Succinic Acid Crystals Research Articles

Calorimetric and Diffractometric Evidence for the Sequential Crystallization of Buffer Components and the Consequential pH Swing in Frozen Solutions

Sequential crystallization of succinate buffer components in the frozen solution has been studied by differential scanning calorimetry and X-ray diffractometry (both laboratory and synchrotron sources). The consequential pH shifts were monitored using a low-temperature electrode. When a solution buffered to pH < pK(a)(2) was cooled from room temperature (RT), the freeze-concentrate pH first increased and then decreased. This was attributed to the sequential crystallization of succinic acid, monosodium succinate, and finally disodium succinate. When buffered to pH > pK(a)(2), the freeze-concentrate pH first decreased and then increased due to the sequential crystallization of the basic (disodium succinate) followed by the acidic (monosodium succinate and succinic acid) buffer components. XRD provided direct evidence of the crystallization events in the frozen buffer solutions, including the formation of disodium succinate hexahydrate [Na(2)(CH(2)COO)(2).6H(2)O]. When the frozen solution was warmed in a differential scanning calorimeter, multiple endotherms attributable to the melting of buffer components and ice were observed. When the frozen solutions were dried under reduced pressure, ice sublimation was followed by dehydration of the crystalline hexahydrate to a poorly crystalline anhydrate. However, crystalline succinic acid and monosodium succinate were retained in the final lyophiles. The pH and the buffer salt concentration of the prelyo solution influenced the crystalline salt content in the final lyophile. The direction and magnitude of the pH shift in the frozen solution depended on both the initial pH and the buffer concentration. In light of the pH-sensitive nature of a significant fraction of pharmaceuticals (especially proteins), extreme care is needed in both the buffer selection and its concentration.

One step recovery of succinic acid from fermentation broths by crystallization

Succinic acid is a valuable four-carbon platform chemical with wide applications in many fields. One step recovery of the desired product succinic acid crystal from the fermentation broths was studied for the first time. In a fed batch fermentation by Actinobacillus succinogenes BE-1, the final concentrations of succinic acid, formic acid, lactic acid and acetic acid in the bioreactor reached 97.8 g/L, 23.5 g/L, 5.1 g/L and 17.4 g/L, respectively. These organic acids have different proportions of dissociated and undissociated forms at different pH values, and the solubility of these forms of acid is different substantially. When the pH value of the fermentation broth was controlled less than 2.0, crystallization of succinic acid could be carried out at 4 °C easily, while major acid by-products such as lactic acid, acetic acid and formic acids were miscible in solution. By this one step recovery method, succinic acid yield was 70%, and the purity was 90%. In comparison, for traditional calcium precipitation coupled ion-exchange adsorption, the yield and purity were 52% and 92%, respectively. Crystallization could be regarded as not only the final purification step but also the first recovery step for the downstream separation process. In this study, succinic acid can be feasibly purified from fermentation broths selectively, which could be integrated with other separation method to optimize the downstream process.

Novel resin-based vacuum distillation-crystallisation method for recovery of succinic acid crystals from fermentation broths

In this paper, a novel resin-based crystallisation method was developed for the recovery of succinic acid (SA) crystals from fermentation broths (FB) using Actinobacillus succinogenes. Direct crystallisation of synthetic fermentation broths was firstly investigated and the results indicated that the synthetic fermentation broth consisting of a mixture of organic acids (in the free acid form rather than in the salt form) could significantly benefit in succinic acid recovery. Therefore, a commercially available cation-exchange resin Amberlite IR 120H was employed to convert the fermentation end-products such as succinate, formate, acetate and pyruvate from the salt form into the free acid form. Then, succinic acid was selectively separated from the acid mixture by vacuum evaporation and crystallisation. Highly purified SA crystals were successfully recovered from both synthetic and real fermentation broths using this method. A higher SA crystal purity (99%) and yield (89.5%) were obtained in the direct crystallisation method using an ion-exchange resin as compared to the direct acid addition method (46% and 35%, respectively). The work presented here sets the stage for the development of an efficient resin-based vacuum-distillation and crystallisation system for the recovery of succinic acid crystals from fermentation broths.

