As a new-type foreign trade service provider driven by both technology transformation and foreign trade services, HiSiaddi has established a service system of "1+2+3+4=1", which can supply original-source Ticagrelor advanced intermediates from multiple well-known brands. As a R&D-oriented foreign trade service provider, HiSiaddi has repeatedly resolved customized product demands for Ticagrelor advanced intermediates through technological transformation cooperation with manufacturers and precise insight into market demands. Below is the case of HiSiaddi addressing customized development demands for Ticagrelor advanced intermediates.
If you need further customized service support, please contact HiSiaddi customer service.
The client is CardioPharma GmbH, a top cardiovascular pharmaceutical enterprise based in Frankfurt, Germany, specializing in R&D and commercialization of novel anticoagulant drugs. Its core product is long-acting sustained-release Ticagrelor formulations supplied to high-end medical markets across Germany, Switzerland, the Netherlands and other European countries. The enterprise complies with the highest standards of EMA, FDA and ICH Q7, imposing stringent requirements on chiral purity, impurity control and customized process of intermediates.
Customization target for this project: Key chiral advanced Ticagrelor intermediate ((1R,2S)-2-(2,3-difluorophenyl)cyclopropanamine), with an annual customized volume of 200 kg for the synthesis of API for self-developed sustained-release formulations. This is a high-difficulty chiral customization project with exclusive process development, with no mature public process available for direct application.
Client Pain Points:
1. Difficult process customization: Exclusive green synthetic route required, prohibiting cyanides, highly toxic reagents and demanding low three-waste discharge. Traditional processes carry explosion risks, difficult impurity removal and fail to meet environmental standards.
2. Ultra-stringent chiral purity requirements: Mandatory chiral purity ≥99.9%, single impurity ≤0.03%, total impurity ≤0.1%, far exceeding conventional industry standards.
3. Low matching degree of domestic suppliers: After contacting 5 manufacturers, none could simultaneously satisfy four major requirements including customized process, ultra-high purity, environmental compliance and stable mass production. Some failed to break through technical bottlenecks while others refused exclusive process development, exposing the client to risks of project suspension and delayed drug registration. The client urgently entrusted HiSiaddi with full responsibility for customized development and mass production implementation.
HiSiaddi’s technical team thoroughly analyzed client requirements and identified three core customization bottlenecks:
1. Precise control of chiral synthesis: The intermediate contains one chiral center and a rigid cyclopropane structure. Traditional synthetic routes deliver poor chiral selectivity, readily generating ineffective enantiomers which cannot be removed via conventional purification, directly compromising API activity and safety.
2. Green process development: The client explicitly banned highly toxic and high-risk reagents including cyanides, aluminum trichloride and diazonium salts. A brand-new route with mild reaction conditions, high atom economy and easy scale-up must be developed to comply with EU REACH environmental standards.
3. Extreme impurity control: 12 key indicators including genotoxic impurities, residual solvents and heavy metals must be controlled, with limits for certain impurities below 1 ppm. Complete impurity traceability and removal validation reports are required to pass EMA audits.
HiSiaddi set up a special task force covering chiral synthesis, green process, quality control and supply chain management, and collaborated with two top domestic GMP-certified manufacturers with robust chiral synthesis capacity and integrated pilot-to-mass production capabilities (Hongbo Pharmaceutical and Ningbo Inno). The team completed lab-scale process development within 28 days, pilot scale-up in 45 days and mass production delivery within 60 days.
1. Innovative route design: Abandoned traditional high-toxic routes and adopted a one-pot chiral epoxide ring-opening + cyclopropanation process. Chiral propylene oxide and 2,3-difluorophenethylamine were used as starting materials to replace cyanides and heavy metal catalysts. Reactions proceed at ≤80°C under atmospheric pressure with no explosion risks, cutting three-waste output by 60% and meeting EU green chemical standards.
2. Optimization of chiral selectivity: New chiral phosphine ligand catalysts were screened to precisely regulate reaction stereoselectivity, lifting chiral purity from the conventional 99.5% to 99.95% with no ineffective enantiomers detected, completely resolving chiral impurity issues.
3. Targeted impurity removal: A three-stage purification system combining crystallization, extraction and rectification was designed to selectively eliminate residual raw materials, by-products and genotoxic impurities, achieving single impurity ≤0.02% and total impurity ≤0.08%, exceeding client requirements.
1. Exclusive quality control standards: Customized COA formulated in accordance with EP 10.0 and USP 43 standards, covering key indicators including chiral purity (chiral-HPLC), full testing of 12 impurities, residual solvents (GC), heavy metals (ICP-MS) and water content (KF). Complete chromatograms, mass spectra and NMR spectra are attached to each batch.
