Quality by Design Driven Improved Process of Abiraterone Acetate

Abstract

Abiraterone is an antiandrogen and selective inhibitor of 17α-hydroxylase/C17,20-lyase (CYP17) and is currently used in the treatment of metastatic castration-resistant prostate cancer and metastatic high-risk castration-sensitive prostate cancer. Here an improved kilogram scale synthesis of Abiraterone is presented, starting from commercially available dehydroepiandrosterone (DHEA) by employing Quality by Design (QbD) principles, statistical design of experiments (DoE), and green metrics parameters to evaluate the environmental impact and efficiency. This article focuses on identifying critical quality attributes (CQAs), exploring the relationship between CQAs and material attributes (MAs), and determining the critical process parameters (CPPs) for synthesizing hydrazone, vinyl iodide intermediates, and the final product, Abiraterone acetate. The presented approach effectively managed critical impurities and achieved impressive yields of 98, 84, and 78% with purity >99% in the hydrazone, vinyl iodide intermediate, and final API, respectively. The improved synthesis was optimized and scaled for multi-kilogram batches, addressing challenges from previous methods and yielding ICH quality material in 65% overall yield.

Abiraterone acetate (1; Figure [1]), developed by Janssen Biotech Inc., chemically identified as 17-(3-pyridinyl)androsta-5,16-dien-3β-ol acetate (C₂₆H₃₃NO₂), is a potent, irreversible, and specific inhibitor of 17α-hydroxylase/C17,20-lyase (CYP17), an enzyme presents in testicular, adrenal, and prostatic tumor tissues.[1] [2] In 2011, regulatory authorities, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), approved the usage of a medication under the brand name Zytiga. This approval was specifically for treating prostate cancer, including conditions such as metastatic castration-resistant prostate cancer and hormone-sensitive high-risk metastatic prostate cancer. Zytiga is an oral targeted agent that inhibits the production of androgens (male hormones) not only by the testes but also by the adrenal glands and the tumor itself. It has been shown to improve outcomes in men with newly diagnosed and resistant prostate cancer, and it may also improve overall survival in African American men with metastatic castration-resistant prostate cancer.[3] The expanded approval was based on clinical trial data, demonstrating its efficacy in various prostate cancer settings.

Several methods were reported to synthesize Abiraterone acetate (1) in the past decades starting from the common intermediates dehydroepiandrosterone (DHEA, 7), dehydroepiandrosterone acetate (DHEA acetate, 2), 3β-acetyloxyandrosta-5,16-diene-17-yl-trifluoromethanesulphonate, 17-iodoandrosta-5,16-dien-3β-ol, and 3-silyl protected DHEA.[4] The drawbacks of the reported methods were longer reaction times, the use of a protection-deprotection strategy, expensive reagents, low overall yields, increased number of steps, and the use of column chromatography for purification.[5] [6] [7] [8] [9] [10] [11] [12]

The four-step synthesis of Abiraterone acetate (1) as shown in Scheme [1] involves hydrazone formation (partial Wolff–Kishner reduction) using the intermediate DHEA acetate (2) with hydrazine hydrate followed by treatment of 3 with iodine (via Barton-vinyl iodide synthesis) using 1,1,3,3-tetramethylguanidine (TMG), which provided 17-iodoandrosta 5,16-dien-3β-ol (4). Subsequently, Suzuki coupling of the intermediate 4 with 3-(diethylboryl)pyridine (5) in the presence of a suitable Pd catalyst followed by oxalate salt preparation affords intermediate 6. Finally, oxalate de-saltification of intermediate 6 in the presence of base followed by acetylation provides the final API (active pharmaceutical ingredient) Abiraterone acetate (1). This method entails various drawbacks, including incomplete reaction during the formation of the hydrazone intermediate 3, resulting in the formation of undesired deacylated impurities (≥5%). Additionally, Suzuki coupling requires higher catalyst loading, and a longer reaction time affording a low yield and purity of 1.

Further modifications to this method include the conversion of DHEA acetate (2) to its triflate intermediate through the use of trifluoromethanesulfonic anhydride in the presence of DTBMP.[13] Subsequently, the triflate intermediate undergoes Suzuki coupling with diethyl(3-pyridyl)borane (5) using bis(triphenylphosphine)palladium(II) chloride as the catalyst, followed by oxalate salt formation and de-saltification with the addition of the base sodium carbonate and further acetylation providing Abiraterone acetate (1). The above method is not commercially viable as it involves the use of expensive DTBMP, formation of undesired impurities, poor yield, and requires column chromatographic purification for all the steps.