“pH Swing” in Frozen Solutions—Consequence of Sequential Crystallization of Buffer Components

Succinate buffer solutions of different initial pH values and concentrations were cooled. The solution pH and the phases crystallizing from solution were monitored as a function of temperature. In a solution buffered to pH 4.0 (200 mM), the freeze-concentrate pH initially increased to 8.0 and then decreased to 2.2. On the basis of X-ray diffractometry (synchrotron source), the “pH swing” was attributed to the sequential crystallization of succinic acid, monosodium succinate, and disodium succinate. A similar swing, but in the opposite direction, was seen when a solution with an initial pH of 6.0 was cooled. In this case, crystallization of the basic buffer component occurred first. The direction and magnitude of the pH shift depended on both the initial pH and the buffer concentration. In light of the pH-sensitive nature of a significant fraction of pharmaceuticals (especially proteins), extreme care is needed, both in the buffer selection and in its concentration.

Chemical transformations of succinic acid recovered from fermentation broths by a novel direct vacuum distillation-crystallisation method

A novel alternative methodology (direct crystallisation) to the traditional calcium precipitation to obtain succinic acid (SA) from defined and wheat-based fermentation broths is reported. SA crystals were successfully recovered from fermentation broths (FB) using this method. A higher SA crystal purity (95%) and yield (70%) were obtained in the direct crystallisation method compared to a slightly modified traditional calcium precipitation method (90% and 24%, respectively). Chemical transformations (e.g. esterifications) to high-added value derivatives of both recovered SA crystals were then investigated using a range of solid acids including our acidic tunable mesoporous carbonaceous materials denoted as Starbon® acids. Results showed that SA crystals could be successfully converted into mono- and diesters in high yields and selectivities employing solid acids regardless of the reaction conditions. The order of reactivity was found to be: pure SA crystals > SA crystals from defined FB > FB SA crystals. Results demonstrate that SA can be effectively purified from actual fermentation broths, showing the importance of integrating the fermentation and downstream processing to optimise the fermentative production of SA and its chemical transformations to produce high-added value derivatives.

Optical and dielectric studies on succinic acid single crystals

AbstractSingle crystals of ferroelectric succinic acid (SA) with very high degree of transparency were grown from aqueous solution by slow evaporation technique. Single crystal X‐ray diffraction analysis reveals that the crystal belongs to monoclinic system with the space group P21/c. Some physical parameters have been determined for grown crystal. The optical absorption study reveals the transparency of the crystal in the entire visible region and the cut off wave length was found to be 240 nm. The optical band gap is found to be 3.75 eV. The dependence of extinction coefficient (k) and refractive index (n) on the wavelength have also been reported. The presence of functional groups was determined qualitatively by using Fourier transform infrared spectrum (FTIR) from which force constant has been calculated. The dielectric constant was also studied as a function of frequency at room temperature and electrical conductivity has been calculated from the Cole‐Cole plot. (© 2008 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

The Evolution of Crystal Shape During Dissolution: Predictions and Experiments

A comparison between a priori model predictions and experimental results for crystal shapes of succinic acid crystals dissolving in aqueous solution is presented. The model is the simplest possible model which neglects all effects other than a determination of which faces to include on the crystal habit and their perpendicular growth rates. The experiments are carried out in a thermostatted peltier cell and are imaged in situ using a microscope with digital imaging capabilities. The predicted and experimentally measured crystal shapes are very similar throughout the dissolution process. Thus, the experiments provide support for the model’s predictive power.

Growth and characterization of succinic acid single crystals

AbstractSingle crystals of ferroelectric succinic acid were grown from aqueous solution by low temperature solution growth technique. The cell parameters and space group are found using powder X‐ray diffraction analysis. The presence of the functional groups has been estimated qualitatively by FTIR analysis. The UV‐Visible spectrum shows the cut‐off wavelength at 240 nm. The thermal stability of the crystal was studied by TG/DTA. The dielectric constant of the crystal studied as a function of frequency shows the pyroelectric property. (© 2007 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

Simultaneous prediction of crystal shape and size for solution crystallization

AbstractCrystals experience changes in both size and shape during growth. A method is developed for the simultaneous prediction of crystal shape evolution and size distribution for solution crystallization processes by combining shape evolution modeling and population balance modeling techniques. When surface integration is the rate‐controlling step and each face grows by the same mechanism (for example, the screw dislocation mechanism), the relative growth rates of crystal faces are constant, and the crystal volume can be represented by a piecewise smooth function of the crystal size. The process can then be described by a simple 1‐dimensional (1‐D) population balance model linked with the shape evolution model. The current method is applicable to tablet‐shaped crystals with a dominant face of arbitrary initial size and shape. Such crystals can be treated as two‐dimensional (2‐D). A case study of succinic acid crystals grown from water illustrates the applicability and simplicity of the proposed method. © 2004 American Institute of Chemical Engineers AIChE J, 50: 2101–2112, 2004

