Solution-mediated Phase Transition Research Articles

Solution-mediated phase transition of protein crystals

A snapshot of the evidence of solution-mediated phase transition of glucose isomerase (GI) crystals more than 7 months after the start of an experiment was successfully captured. The transition to [Formula: see text] crystals started about 2 months after the first I222 crystals nucleated. To conduct such long-term experiments, we developed novel observation cells with liquid paraffin layers to prevent aqueous GI solutions from evaporation of water. Changes in the weights of cells were measured, and much less evaporation was successfully achieved by continuously adding liquid paraffin as a liquid sealant.

Thermodynamic and Kinetic Mechanism of the Phase Transition from Aztreonam Dihydrate to Anhydrates

In this work, two anhydrates (form A and form B) and one dihydrate (form C) of aztreonam were found and were characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis, differential thermal analysis, and Fourier transform infrared spectroscopy. Dynamic vapor adsorption and variable-temperature PXRD experiments were carried out to study their thermal stability and moisture absorption stability. Furthermore, the critical water activity of aztreonam at 10–45 °C was determined, and it was found that the water activity determines the dehydration process of form C. The solubility of form A and form B in methanol solvent was measured at 10–45 °C to decide the thermodynamic stability of the polymorphs, and it was found that form B is thermodynamically stable below 28 °C, while form A is thermodynamically stable above 28 °C. The competitive suspension experiments further proved that form A and form B are enantiotropic polymorphs. In addition, the solution-mediated phase transition (SMPT) process of aztreonam form C was in situ monitored using Raman spectroscopy. The results show that the SMPT process is jointly controlled by the dissolution of the dihydrate and the nucleation of anhydrates, in which temperature plays a very important role. Finally, the SMPT mechanism of the dihydrate form is proposed.

Evidence for Solution-Mediated Phase Transitions in Kidney Stones: Phase Transition Exacerbates Kidney Stone Disease

In this study, we investigated calcium oxalate (CaOx) kidney stones and showed direct evidence of the solution-mediated phase transition of calcium oxalate dihydrate (COD; the metastable phase) to calcium oxalate monohydrate (COM; the stable phase). We examined the crystal phases, crystal textures, and protein distributions within thin sections of calcium oxalate kidney stones. Observation with a polarized-light microscope showed that the outline of the mosaic texture, in which COM crystals are assembled in a mosaic pattern, roughly coincides with COD’s crystallographically stable face angles. Microfocus X-ray CT measurement captured the intermediate process of the phase transition, starting inside the COD single crystal and gradually transforming to COM crystals. In addition, the distribution of osteopontin and prothrombin fragment-1, common proteins contained in urine and visualized by multicolor fluorescence immunostaining, showed no apparent striations inside the COM single crystals with the mosaic texture, although the striation is apparent inside the COD single crystals. This is probably because the phase transition of mosaic-like COM occurred in a semiclosed system inside the COD single crystal, so the effect of periodic (day–night, seasonal, etc.) urinary protein concentration changes was small. On the other hand, striations were visible in concentrically laminated COM. This indicated that concentrically laminated COM formed in response to the changes in urinary protein concentrations. From the above, we conclude that the COD single crystals and the concentrically laminated COM seen in CaOx stones are primary structures, and the mosaic COM is a secondary structure that is a pseudomorph formed by the solution-mediated phase transition from COD single crystals.

Solution-mediated phase transition of pharmaceutical compounds: Case studies of acetaminophen and aspirin

Polymorphism is crucial in organic solid-state chemistry because different polymorphs exhibit different physical properties. Thus, the control of crystal polymorphism is a long-standing issue. We have been engaged in crystal polymorph control research, mainly targeting pharmaceutical compounds. Three processes to control the polymorphism must be considered: nucleation, crystal growth, and phase transition. Finding a metastable phase by nucleation control techniques is the first step. The next crucial step is controlling phase transition and keeping the metastable phase as long as possible. Understanding the phase transition from metastable to stable phase is essential, especially to realize the high stability metastable phase. Herein we will show the phase transition processes of acetaminophen and aspirin as model materials.

Growth of Acetaminophen Polymorphic Crystals and Solution-Mediated Phase Transition from Trihydrate to Form II in Agarose Gel

The growth of acetaminophen polymorphic crystals and the solution-mediated phase transition from trihydrate to form II in agarose gel were investigated. The form II crystals grown in gels, presumably because of the agarose content, dissolved less rapidly at high temperatures and were more stable than in water. The trihydrate crystals in the gel were also expected to be stabilized by containing agarose, but in fact the fine morphology resulted in reduced stability. The solution-mediated phase transition from trihydrate to form II via form II seeding took longer in the gel because the gel slowed down the dissolution of the trihydrate by hindering the dispersion of the form II seeds and delayed the growth of form II by reducing the diffusion rate of the molecules dissolved from the trihydrate. Delays in solution-mediated phase transition and changes in stability for crystals grown in gels indicate the effectiveness of gels in controlling polymorphisms in pharmaceutical compounds.

