Publication: Nuevas estrategias sintéticas para la producción a escala industrial de agentes de contraste para resonancia magnética nuclear medicinal basados en gadolinio
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Date
2025-10-03
Authors
Jiménez García, Adrián José
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Escuelas::Escuela Internacional de Doctorado
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García López, José Antonio ; Frutos Pedreño, Roberto
Publisher
Universidad de Murcia
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DOI
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info:eu-repo/semantics/doctoralThesis
Description
Abstract
Objetivos de la tesis
Los objetivos generales se pueden estructurar en los siguientes hitos:
Hito 1. Optimización de la síntesis del ligando butrol y su correspondiente complejo de coordinación a gadolinio(III), denominado gadobutrol.
Hito 2. Optimización de la síntesis del ligando DOTA y su correspondiente complejo de coordinación a gadolinio(III), el ácido gadotérico, o su sal de interés comercial denominada gadoterato de meglumina.
Hito 3. Optimización de la síntesis del ligando HP-DO3A y su correspondiente complejo de coordinación a gadolinio(III), denominado gadoteridol.
Hito 4. En función del desarrollo o del interés comercial de los anteriores se considerará el desarrollo de una ruta de síntesis de complejos de Ca2+, como por ejemplo el calcobutrol, utilizado ampliamente como aditivo en tratamientos con gadobutrol.
Metodología
Los equipos y materiales utilizados en los procesos de síntesis fueron equipos de laboratorio I+D tanto en las fases de optimización como en las de escalado. Para el análisis de los productos, se han empleado técnicas analíticas de cromatografía líquida de alta eficacia. En menor medida, también se han empleado técnicas de espectroscopía de masas, infrarroja, resonancia magnética nuclear y análisis elemental. También, se ha analizado en laboratorios externos el contenido de gadolinio de los complejos finales mediante espectroscopía de emisión atómica con plasma acoplado inductivamente.
Resultados o conclusiones
1. La síntesis del ligando butrol·LiCl, un precursor potencial para la síntesis del agente de contraste gadobutrol, se ha logrado utilizando materias primas sencillas, disolventes ecológicos y sin costosas técnicas de purificación. Además, se ha escalado hasta un kilogramo mediante un cuidadoso control de diversos parámetros de reacción.
2. Se han obtenido muestras de gadobutrol a escala de laboratorio a partir de butrol·LiCl, con una pureza superior a la exigida por la farmacopea, sin realizar costosos procesos de purificación como el uso de resinas de intercambio iónico. El proceso completo de síntesis de gadobutrol se ha escalado en un reactor de veinte litros, junto con un proceso de validación, cumpliendo con los protocolos de fabricación estipulados por el departamento de control de calidad de Kinsy.
3. Se ha estudiado la optimización del desarrollo sintético de DOTA·2HCl y su posterior transformación en el producto DOTA variando diferentes parámetros de reacción y sin necesidad de purificación con resinas de intercambio iónico.
4. Utilizando el ligando DOTA se ha preparado ácido gadotérico a escala de 100 gramos con altos valores de pureza y rendimiento. El mismo hito se ha alcanzado utilizando el precursor DOTA·2HCl, obteniendo un producto final con un contenido de gadolinio del 98-102 % respecto al esperado para el ácido gadotérico puro, que cumple con los requisitos establecidos para este parámetro en la farmacopea del gadobutrol.
5. Se han obtenido muestras de gadoterato de meglumina con diferentes valores de contenido de meglumina, algunas conformes a la norma, y se ha definido una ruta de síntesis adecuada a las especificaciones conocidas del producto. El procedimiento sintético podría ser el punto de partida para una futura etapa de escalado.
6. Se ha logrado la síntesis de DO3A·2HCl con alta pureza y rendimiento, y se ha demostrado su utilidad como precursor del agente de contraste gadoteridol. Además, se ha utilizado para sintetizar 100 gramos de DO3A sin moléculas de clorhidrato, lo que también presenta interés comercial como precursor del gadoteridol u otros agentes de contraste como el gadobutrol.
7. Se obtuvieron sólidos de gadoteridol a escala de 100 gramos con purezas superiores al 97 %, analizados por HPLC con métodos analíticos desarrollados por Kinsy. Estas muestras también mostraron un contenido de gadolinio dentro del rango del 98-102 %, en comparación con el esperado para el gadoteridol puro.
