase growth during crystallization severely affects deliverable output of explosive materials. Appearance and incomplete transformation of metastable phases are a major source of polymorphic impurities. This article presents a methodical and molecular level understanding of the metastable phase transformation mechanism during crystallization of cyclic nitramine explosives, viz. RDX, HMX and CL-20. Instantaneous reverse precipitation yielded metastable γ-HMX and β-CL-20 which undergo solution mediated transformation to the respective thermodynamic forms, β-HMX and ε-CL-20, following 'Ostwald's rule of stages'. However, no metastable phase, anticipated as β-RDX, was evidenced during precipitation of RDX, which rather directly yielded the thermodynamically stable α-phase. The γ→β-HMX and β→ε-CL-20 transformations took 20 and 60 minutes respectively, whereas formation of α-RDX was instantaneous. Density functional calculations were employed to identify the possible transition state conformations and to obtain activation barriers for transformations at wB97XD/6-311++G(d,p)(IEFPCM)//B3LYP/6-311G(d,p) level of theory. The computed activation barriers and lattice energies responsible for transformation of RDX, HMX and CL-20 metastable phases to thermodynamic ones conspicuously supported the experimentally observed order of phase stability. This precise result facilitated an understanding of the occurrence of a relatively more sensitive and less dense β-CL-20 phase in TNT based melt-cast explosive compositions, a persistent and critical problem unanswered in the literature. The crystalline material recovered from such compositions revealed a mixture of β- and ε-CL-20. However, similar compositions of RDX and HMX never showed any metastable phase. The relatively long stability with the highest activation barrier is believed to restrict complete β→ε-CL-20 transformation during processing. Therefore a method is suggested to overcome this issue.

Selective thorium and uranium extraction from monazite: II. Approaches to enhance the removal of radioactive contaminants

In the first paper of this series, the selective leaching of thorium and uranium from ground monazite with ammonium oxalate was found to depend, inter alia, on their solubility in the lixiviant, which depended on the solution pH, phosphate concentration and temperature. These actinides were released from the monazite matrix during the solution-mediated transformation of the rare earths to oxalates. The latter appeared to eventually passivate the monazite, limiting thorium and uranium leaching. The present article examines the effect of different pretreatments, leach additives, and sonication on the thorium and uranium extraction, and the recovery of the rare earth elements contained in the monazite. Different approaches were explored to suppress the re-precipitation of thorium as phosphate: strongly complexing ligands (citrate and EDTA) and the addition of ferric or aluminum ions that were expected to selectively precipitate phosphate from solution. However, none of these proved successful in experimental testing. Pretreatment with concentrated sodium hydroxide solutions, which removed most of the phosphate, yielded a residue that was amenable to selective leaching of thorium and uranium by oxalate and subsequent extraction of the rare earths with citrate.