Process Analytical Technology (PAT) Aided Identification of Operational Spaces Leading to Tailored Crystal Size Distributions in Azithromycin Crystallization via Coordinated Cooling and Solution Mediated Phase Transition

Online imaging and ATR-FTIR were applied to azithromycin crystallization in a mixture of acetone and water to identify the operational spaces that consistently led to tailored crystal size distribu...

Change in Luminescence Induced by Solution-Mediated Phase-Transition of Cyclometalated Platinum(II) Complex with Isoquinoline Carboxylate.

Changes in luminescence due to solution-mediated phase transition (SMPT) and crystal-to-crystal phase transitions of a novel cyclometalated platinum(II) complex with isoquinoline-1-carboxylate (Iq-1-COO-) [Pt(bzq)(Iq-1-COO)] (bzq-: benzoquinolinate) were studied experimentally and theoretically. Recrystallization of the complex allowed three crystal forms depending on the solvent: red polymorph RDMF (λemi = 689 nm), yellow polymorph YDMSO (λemi = 641 nm), and red pseudopolymorph RBCHCl3 (λemi = 721 nm). Crystals of RDMF in the DMF solution at room temperature showed SMPT to yellow crystals YDMF (λemi = 627 nm), in which RDMF first dissolved partly into the solution, and then the dissolved complex crystallized as YDMF. RBCHCl3 exhibited crystal-to-crystal phase transitions to RDMF and YDMF by being heated to 150 °C and stored in atmospheric conditions, respectively. Molecular structures of each of the four crystal forms, analyzed by X-ray crystallography, showed different planarities because of the dihedral angles between the bzq- and Iq planes being 3.15, 4.80, 8.35, and 17.7° for RBCHCl3, RDMF, YDMSO, and YDMF, respectively. The planar complexes in RDMF and RBCHCl3 constructed dimers through intermolecular Pt-Pt and π-π interactions, whereas the distorted complexes in YDMF and YDMSO remained as monomers. Density functional theory (DFT) calculations, which reveal the relation between the molecular structure and thermodynamic stability, suggest that the SMPT is triggered by thermodynamic transformation from the metastable planar structure to the stable distorted structure. The intradimer interactions in RDMF and RBCHCl3 induced red-shifts in the absorption and emission colors from those of YDMF and YDMSO; thus, the photophysical properties of RBCHCl3 and RDMF originate from the MMLIqCT state in contrast with the MLIqCT/LbzqLIqCT character for YDMF and YDMSO. DFT and time-dependent DFT (TD-DFT) calculations in the ground and excited states provide insight into the structural, electronic, and optical properties.

Emergence and Amplification of Chirality via Achiral–Chiral Polymorphic Transformation in Sodium Chlorate Solution Growth

Chiral symmetry breaking during the chiral crystallization from a sodium chlorate (NaClO3) aqueous solution is an intriguing phenomenon because it provides insights into the prebiotic process of biohomochirality. However, a mechanism of the emergence and amplification of chirality remains controversial, especially for crystallization from highly supersaturated solution, and one of the hypotheses proposed before is a transition toward the homochiral state during the early stages of crystallization. In this contribution, we directly examined the early stage of crystallization by in situ polarized-light microscopy. The observation revealed that achiral crystals, which appear prior to the formation of chiral crystals, transform to the chiral crystal through two kinds of polymorphic transformations: (1) martensitic transformation (MT) and (2) solution-mediated phase transition (SMPT). The SMPT is remarkably facilitated by contact with a chiral crystal. Notably, the resulting enantiomorph through contact-facili...

In Situ Monitoring of Cocrystallization Processes – Complementary Use of Sensing Technologies

AbstractTwo in situ process analytical technologies were used to investigate a cocrystallization process: a focused beam reflectance measurement probe and a video probe. The cocrystallizations were conducted batch‐wise in a stirred thermostatted vessel with carbamazepine and nicotinamide. The experiments were started in three domains of the phase solubility diagram. When carbamazepine crystals were also formed, a solution mediated phase transition from carbamazepine crystals towards cocrystals was initiated by the addition of the cocrystallizing agent (nicotinamide crystals). As the carbamazepine crystals and the carbamazepine/nicotinamide cocrystals exhibit prism‐like and needle‐like habits, respectively, it was possible to discriminate between them with the two sensors. The mechanisms involved in the solution mediated phase transition were investigated.

