Thermodynamic Study on the Amorphous Form and Crystalline Hydrates Using in Situ Raman and FBRM

Crystal Research and Technology

2022

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A screening of amorphous, heptahydrate, and tetrahydrate forms of disodium guanosine 5′-monophosphate is investigated using an antisolvent crystallization process with the aim to selectively produce each solid form. The concentrations of the solution and solid forms are monitored by in situ Raman spectroscopy using a calibration tool. Particle sizes and particle counts are measured with elapsed time by a focal beam reflection measurement. Concentrations of amorphous and hydrates phases are determined using in-line measurement techniques. The variables studied are temperature, initial concentration, addition rate, and solvent fraction. The results demonstrate that transformation from amorphous to hydrate forms consists of four stages, which are the nucleation of the amorphous form, predissolution of amorphous form, the nucleation of hydrate crystal and dissolution of amorphous solid, and the growth of hydrate crystal. The rate-controlling step, in this case, is the dissolution of amorphous form. Transformation between heptahydrate to tetrahydrate crystals is a nucleation-growth-controlled step. It is possible to obtain selectively the solid forms of disodium guanosine 5′-monophosphate by referring to the supersaturation and solubility data.

Section: Solubility and Supersaturationmentioning

confidence: 96%

Section: Raman Spectroscopy and Fbrmmentioning

confidence: 99%

Section: Characterization Of Solids and Raman Calibrationmentioning

confidence: 99%

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Finding Conditions to Process Hydrate Crystals and Amorphous Solids of Disodium Guanosine 5′‐Monophosphate by an Antisolvent Crystallization Process

Crystal Research and Technology

2022

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“…An industrial crystallization of GMP is often conducted at a high supersaturation degree, resulting in the formation of the amorphous form first, which is undesirable because it necessitates a long transformation time and lowers product quality. Tetrahydrate and heptahydrate can be synthesized selectively by choosing the right thermodynamic and kinetic conditions depending on the working conditions. − The economically necessary ingredient is heptahydrate. Setting ideal operating conditions to change from amorphous to heptahydrate following amorphous formation is critical in the industrial crystallization process.…”

Section: Introductionmentioning

confidence: 99%

“…The transformation of GMP has been investigated; however, no study has been conducted on the kinetics and rate-controlling steps in the transformation from amorphous to heptahydrate. Previous research has studied the solubility of solid forms, the metastable zone limits for amorphous and heptahydrate formation, amorphous to heptahydrate transformation, and heptahydrate nucleation behavior. − Ostwald’s rule of stages states that the metastable polymorph appears before the stable polymorph . The following restrictions apply to this regulation: The nucleation of metastable and stable forms is determined by the widths of the corresponding metastable zones, and stable forms can be produced without transformation …”

Section: Introductionmentioning

confidence: 99%

Dissolution and Growth Kinetics and the Rate-Controlling Step in Transformation of Amorphous to Crystalline Phase Using Antisolvent Crystallization

2022

Ind. Eng. Chem. Res.

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The kinetics of the formation of amorphous disodium guanosine 5′-monophosphate and its transformation to the heptahydrate phase were studied under various operating conditions using in situ Raman and focused beam reflectance measurement (FBRM). Supersaturation, solvent composition, feed concentration, addition rate, and viscosity were shown to affect the rate-determining steps of the transformation. The rate-controlling mechanisms in the overall kinetics have been confirmed. The observation of the slurry viscosity of the suspension of the amorphous phase shows the option to observe the phase transformation. The transformation process was affected by the dissolution, growth, and supersaturation in which the rate-controlling step was divided into two sections, such as the initial and later sections of the transformation. The overall rate constants were determined by combining the constants of the dissolution rate and the growth rates of each section. In situ Raman spectroscopy examination of the concentration of solution and solids can determine the rate-limiting processes during the transformation. The zero-order, first-order, and surface reaction equations as kinetic equations are highlighted and compared for the dissolution of the amorphous solids and the growth of the heptahydrate crystals. The dissolution of the amorphous (metastable form) and the growth of the heptahydrate (stable form) were found to be best fitted to the zero-order kinetic model. In particular, the variation of particle size distribution over time can give the rate-determining steps. These results suggest that the data measured by Raman spectroscopy and FBRM can be successfully coupled into a dissolution and growth model to further grasp and interpret the phase transformation. A dissolution rate-controlling step was dominated by a pattern in which both supersaturation and amorphous dissolution decreased simultaneously, and the growth rate-controlling step was shown in a pattern in which either supersaturation or amorphous dissolution was constant. Furthermore, the growth of heptahydrate crystals at a viscosity of the suspension with the amorphous solids below 70 cp and the dissolution of the amorphous solids above it can be used as the key determinant. Using the method developed and the kinetic constants obtained in this work, it is possible to create an appropriate control strategy to produce the desired form in the final product.

Nucleation Behavior in a Transformation of the Amorphous State to the Crystalline State during Antisolvent Crystallization

2022

Ind. Eng. Chem. Res.

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The liquid-mediated phase transformation of an amorphous form to a crystalline heptahydrate form of guanosine 5′-monophosphate was studied in antisolvent crystallization using methanol–water mixtures as solvents. Three steps were monitored: the formation of the amorphous form, dissolution of the amorphous form, and growth of the heptahydrate crystals using in situ Raman spectroscopy, focused beam reflectance measurement (FBRM), and particle vision measurement (PVM) and off-line methods like viscosity, thermal gravimetric analysis (TGA), and powder X-ray diffraction (PXRD). Effects of the antisolvent fraction, initial concentration, and addition rate of the antisolvent on the transformation process were discussed. Solid forms, solute concentration, particle size, counts, induction time, metastable zone width, solution viscosity, and amorphous slurry viscosity were all measured for 18 experiment runs. The induction time of the crystalline hydrate increased with the supersaturation but decreased with the increasing viscosity of the amorphous slurry. Both are not as expected. The induction time correlates nicely in the opposite direction with the viscosity of the amorphous slurry concentration. The amorphous slurry viscosity is about 20 times higher than the solution viscosity. Viscosity of the amorphous slurry was discovered to be a crucial factor influencing the transition of the amorphous slurry to the crystalline form in the pre-exponential component of the classical nucleation rate equation. The metastable zone boundaries of the amorphous and heptahydrate crystalline forms were shown in a plot of the solute concentration versus the mass fraction of methanol in the mixed solvent. The amorphous and heptahydrate crystalline forms can be selectively produced under all the conditions of this study. The pre-exponential factor of the nucleation rate equation factor is crucial in comprehending the transformation from an amorphous to a crystalline state.