In the literature, several improvements to this method were carried out altering the use of homogenous Pd catalysts, changing the base during the triflate formation, various Abiraterone salt preparations using different acids, and carrying out the triflation step till the final stage of the synthesis. Recently, we patented the process for the preparation of crystalline Form-A of Abiraterone acetate oxalic acid salt, which is amenable for industrial filtration and avoiding the undesired impurities.[14] While this method proved feasible at a commercial scale, several other challenges have been encountered during the scale-up campaigns. One of the challenges of this process was the Suzuki coupling of the vinyl iodide intermediate with 3-(diethylboryl)pyridine (5), catalyzed by palladium(II)bis(triphenylphosphine) dichloride, which led to the formation of Abiraterone acetate (1) and Abiraterone (1a) in the ratio of 3:1. However, this resulted in poor yield during the preparation of the oxalate salt of Abiraterone acetate oxalate salt 6. Additionally, the process failed to control the palladium content within acceptable limits and maintain the desired purity of the final API due to the presence of unwanted related substances.

In 2016, a comparable method was documented in the literature (Patent WO2016004910A1) starting from DHEA (7), involving reactions conducted on a gram scale level, resulting in a final Abiraterone acetate (1) of inferior quality.[15] Similarly another process has been documented by Madhra et al., which proceeds through a bromo intermediate 13 as depicted in Scheme [ 2 ]. However, this method has several drawbacks, including lower yields and less favorable greener attributes such as Process Mass Intensity (PMI 320 kg/kg), Reaction Mass Efficiency (RME 5.33%), Atom Efficiency (AE 6.39%), and Environmental Factor (E-factor 196 kg/kg).

Considering unfavorable process features, we identified improvement windows directed toward overcoming associated challenges. Hence, it warranted us to develop an improved process with respect to efficiency and cost. Herein, we report an improved kilogram scale process for Abiraterone acetate (1) as depicted in Scheme [ 3 ].

Synthesis of Hydrazone Intermediate 8

In our initial experiments, the hydrazone intermediate 8 was synthesized by treating DHEA (7) with hydrazine hydrate in a mixture of methanol and water. In this transformation, incomplete conversion and unwanted impurities were observed to impact the quality and yield of the hydrazone intermediate. To address these challenges related to the quality of the material and scalability, we decided to optimize hydrazone intermediate 8 syntheses using the design of experiments approach. As part of the DoE study, a cause-and-effect analysis was conducted for the hydrazone 8 formation reaction as illustrated in Figure [2]. Possible factors to improve selectivity[16] [17] [18] [19] were identified as reaction temperature, RPM, hydrazine hydrate mole equivalent, and methanol volume.

Table [1] lists the identified variables and their corresponding levels. This evaluation enabled us to employ a statistical multivariate experimentation approach for a better understanding of the reaction profile. The reaction mass samples were analyzed using high-performance liquid chromatography (HPLC) with the area normalization method. Also, fractional factorial design was selected for the experimentation, involving four factors at two levels, resulting in 8 experiments (2^(4–1) = 8). Additionally, three center points were included to assess repeatability.

Table [2] presents all experimental results. Out of three responses, except dimer 11 ( Figure [3]), the remaining two responses were observed with minimum variation; hence dimer 11 has been statistically evaluated. The statistical analysis summary indicates that temperature has a positive effect, hydrazine hydrate mole ratio and RPM have a negative effect, and methanol volume has no effect on the dimer 11 as depicted in Figure [4]. Based on the downstream process capability, a design space was created (Figure [5]) considering the criteria that dimer 11 content not more than 0.40%. The proven acceptable range (PAR) for the parameters is 4 to 8 volume of methanol, 4 to 8 equivalents of hydrazine hydrate, 25–40 °C of reaction temperature, and 300 to 400 RPM.