Cocrystal formation in solution: Inducing phase transition by manipulating the amount of cocrystallizing agent

The purpose of this work was to assess the possibility of inducing solution mediated phase transition (SMPT) by manipulating the amount of the cocrystallizing agent. The cocrystal, composed of an active pharmaceutical ingredient (carbamazepine, CBZ) and its cocrystallizing agent (a vitamin—nicotinamide, NCT), was selected as a model compound. Batch experiments were performed in a stirred vessel. The solute concentrations of both CBZ and NCT were monitored using in situ ATR-FTIR spectroscopy. The introduction of NCT in dry form allowed a shift in the phase diagram, leading to an SMPT from CBZ crystals toward cocrystals. The concentration profiles gave information on the phase transition kinetics, i.e., the kinetics of nucleation, growth and dissolution mechanisms of the solid phases involved. Several situations were analyzed. This procedure could also be used to correct a process deviation that led to CBZ crystals instead of cocrystals.

Polymorphism in Processes of Crystallization in Solution: A Practical Review

Here we review the polymorphism of organic molecules, obtained through batch crystallization in solution carried out in a stirred vessel. Preferential formation of a polymorph, crystal habit, and size depend strongly on the kinetics of the mechanisms involved. First, we recall the concepts of crystallization from solution. Second, phase transitions are introduced, discussed, and illustrated. Third, we focus on the development of batch-crystallization processes to obtain a given polymorph. Prerequisites are recalled, and experimental techniques used for the screening of polymorphs are presented. Recent developments in the determination of the kinetics of solution-mediated phase transition are reviewed, and the advantages and drawbacks of using process analytical technologies to monitor such transitions are discussed. Lastly, we present control strategies.

Rapid crystal growth without inherent supersaturation induced by nanoscale fluid flows?

AbstractCrystal growth is a process that only takes place under non‐equilibrium conditions and a necessary prerequisite is that the crystal is exposed to a phase that is supersaturated in the material the crystal is composed of, be it a solution, a vapour or a supercooled melt. In industrial mass crystallization the growth rate for a population of crystals (in suspension growth processes [1]) rarely exceeds mean linear velocities of 10‐7 ms‐1. Here we present a mass crystallization process which is accompanied by rapid crystal growth several orders of magnitude faster and into a region of solution that is without inherent supersaturation. The material investigated is a solid hydrate that exhibits a solution mediated phase transition to its anhydrous form in the presence of methanol [2]. The phase transition is initiated simply by placing an amount of hydrate crystals into the solvent and is characterized by the rapid emergence of needle‐shaped crystals. The needles emanate from the crystal faces of the hydrate crystals and grow into the solution, which is nominally free of the substance to be crystallized. The high growth rate of the crystals, which of the order of up to 10‐4 ms‐1 is surprising. Although rapid needle growth has been observed before [3‐9], to date a satisfactory explanation for needles growing under the abovementioned conditions is still outstanding. Based upon the topology of the crystals we propose a tentative mechanism for this phenomenon capable of explaining the unusually rapid growth and highlight those questions that need addressing in order to verify this mechanism. X‐ray powder diffraction is used to characterize the crystal phase of the needles; confocal fluorescence microscopy reveals that the needles are hollow. The width of these needles is between 0.5 and 5 μm, their length appears to be limited only by the amount of hydrate available for their formation. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)

Understanding the Polymorphic Behavior of Sibenadet Hydrochloride through Detailed Studies Integrating Structural and Dynamical Assessment

Three polymorphs of sibenadet hydrochloride (AR-C68397AA, Viozan) have been shown to exist at ambient temperature and have been characterized. Each undergoes a solid-state transition to a common high temperature form, which melts at approximately 220 degrees C. X-ray powder diffraction (XRPD) indicates that Polymorphs I and II share a similar layered structure not exhibited by Polymorph III. All three ambient temperature polymorphs show evidence of varying degrees of dynamic disorder of the terminal phenyl group as shown by solid-state NMR spectroscopy. Furthermore, the carbons alpha to the ether link also undergo different rates of mobility in Polymorphs I and II. This variation in the extent of dynamic disorder results in an alteration in the short-range structure resulting in distinct polymorphs. Polymorph I is the thermodynamically stable form at room temperature as indicated by solution calorimetry and assessment by thermodynamically driven solution mediated phase transition studies. The present study aims to address the types of discriminatory data required to make a clear distinction between physical forms and define, unequivocally, the presence of polymorphism.