2. Full analytical method validation: Complete validation of all testing methods (accuracy, precision, linearity, range, robustness) delivered, alongside 3 batches of stability data (6-month accelerated + 12-month long-term), impurity traceability reports and removal validation reports, directly applicable for EMA/FDA audits.
3. Batch traceability: A dedicated customized batch traceability system was established to realize full-process traceability and reproducible data from raw material procurement, reaction procedures and purification steps to finished product testing, packaging and delivery.
1. Lab-scale stage (28 days): Cooperated with Ningbo Inno laboratory to complete 10g lab trials, optimize reaction parameters and verify process feasibility. 3 batches of qualified samples were produced with chiral purity ≥99.92% and compliant impurity levels.
2. Pilot scale-up (17 days): Transferred to Hongbo Pharmaceutical’s pilot workshop equipped with 50L reactors to complete 5kg pilot trials, validate process stability and optimize scale-up parameters to resolve scale-up challenges including uneven reaction and low purification efficiency. 2 batches of qualified pilot samples were produced.
3. Mass production launch (15 days): Switched to GMP mass production workshop with 500L reactors and built an exclusive production line with customized light-proof, oxygen-free and constant-temperature production environments. The first 20kg mass production batch delivered test results: chiral purity 99.95%, single impurity 0.02%, total impurity 0.07%, fully meeting customized requirements.
4. Flexible supply: Dual-manufacturer backup production capacity established to guarantee stable annual supply of 200kg, supporting regular monthly orders of 15kg plus urgent supplementary orders with 7-day delivery.
1. Customized compliance document package: A full set of English compliance documents including customized process specifications, technical disclosure documents, COA, spectrograms, stability data, REACH registration certificates, SDS and GMP certificates provided, passing the client’s internal audit in one go.
2. Customized packaging: Double-layer vacuum aluminum foil bags with nitrogen sealing, packed in light-proof hard cartons with desiccants and customized traceability labels. Labels feature English product information, batch number, purity, chiral value, expiry date and storage conditions, complying with EU pharmaceutical packaging standards.
3. Full technical support: Dedicated technical liaison assigned to follow up the client’s whole production process, offering process training, technical guidance and rapid response within 24 hours for all inquiries.
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Quality Exceeds Target Specifications Upon arrival of the first 20kg customized intermediate batch, the client’s internal testing showed chiral purity of 99.95% (far exceeding the ≥99.9% requirement), single impurity 0.02%, total impurity 0.07%, water content 85 ppm and heavy metals <5 ppm. All indicators 100% met customized standards, placing chiral purity and impurity control at a globally leading level.
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Superior Process & Environmental Performance The customized green process eliminates highly toxic reagents, operates under mild conditions and generates low three-waste discharge, passing EU REACH environmental certification. The client commented: “This process not only resolves technical challenges but also aligns with our sustainable development philosophy, laying a foundation for subsequent green certification of our pharmaceutical products.”
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Efficient Delivery Ensures Project Timeline Only 60 days elapsed from demand confirmation to delivery of the first batch, 30 days ahead of the client’s expected timeline. Subsequent monthly 15kg deliveries were stable with zero delays and zero quality complaints, directly enabling the client’s sustained-release formulation to enter Phase III clinical trials on schedule and avoiding losses caused by registration delays.
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Deep Client Recognition & Upgraded Long-Term Cooperation The client’s R&D Director commented highly: “HiSiaddi is a truly professional partner proficient in high-end customization, chiral synthesis and EU-US compliance. They not only helped us break through technical bottlenecks but also built a stable, compliant and sustainable customized supply chain, far exceeding our expectations!”
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A five-year exclusive customization agreement was signed between both parties. The client entrusted HiSiaddi with customized development and supply of all advanced Ticagrelor intermediates and intermediates for 3 follow-up novel anticoagulant drugs under research, making HiSiaddi their exclusive strategic supplier for customized intermediates in China.
For high-end European and American pharmaceutical enterprises customizing Ticagrelor advanced intermediates, core pain points revolve around four aspects: precise chiral control, green process development, extreme impurity management and stable mass production implementation. Most domestic suppliers struggle to take on such projects due to insufficient technical reserves, weak customization capacity and inadequate compliance awareness.
HiSiaddi’s core competitiveness lies in in-depth understanding of high-end customization demands and EU-US regulatory standards, alongside full-chain capabilities covering chiral synthesis technology, green process development, supply chain integration and compliant delivery. Through exclusive process development, customized quality control systems, dual-manufacturer production capacity guarantees and end-to-end technical support, HiSiaddi fully resolved all customization pain points, helping overseas mid-to-high-end clients break technical barriers, secure project timelines and achieve compliant mass production. Meanwhile, it boosts the global competitiveness of domestic high-end pharmaceutical intermediates in chiral customization and green synthesis fields.
If you need further customized service support, please contact HiSiaddi customer service.
+86-13120989737 
info@hisiaddi.com 
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