Synthesis of Vinyl Iodide Intermediate 9

Similarly, DoE studies were conducted to improve conversion and selectivity in the Barton vinyl iodide synthesis[20] [21] [22] [23] [24] (Scheme [3]), as described in the literature, starting from DHEA hydrazone 8. Our initial lab scale experiments revealed the incomplete conversion of DHEA hydrazone 8 and the formation of two critical API-related substances, dimer 11 and 17-methyl impurity 12 (Scheme [4]), resulting in poor product quality and yield. Based on the literature precedent for methyl-to-cation 1,2-shift,[25] the plausible mechanism for the formation of 17-methyl impurity 12 involving I₂-mediated redox chemistry is proposed in Scheme [4].

A cause-and-effect analysis (Figure [6]) was performed and identified six critical process parameters, mole equivalents of iodine and TMG, reaction temperature, dichloromethane volume, addition time of hydrazone 8 solution, and RPM. Table [3] lists these factors and their respective levels. A fractional factorial design was selected for the experimentation with six variables, a total of 18 runs including two center points. Experimental details and the results were captured in Table [4].

Statistical analysis of unreacted hydroxy hydrazone 8 infers that iodine equivalent has a negative effect and other factors have no significant effect as depicted in Figure [7]. TMG equivalent has a negative effect on dimer 11 content and addition time has a positive effect. Dichloromethane volume has an interaction effect with addition time, and other factors have no effect on dimer 11 as depicted in Figure [8]. TMG equivalent has a negative effect, DCM volume has a positive effect on the formation of 17-methyl impurity 12 and addition time has an interaction effect with dichloromethane volume as shown in Figure [9]. A purity of 9 was positively influenced by TMG equivalent, and addition time has an interaction effect with dichloromethane volume as depicted in Figure [10]. Interestingly, the reaction temperature does not have a notable effect on these responses. A design space graph was created for vinyl iodide 9 synthesis with the criteria of hydroxy hydrazone 8 <0.50%, product 9 purity >72.0%, 17-methyl impurity 12 <10.0%, and dimer 11 <4.5% as depicted in Figure [11].

Suzuki Coupling in the Synthesis of Abiraterone (1a)

Abiraterone (1a) was prepared by reacting hydroxy vinyl iodide intermediate 9 with BET (5) in the presence of Na₂CO₃ as base and bis(triphenylphosphine)palladium(II) dichloride catalyst in aqueous isopropyl alcohol (IPA) as the solvent at elevated temperature, that is, 78–82 °C as described in Scheme [3]. In this process, the presence of unreacted starting material vinyl iodide 9 was observed majorly in the reaction mass, as previously noted in Scheme [1], which led to poor yields.

A fishbone analysis (Figure [12]) was performed and identified volume of IPA, equivalents of BET (5), equivalents of sodium carbonate, percent of water in IPA, and RPM were critical factors for the incompletion of the reaction, as captured in Table [5]. A response surface method design was chosen for the experimentation by conducting a total of 14 number of trials. Reaction mass samples were monitored by HPLC, as presented in Table [6].

Experimental results were statistically evaluated, starting material vinyl iodide 9 was negatively influenced by solvent volume, sodium carbonate equivalent, and percent of water has a nonlinear effect. Sodium carbonate equivalent has an interaction effect with percent of water as depicted in Figure [13]. Solvent volume and sodium carbonate equivalent have a positive influence, percent of water in the solvent has a nonlinear effect on product 10 formation. Sodium carbonate equivalent has an interaction effect with percent of water in solvent as shown in Figure [14]. Design space was created by considering vinyl iodide 9 not more than 1% and product 10 more than 90% as illustrated in Figure [15].