Fabrication of unusually stable amorphous calcium carbonate in an ethanol medium

We report a novel approach to preparing amorphous calcium carbonate (ACC) using ethanolic CaCl2 and ammonium carbonate as the sources of calcium and carbon dioxide, respectively. Other additives or any elaborating pH control are not necessary to form the precursor of ACC, viz., calcium carbonate precipitate (CCP). Ammonia maintains the reaction medium in a neutral or weakly basic condition, and it also retards the crystallization of ACC. On the other hand, ethanol itself inhibits the dissolution of ACC so that the solution mediated phase transition of ACC to vaterite or calcite can barely take place. The freshly prepared CCP contains substantial amount of ammonia and carbon dioxide, and a gentle heating (∼100°C) of the CCP results in ACC, which can further be converted to calcite simply by heating or exposing it to a humid atmosphere. It is thus expected that calcium carbonate crystals of defined morphology are produced by transforming those ACC precursors within a constrained volume.

Polytypic Transition of n-Hexatriacontane during Solution Crystallization

The crystallization process of n-hexatriacontane (n-C36H74) was investigated by means of micro-FTIR spectroscopy. From the results of in-situ oblique IR transmission measurements, it was confirmed that single crystals of the M011 modification exhibited a polytypic transformation during solution growth. At the initial stage of the crystallization, single crystals appeared as the single-layered polytype (Mon). The overgrowth of the double-layered polytype (Orth II) took place subsequently on the (001) face of the single crystal. After that, the single crystal gradually transformed into a single crystal of the Orth II type through a solution-mediated phase transition. It was suggested that the transformation from Mon to Orth II was caused by a drop in the supersaturation of the solution.

Dissolution and phase transition of pharmaceutical compounds

This paper presents a laboratory study of a solution-mediated phase transition of irbesartan form A into form B. The following stages are observed and studied: dissolution of form A until the apparent saturation is reached, form A dissolution which strictly compensates for the form B nucleation and growth, form A is completely dissolved and crystallization of form B is only observed until the concentration reaches the solubility of form B. In the first stages of the transformation, the dissolution of form A, we evidenced two distinct behaviors in function of undersaturation: (1) at higher undersaturation, dissolution is controlled by mass transfer and (2) at lower undersaturation, dissolution is controlled by surface process. The influence of the temperature is also shown. In the last part of this work we showed that from the knowledge of the crystal structure and experimental morphology additives can be selected. A surfactant, dodecyl amine chloride, has an accelerating effect on the dissolution of form A and hinder the growth of form B. Adipic acid slows down the dissolution rate of form A, but has no effect on the growth rate of form B.

Polytypic transformation during crystal growth monitored by newly developed micro-FTIR system for three-dimensional structural studies

To obtain three-dimensional structural information about growing single crystals, a FTIR microscope for the oblique transmission method was developed. A newly designed optical system enabled oblique irradiation from any direction of incidence with high efficiency. This system was employed for the study on the crystallization process of n-C 36H 74. The in-situ IR measurement carried out on a growing single crystal showed that a polytypic transformation took place during the solution crystallization of the M 011 modification. At the inception of crystallization, single crystals were of the single-layered polytype. The double-layered polytype was generated immediately through a heterogeneous nucleation on the single crystals, and then grew through the solution-mediated phase transition from the single-layered to the double-layered polytype. At the end, single crystals changed completely to the double-layered polytype.

Crystallization and dissolution of pharmaceutical compounds: An experimental approach

In pharmaceutical industry growth and dissolution are important stages for different reasons. In industrial processes crystallization is an important operation which controls the physical properties of the material such as the crystal habit, crystal size distribution and polymorphism. For economic and technical reasons before patenting a drug it is important to search all the possible polymorphs. In the case of organic drugs which are slightly soluble in gastrointestinal fluids, the dissolution rate of the solid dosage form is an important factor determining the rate of absorption. The kinetics of solubilization will depend mainly on the crystal habit, crystal size distribution and on the polymorphs. This paper presents a laboratory study of the dissolution of crystals of an organic drug in a crystallizer equipped with an in situ conductivity probe and an UV analyzer on-line. The rate of dissolution and evolution of the crystal size distribution are measured. A solution mediated phase transition of the drug is observed. The final objective is to model the dissolution process from kinetic data and determine the influence on the dissolution of under-saturation, temperature, crystal habit and crystal size distribution.