Objectives of the thesis The general objectives can be structured into the following milestones: Milestone 1. Optimization of the synthesis of the butrol ligand and its corresponding gadolinium(III) coordination complex, called gadobutrol. Milestone 2. Optimization of the synthesis of the DOTA ligand and its corresponding gadolinium(III) coordination complex, gadoteric acid, or its commercially interesting salt called meglumine gadoterate. Milestone 3. Optimization of the synthesis of the HP-DO3A ligand and its corresponding gadolinium(III) coordination complex, called gadoteridol. Milestone 4. Depending on the development or commercial interest of the above, the development of a synthesis route for Ca2+ complexes, such as calcobutrol, widely used as an additive in gadobutrol treatments, will be considered. Methodology The equipment and materials used in the synthesis processes were R&D laboratory equipment in both the optimization and scale-up phases. High-performance liquid chromatography analytical techniques were used for product analysis. To a lesser extent, mass spectroscopy, infrared, nuclear magnetic resonance, and elemental analysis techniques were also employed. The gadolinium content of the final complexes was also analyzed in external laboratories using inductively coupled plasma atomic emission spectroscopy. Results or conclusions 1. The synthesis of the ligand butrol·LiCl, a potential precursor for the synthesis of the contrast agent gadobutrol, has been achieved using simple starting materials, environmentally friendly solvents, and without expensive purification techniques. Furthermore, it has been scaled up to one kilogram by carefully controlling several reaction parameters. 2. Laboratory-scale samples of gadobutrol have been obtained from butrol·LiCl, with a purity higher than that required by the pharmacopoeia, without performing costly purification processes such as the use of ion exchange resins. These samples have also proven capable of meeting the specifications of the Chinese and American pharmacopoeias regarding the clarity or opalescence test. The complete gadobutrol synthesis process has been scaled up in a twenty-litre reactor, along with a validation process, complying with the manufacturing protocols stipulated by Kinsy's quality assurance department. 3. The optimization of a synthetic development of DOTA·2HCl and its subsequent transformation into the DOTA product has been studied by varying different reaction parameters and without requiring purification by ion exchange resins. 4. Using the DOTA ligand synthesised as described above, gadoteric acid has been prepared on a 100-gram scale with high purity and yield values. The same milestone has also been achieved using the precursor DOTA·2HCl, yielding a final product with a gadolinium content in the range of 98–102 % relative to that expected for pure gadoteric acid, which accomplishes the requirements established for this parameter in the pharmacopoeia of the gadobutrol. 5. Samples of meglumine gadoterate with different meglumine content values have been obtained, some conforming to the standard, and a synthesis route appropriate to the known product specifications has been defined. The synthetic procedure may be the starting point for a future scaling-up stage. 6. The synthesis of DO3A·2HCl has been achieved with high purity and yield, and its usefulness as a precursor to the contrast agent gadoteridol has been proven. Furthermore, it has been used to synthesize 100 grams of DO3A without hydrochloride molecules, which is also of commercial interest as a precursor to gadoteridol or other contrast agents such as gadobutrol. 7. Gadoteridol solids were obtained on a 100-gram scale with purities exceeding 97 %, analysed by HPLC with analytical methods developed by Kinsy. These samples also showed a gadolinium content within the range of 98–102 % compared to that expected for pure gadoteridol.
Objectives of the thesis The general objectives can be structured into the following milestones: Milestone 1. Optimization of the synthesis of the butrol ligand and its corresponding gadolinium(III) coordination complex, called gadobutrol. Milestone 2. Optimization of the synthesis of the DOTA ligand and its corresponding gadolinium(III) coordination complex, gadoteric acid, or its commercially interesting salt called meglumine gadoterate. Milestone 3. Optimization of the synthesis of the HP-DO3A ligand and its corresponding gadolinium(III) coordination complex, called gadoteridol. Milestone 4. Depending on the development or commercial interest of the above, the development of a synthesis route for Ca2+ complexes, such as calcobutrol, widely used as an additive in gadobutrol treatments, will be considered. Methodology The equipment and materials used in the synthesis processes were R&D laboratory equipment in both the optimization and scale-up phases. High-performance liquid chromatography analytical techniques were used for product analysis. To a lesser extent, mass spectroscopy, infrared, nuclear magnetic resonance, and elemental analysis techniques were also employed. The gadolinium content of the final complexes was also analyzed in external laboratories using inductively coupled plasma atomic emission spectroscopy. Results or conclusions 1. The synthesis of the ligand butrol·LiCl, a potential precursor for the synthesis of the contrast agent gadobutrol, has been achieved using simple starting materials, environmentally friendly solvents, and without expensive purification techniques. Furthermore, it has been scaled up to one kilogram by carefully controlling several reaction parameters. 2. Laboratory-scale samples of gadobutrol have been obtained from butrol·LiCl, with a purity higher than that required by the pharmacopoeia, without performing costly purification processes such as the use of ion exchange resins. These samples have also proven capable of meeting the specifications of the Chinese and American pharmacopoeias regarding the clarity or opalescence test. The complete gadobutrol synthesis process has been scaled up in a twenty-litre reactor, along with a validation process, complying with the manufacturing protocols stipulated by Kinsy's quality assurance department. 3. The optimization of a synthetic development of DOTA·2HCl and its subsequent transformation into the DOTA product has been studied by varying different reaction parameters and without requiring purification by ion exchange resins. 4. Using the DOTA ligand synthesised as described above, gadoteric acid has been prepared on a 100-gram scale with high purity and yield values. The same milestone has also been achieved using the precursor DOTA·2HCl, yielding a final product with a gadolinium content in the range of 98–102 % relative to that expected for pure gadoteric acid, which accomplishes the requirements established for this parameter in the pharmacopoeia of the gadobutrol. 5. Samples of meglumine gadoterate with different meglumine content values have been obtained, some conforming to the standard, and a synthesis route appropriate to the known product specifications has been defined. The synthetic procedure may be the starting point for a future scaling-up stage. 6. The synthesis of DO3A·2HCl has been achieved with high purity and yield, and its usefulness as a precursor to the contrast agent gadoteridol has been proven. Furthermore, it has been used to synthesize 100 grams of DO3A without hydrochloride molecules, which is also of commercial interest as a precursor to gadoteridol or other contrast agents such as gadobutrol. 7. Gadoteridol solids were obtained on a 100-gram scale with purities exceeding 97 %, analysed by HPLC with analytical methods developed by Kinsy. These samples also showed a gadolinium content within the range of 98–102 % compared to that expected for pure gadoteridol.
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