ATR-FTIR for Determining Optimal Cooling Curves for Batch Crystallization of Succinic Acid

The temperature profile applied during batch cooling crystallization affects the supersaturation level, which in turn affects the crystal size distribution. It is possible, in principle, to calculate the optimal cooling profile; however, the nucleation and growth kinetics are rarely known to the degree of accuracy necessary for this calculation. The current study demonstrates an alternative approach to determination of the optimal cooling profile without any prior knowledge of kinetic data or subsequent modeling. An attenuated total reflectance−Fourier transform infrared (ATR-FTIR) spectrometer was used to monitor the supersaturation level during batch cooling crystallization. The ATR-FTIR was interfaced to a LABMAX automatic reactor system that was used in a feedback mode to control the cooling rate so that the supersaturation level remained close to the solubility throughout the cooling process. The resulting temperature profile corresponds to the optimal operating conditions for the maximum in the mean crystal size.

Liquid inclusions in crystals produced in suspension crystallization

Sodium chloride, potassium chloride, succinic acid and potassium hydrogen phthalate crystals were crystallized batchwise in an agitation vessel and the total volume of liquid inclusions per crystal, V (μm 3), was measured as a function of crystal size, d (μm). The found data of the total volume, including literature data from a continuous crystallizer, was correlated with a simple equation, V=4.0×10 −6 d 4. Most of the inclusions observed in sodium chloride and potassium chloride crystals were layer inclusions, which were aligned two-dimensionally in parallel with crystal faces. This type of inclusion pattern was suggested, with the help of the results of additional in situ experiments under a microscope, to be caused by the adhesions of small crystals to growing crystals and mechanical contacts imposed to these crystals during growth. Although the layer pattern was not found in the other crystals examined, the same mechanism was considered to work for the inclusion formation.

Development of Controlled-Release SK&F 82526-J Buffer Bead Formulations with Tartaric Acid as the Buffer

ABSTRACTThe purpose of this research was to design and develop a novel controlled-release bead formulation for oral administration with buffer crystals as a carrier for loading offenoldopam mesylate, an intravenous antihypertensive agent, which provides an in vitro release rate of 30–50 mg/hr for 6–8 hr. Buffer crystals were coated in a jluid-bed granulator with a blend of gastrointestinal (GI) insoluble/ enteric Eudragit® polymers (such as RSPM/S100 polymer blend), drug was layered on these polymer-subcoated buffer beads by a slurry coating process, and the drug-layered beads were subsequently overcoated using a blend of GI insoluble/enteric polymers. The release offenoldopam and tartaric acid was monitored by a two-stage dissolution procedure using USP Apparatus 2 (paddles at 50 rpm) and HPLC methodologies. The overcoating of drug-layered tartaric acid crystals with Eudragit polymers with different permeabilities significantly affected the release offenoldopam. However, even the least permeable polymer, Eudragit RS, could not sustain the release of tartaric acid beyond 2 hr, suggesting the need to subcoat freely water-soluble tartaric acid crystals prior to drug layering. By varying the typehatios of the GI insoluble/enteric polymers for subcoat and overcoat, capsule formulations were developed, which released fenoldopam and tartaric acid at different rates. The use of Eudragit polymer blends at the optimized ratios for both subcoat and overcoat resulted in a significant retardation in the release of tartaric acid; still, the tartaric acid release was faster than that of fenoldopam, suggesting the need to use a less water-soluble fumaric or succinic acid crystals as the buffer. However, the technology described using tartaric acid crystals as the buffer will be highly useful for weakly basic drug substances with less stringent pH-dependent solubility profiles.

Macromolecular solvation energies derived from small molecule crystal morphology.

The morphology of small molecule crystals provides a model for evaluating surface solvation energies in a system with similar packing density to that observed for amino acid residues in proteins. The solvation energies associated with the transfer of methylene and carboxyl groups between vacuum and aqueous phases are estimated to be approx. $40 and -260 cal/A2, respectively, from an analysis of the morphology of succinic acid crystals. These solvation energies predict values for contact angles in reasonable agreement with measurements determined from macroscopic monolayer surfaces. Transfer free energies between vapor and water phases for a series of carboxylic acids are also predicted reasonably well by these solvation energies, provided the surface exposure of different groups is quantitated with the molecular surface area rather than the more traditional accessible surface area. In general, molecular surfaces and molecular surface areas are seen to have important advantages for characterizing the structure and energetics of macromolecular surfaces. Crystal faces of succinic acid with the lowest surface energies in aqueous solution are characteristically smooth. Increasing surface roughness and apolarity are associated with higher surface energies, which suggests an approach for modifying the surface properties of proteins and other macromolecules.