Green Metric Evaluation

Our goal was to develop efficient, environmentally sustainable, and innovative manufacturing processes for APIs using greener approaches. A thorough green metrics analysis has been evaluated for Schemes 1, 2, and 3. Figures [16] and 17 offer a Green Metric comparison of the disclosed process. The green metrics evaluated include reaction mass efficiency (RME), process mass intensity (PMI), E-factor (kg waste/kg product), atom economy (molecular weight of product/sum of molecular weights of starting materials), effluent water, and hazardous waste. A focused effort to develop an efficient synthesis of Abiraterone acetate (1) as shown in Scheme [3] has led to a significant reduction in the process mass intensity (PMI) for the synthetic process in comparison with Schemes 1 and 2, accomplishing nearly 63% reduction in PMI compared to the traditional process (Scheme [1]) and a 60% reduction in PMI relative to the Madhra et al. process (Scheme [2]), leaving behind 127 kg per kg of API. Solvent usage in Scheme [3] is also substantially reduced, down to 60% compared to Scheme [1] and 55% compared to Scheme [2]. Scheme [3] only uses 52 kg water per kg of API (Figure [17]). In Scheme [3], the process begins with DHEA (7), eliminating oxalate salt formation and other by-product formation. This leads to the usage of lower vol of solvents and lesser quantities of reagents, resulting in a PMI reduction to approximately 63% of that in previously reported schemes (Figure [17]). Even though the Scheme [2] process also begins with DHEA (7) via the bromo intermediate 13, its overall yield is only 33%, which is considerably lower than the 65% overall yield of Scheme [3], which utilizes the iodo intermediate 9 (Figure [17]). We have also evaluated the greenness of the established synthetic process disclosed in this report. It was found that the Scheme [3] process exhibited comparatively lower PMI, which was manually calculated and cross-verified using the PMI calculator available at PMI Calculator.[26] Details of the PMI evaluation are provided in Figure [16]. Similarly, a comparative bar chart considering green chemistry metrics has been presented to gauge the greenness of the processes featured in Schemes 1, 2, and 3 as shown in Scheme [5].

Scheme [5] illustrates a detailed comparative process for each Scheme [1, 2], and 3 stage. It clearly outlines the reaction conditions, quantities of raw materials, reagents, volume of solvents, and water used in each synthetic route.

In conclusion, this study describes a cost-effective, practical, greener, and overall improved chemical process for manufacturing Abiraterone acetate (1) at a multikilogram scale optimized by employing a quality-by-design approach compared to other reported processes. Conclusively, the improved process is developed in such a way that obviates oxalate salt of the Abiraterone acetate, column chromatography, and multiple recrystallizations enabling us to manufacture Abiraterone acetate (1) in higher yield with the ICH (The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) quality[27] [28] [29] and relatively better efficiency in comparison to the hitherto known processes starting from commercially available DHEA (7).

The syntheses of all intermediates and final API were carried out at the Research and Development Center, IPDO, Dr. Reddy’s Laboratories Ltd., Telangana., India. All experiments were performed under an inert atmosphere (N₂ or argon) using commercially available or laboratory reagent-grade chemicals and solvents and maintained anhydrous conditions. Reactions were carried out in a reaction vessel or cylindrical vessel with a mechanical stirrer. Purified water used in the workup process was collected from a Millipore Water purified system. Distillation operations were carried out in a Büchi rotary evaporator system under vacuum. Filtration operations were performed in a Büchner funnel and dried under vacuum in a calibrated vacuum tray dryer. Yields calculated based on the input and output weights for every intermediate and final product were calculated on dry weight. All materials were stored with proper labels with suitable storage conditions. HPLC-grade MeCN and MeOH, orthophosphoric acid, potassium dihydrogen phosphate, tetrabutylammonium hydrogen sulfate, and trifluoroacetic acid were procured from Merck Life Science. Chromatographic purification of products was carried out by flash column chromatography on silica gel (60–120 mesh) for purification of compounds using Reveleris^® X2 Flash Chromatography System from Büchi.

Starting materials DHEA (7; purity >95%) and BET (5; purity >95%) were obtained from external sources and were used for the synthesis of intermediates and API at Dr. Reddy’s Laboratories. Commercial grade reagents, aq HCl from Spectrochem Pvt. Ltd. (Hyderabad, India), 30% H₂O₂, and NaOH) were from Sigma-Aldrich (Hyderabad, India). NMR solvent CDCl₃ was purchased from Sigma-Aldrich and ¹H and ¹³C NMR experiments for intermediate or impurities, and API were recorded on Bruker Avance 500, 600 MHz and 125, 150 MHz NMR spectrometers, respectively, in CDCl₃ solvent. The instrument was equipped with a cryogenic probe to regulate the sample temperature at 25 °C. 1D data, i.e., ¹H and ¹³C chemical shift values were reported with reference to the CDCl₃ solvent peak at 7.25 ppm and 77 ppm. Mass spectra were recorded using electrospray (ESI) techniques. Low- and High-resolution mass spectra were measured with a Finnigan TSQ70 and VG, analytical ZAB2-E instruments, respectively. The FTIR spectra were recorded on the PerkinElmer model spectrum series FT-IR as a KBR pellet.

