Foreword

Upatinib (Upadacitinib, Figure 1) is a highly efficient and selective JAK1 inhibitor. In biochemical assays, its selectivity for JAK-1 is 74 times higher than that for JAK-2 (involved in erythropoiesis) and 58 times higher than that for JAK-3 (involved in immune surveillance).

In terms of clinical application, upatinib has been approved for more than 7 indications in China, mainly for the treatment of rheumatoid arthritis, Crohn's disease, atopic dermatitis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, giant cell arteritis and other autoimmune diseases.

Upatinib impurities refer to non-target compounds or degradation products generated during the production, storage or use of Upatinib. These impurities may affect the efficacy, safety and stability of upatinib. Therefore, it is necessary to strictly monitor and control its content in the process of drug production and quality control to ensure that the purity and quality of the product meet the relevant standards and regulations.

Figure 1. Chemical structural formula of upatinib (Upadacitinib)

Amide bond and carbamoyl group in upatinib molecule are weak sites of chemical stability: according to forced degradation research, it is easy to hydrolyze and break under acid/alkaline conditions; Under oxidation and light conditions, the fused aromatic ring and ethyl side chain are easy to produce oxidation/photolysis impurities, and more than 10 degradation impurities have been reported. At the same time, the original synthetic route involves heterocyclic ring closing, formylation, chiral pyrrolidine condensation and other steps, which are easily accompanied by process impurities such as bis-formylation by-products, (3R,4S) epimers, 6-position ethylated impurities and Ts protecting group residues (WPT-4).

, under the traditional route, such impurities need to be prepared and separated from the forced degradation mixture: the polarity is close to the main component, and the separation is not clean; The chiral center is difficult to control and the purity fluctuates greatly. The alkaline solution is unstable and the yield is extremely low. The end result is a low spot supply and high unit price, which directly slows down the progress of method development and stability research.

this cycle of death, we have broken. Based on the degradation and process impurity characteristics of upatinib, our research and development team has successfully launched upatinib impurity 15(Upadacitinib Impurity 15) :U19866 (fig. 2) through customized synthesis, separation and purification, providing a more cost-effective reference substance for the development of related substance methods and stability research.

Figure 2. Upatinib impurity 15(Upadacitinib Impurity 15),U19866

The synthesis of upratinib impurity 15 is difficult, involving multiple steps and strict purification control. Based on the degradation and process impurity characteristics of upatinib, the research and development team completed the directional synthesis and separation purification of the impurity, and completed the structure confirmation by means of nuclear magnetic (H-NMR, Figure 3-1), mass spectrometry (MS, Figure 3-2), high performance liquid (HPLC, Figure 3-3) and so on. A traceable file is established for each batch to ensure inter-batch consistency and data integrity, so that the control can truly withstand inspection.

Now our company has a large number of upatinib impurity standard products, welcome to purchase.

Figure 3-1. The H-NMR of Upatinib Impurity 15

Figure 3-2. MS of upatinib impurity 15

Figure 3-3. HPLC of Upatinib Impurity 15

PART 03

-impurity profile study: used for the location confirmation and attribution of specific impurities in upatinib raw materials and preparations.

• Methodology development and validation: support the validation of substance-related methods for specificity, accuracy and durability.

• Stability studies: used as a qualitative/quantitative reference in forced degradation and long-term stability studies.

• Registration declaration support: Provides experimental basis for impurity control for DMF and declaration materials.

References

1.Nakayamada S, Tanaka Y, Parmentier JM, et al. Recent Progress in JAK Inhibitors for the Treatment of Rheumatoid Arthritis. BioDrugs. 2016;30(5):407-419.

2. Abbott Pharmaceutical Trading (Shanghai) Co., Ltd. Upatinib Sustained-release Tablets (Ruifu®) Chinese instructions; National Medical Security Administration. 2025 National Medical Insurance Drug Catalog Payment Scope Materials.

3.Chaganti S, Nelapati C, Jain D, Roshitha KR, Kanchupalli V, Samanthula G. Separation and characterization of degradation impurities of upadacitinib by liquid chromatography and high resolution mass spectrometry. J Chromatogr B. 2024;1247:124319. doi:10.1016/j.jchromb. 2024.124319

4.ISP Standards. Upadacitinib Impurity 15 (ISP-U005017). C₁₇H₁₉F₃N₆O, MW 380.4, (3R,4S)/(3S,4R) 1:1. https://ispstandards.com/product/upadacitinib-impurity-15/PART 01 R & D BackgroundPART 02 R & D ProcessApplication scenario