The morphology of succinic acid crystals: The role of solvent interaction

Succinic acid crystals grown from aqueous solutions are platy with a (100) basal plane and side faces (111) and (011), while crystals grown from iso-propanol are needle-like with (100) and (010) planes. These habits are not predicted from PBC analyses. In this study, the role of solvent interaction is related to habit controlling factors in the screw dislocation mechanism. The solvent interaction with various faces of succinic acid crystals was determined with the aid of molecular mechanics calculations. The observed habits from water and from iso-propanol could be explained satisfactorily in a semi-quantitative way.

Growth and dissolution of succinic acid crystals in a batch stirred crystallizer

AbstractGrowth and dissolution of succinic acid crystals have been studied in an isothermal stirred tank crystallizer. Seeded desupersaturation and deundersaturation experiments have been performed. Parameters of a desired growth rate equation are estimated by fitting the supersaturation balance equation directly to the supersaturation measurements. The procedure is based on nonlinear optimization techniques. Thus, uncertainties in the traditional approximation of the concentration vs. time curve are circumvented. The growth process for succinic acid crystals in an aqueous solution is found to be controlled by a significant resistance in both the volume diffusion step and in the surface integration step. An implicit equation is given to accurately represent the crystal growth rate as a function of the supersaturation. When extrapolating outside the range of experiments, this equation is shown to predict growth rates that are significantly different from those predicted by a corresponding power law expression. The dissolution rate exhibits a nonlinear dependence on undersaturation which is interpreted as changes in the crystal shape. Initial dissolution rate coefficients are in good agreement with volume diffusion coefficients obtained from growth experiments.

Habit modification of succinic acid crystals grown from different solvents, R. J. Davey, J. W. Mullin and M. J. L. Whiting, J. Cryst. Growth, 58, 304-312, (1981) : モルフォロジー

Habit modification of succinic acid crystals grown from different solvents, R. J. Davey, J. W. Mullin and M. J. L. Whiting, J. Cryst. Growth, 58, 304-312, (1981) : モルフォロジー

Habit modification of succinic acid crystals grown from different solvents

Succinic acid crystals grown from aqueous solution are plate-like with a dominant (001) basal plane. Growth from isopropanol solution modifies this habit to give needle-like crystals. A periodic bond chain analysis of the succinic acid structure does not predict the observed habit, thus highlighting the important role played by the solvent. Consideration of the relevant solution chemistry and measurement of crystal growth kinetics in the two solvents allows an explanation of the observed morphological change in terms of solute - solvent interactions.

Polymorphic transition in succinic acid crystals

Polymorphic transition in succinic acid crystals

Heterogeneous nucleation of bubbles at solid surfaces in gas-supersaturated aqueous solutions

CH 4, Ar, and N 2 supersaturation thresholds for cavitation in saturated aqueous solutions of succinic acid, potassium nitrate, and potassium chloride were determined at room temperature in the presence and absence of crystalline precipitates. To avoid the introduction and interference of preformed gaseous nuclei, crystals were formed in situ by cooling prior to decompression, after the solutions had been equilibrated with gas at elevated pressure and temperature. In the succinic acid and potassium nitrate systems, bubbles first occurred during decompressions in exclusive association with crystals. At ambient pressure, such cavitation occurred with supersaturations below 10 atm, while cavitation without crystals required supersaturations over 100 atm. In contrast, cavitation with potassium chloride crystals required supersaturations exceeding 100 atm. It is concluded that thresholds with succinic acid and potassium chloride crystals accurately reflected particular properties of the crystal-liquid interfaces, while the low thresholds observed with potassium nitrate crystals may also have reflected certain effects of the preceding crystallization processes per se. Results may be of particular biological significance because thresholds with succinic acid crystals at atmospheric pressure were within 5 atm of the supersaturations which elicit bubble-induced trauma in animals and man.

ESR study of 13C hyperfine splittings for the single line radical produced in γ-irradiated single crystals of succinic acid

ESR studies of γ-irradiated single crystals of succinic acid-d6 have enabled evaluation of 13C hyperfine splittings for the single line radical species. The data confirm the structure as HOOCCH2CH2C=O. Isotropic 13C hyperfine splittings of 131.8 and 47.7 G have been obtained for the carbonyl carbon and the adjacent methylene carbon. Spin density calculations show that the majority of the unpaired electron density is localized in the σ orbital arising from the rupture of a C–OH bond in the undamaged molecule.