QbD: Quality by design; DHEA: Dehydroepiandrosterone; BET: Diethyl(3-pyridyl)borane; API: Active pharmaceutical ingredient; HPLC: High-performance liquid chromatography; ANOVA: Analysis of variance; SM: Starting material; DoE: Design of experiments; TMG: Tetramethylguanidine; IPA: Isopropyl alcohol.

Synthesis and Characterization of the Intermediate and API

Synthesis of Hydroxy Hydrazone 8 Intermediate

Dehydroepiandrosterone (7; 10 kg, 34.7 mol), MeOH (60 L), and hydrazine hydrate (8.67 kg, 173 mol) were added to the reaction vessel at rt. The reaction mixture was heated to 35 ± 5 °C and stirred at 40 RPM for 12–14 h. An amount of 50% of the solvent was distilled off at 40 °C under vacuum (680 mmHg). H₂O (60 L) was added to the reaction mixture and the mixture was stirred at 25–35 °C for 1–2 h at 40 RPM. The solid product was collected by filtration and washed with H₂O (40 L). The wet cake was dried under vacuum (680 mmHg) at 60–65 °C for 6 h to obtain the final product 8; yield: 10.3 kg (98%); HPLC purity: 99%.

IR (KBr): 3435.46, 2927.34, 2927.34, 1655.22, 1628.53, 1604.37, 1475.12, 1389.05, 1376.23, 1299.76, 1248.98, 1208.80, 1185.43, 1104.93, 1048.28, 1022.10 cm^–1.

¹H and ¹³C NMR: The chemical shift assignments of product 8 are shown in Table [7].

HRMS: m/z calcd for C₁₉H₃₀N₂O + H⁺: 303.46 [M + H]⁺; found: 303.2419.

Synthesis of Vinyl Iodide Intermediate 9

Hydroxy hydrazone 8 (10 kg, 33 mol), MeOH (70 L), and CH₂Cl₂ (7.5 L) were charged into the reaction vessel. The mixture was stirred at 40 RPM and the dissolution was checked at 0–10 °C. MeOH (2.5 L), CH₂Cl₂ (47.5 L), and I₂ (16.8 kg, 66.2 mol) were charged into a separate reaction vessel. The mixture was cooled to –10 to 0 °C and tetramethyl guanidine (26.65 kg, 231.7 mol) was added to the I₂ solution at –10 to 0 °C over 30–45 min. The hydroxy hydrazone 8 solution was added slowly to the iodine solution over 3 h at –10 to 0 °C and the temperature was maintained for an additional 2–3 h. The temperature of the reaction mixture was raised to 0–10 °C and maintained for 1–2 h. The solvent was distilled off from the reaction mixture under vacuum (680 mmHg) below 40 °C. H₂O (100 L) was added to the residue and stirred at 40 RPM for 1–2 h at 25–35 °C. The solid compound formed was collected by filtration and washed with H₂O (20 L). After drying, CH₂Cl₂ (50 L) was added and the mixture stirred at 40 RPM for 10–15 min to obtain a clear solution. Aq 0.1 N HCl (20 L) was added to the reaction mixture and the pH was maintained acidic. The layers were separated and the organic layer was washed with aq Na₂S₂O₃ (3 kg in 20 L H₂O) followed by aq 5% NaCl (1.5 kg NaCl in 20 L H₂O). The solvent in the organic layer was distilled off under vacuum (680 mmHg) below 40 °C until 2–3rd of the volume remained. MeOH (10 L) was added and distill off below 60 °C under vacuum (680 mmHg) until 5–6th of the volume remained. The reaction mixture was cooled to 0–5 °C and stirred at 40 RPM for 60–90 min. The solid part was collected by filtration and washed with MeOH (10 L). The product was dried at 50–55 °C under vacuum (680 mmHg) for 5–6 h to afford compound 9; yield: 11.1 kg (84%); purity 99%.

IR (KBr): 3638.07, 3309.50, 2968.35, 2929.93, 2902.38, 2834.30, 1458.76, 1450.62, 1437.47, 1367.71, 1246.23, 1062.08, 1043.71, 1018.21, 1007.26, 993.60, 952.01, 833.13, 744.21, 635.74 cm^–1.

¹H and ¹³C NMR: The chemical shift assignments of product 9 are shown in Table [8].

HRMS: m/z calcd for C₁₉H₂₇IO·H₂O + H⁺: 381.11 [M + H – H₂O]⁺; found: 381.1058.

Synthesis of Abiraterone Acetate (1)

Vinyl iodide intermediate 9 (25 kg, 28.69 mol), i-PrOH (150 L), diethyl (3-pyridyl)borane (5; (8.95 kg, 27.84 mol), and bis(triphenylphosphine)palladium (II) dichloride (0.197 kg, 0.13 mol) were charged into the reaction vessel. The mixture was stirred at 40 RPM for 10–15 min. Aq Na₂CO₃ (46.5 kg, 202.72 mol in 100 L H₂O) was added to the reaction mixture and stirred for 10 min. The reaction mixture was heated to 78–82°°C and stirred at 40 RPM for 2–3 h. The reaction mixture was cooled to 25–30 °C and extracted with toluene (75 L). The toluene layer was transferred to a reaction vessel, and MeOH (100 L) and H₂O (100 L) were added, and heated to 50–60 °C. The pH was adjusted to 0.5–1.0 using aq HCl (7.5 L HCl in 7.5 L H₂O). The layers were separated and the aqueous layer was washed with toluene (50 L). Thiosilica (1.0 kg, 4% w/w) was added to the organic layer and stirred at 40 RPM for 20–30 min at 65–70 °C. The mixture was cooled to 50–55 °C, then aq NaOH (5.4 kg, 136 mol in 25 L H₂O) was added and stirred at 50–55 °C for 5 h. The aqueous and organic layers were separated at 50–55 °C. Thiosilica (4 kg) was added to the organic layer and stirred at 65–70 °C for 30 min. The thiosilica was filtered off on a Celite bed. Toluene was distilled off from the filtrate below 50 °C under vacuum (680 mmHg) until the reaction mass was 3.0–3.5 times the batch size. The reaction mass was cooled to 5–10 °C and stirred at 40 RPM for 60 min. The solid material was collected by filtration and dried under vacuum (680 mmHg) at 65–70 °C for 5–6 h (dry weight: 23 kg). Acetone (125 L), Et₃N (14.9 kg, 147 mol), and 4-(dimethylamino)pyridine (0.72 kg, 5.89 mol) were added to the dried compound at 25–35 °C under a N₂ atmosphere and the reaction mass was heated to 38–42 °C. Ac₂O (12 kg, 117 mol) was added slowly and the reaction mass was stirred at 40 RPM for 3–4 h at 38–42 °C. Ultra DX carbon (2.5 kg, 10% w/w) and thiosilica (0.5 kg, 2% w/w) were added to the reaction mass and stirred for 20–30 min. The reaction mass was filtered through a Celite bed followed by a 0.2-micron filter and the bed was washed with acetone (25 L). The filtrate was transferred to a reaction vessel, H₂O (75 L) was added slowly, and stirred for 1–2 h at 25–30 °C. The solid was collected by filtration and washed with H₂O (50 L). The compound as dried under vacuum (680 mmHg) at 40–45 °C for 5–6 h to afford the title compound 1; yield: 19.2 kg (78%); purity: 99.7%.

IR (KBr): 3439.34, 3047.06, 2936.97, 2891.55, 2854.99, 1735.17, 1667.84, 1602.31, 1559.28, 1374.26, 1244.99, 1138.44, 1244.99, 1034.85 cm^–1.

¹H and ¹³C NMR: The chemical shift assignments of product 1 are shown in Table [9].

MS: The ESI +ve ionization mass displayed protonated molecular ion at m/z = 392.3 matching with the corresponding formula C₂₆H₃₃NO₂.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

Dr. Reddy’s communication number: IPDO-IPM-00719.

We duly acknowledge the management of Dr. Reddy’s Laboratories Ltd., for allowing us to carry out the present work. The authors thank their colleagues in the analytical research and development department for their support in analytical results and cooperation.

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Corresponding Authors

Publikationsverlauf

Eingereicht: 19. Februar 2025

Angenommen nach Revision: 26. März 2025

Artikel online veröffentlicht:
28. April 2025

© 2025. Thieme. All rights reserved

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