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 proposed formulation optimization schemes and application improvement suggestions for Ticagrelor advanced intermediates via technological transformation cooperation with manufacturers and precise insight into market demands. Below is HiSiaddi’s consulting case on formulation optimization of Ticagrelor advanced intermediates.
If you need further formulation optimization consulting services, please contact HiSiaddi customer service.
The client is Nordic Pharma AB, a high-end pharmaceutical enterprise headquartered in Stockholm, Sweden, specializing in cardiovascular pharmaceuticals. Its core products are original-derived Ticagrelor formulations supplied to high-end medical institutions and pharmaceutical R&D organizations across Northern and Western Europe. All its production facilities adhere to FDA, EMA and ICH Q7 quality specifications, imposing stringent requirements on raw material purity, reaction compatibility and batch-to-batch stability.
The client has long purchased pyrimidine-ring advanced Ticagrelor intermediates with an annual procurement volume of 220 kg for continuous API synthesis production lines. As a leading mid-to-high-end pharmaceutical enterprise in the industry with mature self-developed production formulations, the client encountered successive production abnormalities after bulk adoption of domestically supplied intermediates: decreased reaction yield, excessive characteristic impurities, uneven material dissolution and unstandardizable process parameters. Multiple internal adjustments to original formulations and production parameters failed to resolve the issues completely, disrupting production schedules and exposing the enterprise to risks of pharmaceutical quality audits. The client therefore entrusted HiSiaddi with full-process technical troubleshooting, formulation optimization and on-site production process guidance.
HiSiaddi formed a special technical team covering organic synthesis, process optimization and quality analysis. Cross-source tracing was conducted combining raw material test reports, the client’s existing reaction formulations, workshop operating conditions and multi-batch production data, ultimately identifying four core issues and root causes:
1. Mismatch between original reaction formulation and raw material properties exacerbates side reactions The client adopted a single acid-binding agent system for condensation reactions. The molecular structure of this Ticagrelor intermediate contains propylthio and chloropyrimidine rings with a special active reaction window. Trace polar residues in raw materials trigger side reactions with the alkali system in the original formulation, generating hard-to-remove polymeric impurities and chloride impurities. Total impurity levels approached EU limits while target reaction conversion dropped by 11%.
2. Single-solvent system leads to poor powder dissolution and dispersion The client exclusively used a single polar organic solvent. Uneven particle size distribution of the intermediate powder causes local agglomeration and sedimentation within the reaction system, leading to inconsistent feeding concentrations, partial over-reaction or incomplete reaction, and substantial material loss in subsequent filtration and extraction procedures.
3. Improper temperature and residence time control induces degradable impurities The client’s production line adopted conventional temperature control ranges, while the intermediate exhibits weak thermal stability. Prolonged high-temperature reactions trigger pyrimidine ring ring-opening degradation and generate characteristic degradable impurities. Meanwhile, mismatched material residence time under continuous-flow production further amplifies impurity formation.
4. Poor batch-to-batch compatibility prevents standardized production parameters Minor fluctuations in trace residual solvents and crystal forms across different raw material batches were not matched with flexible process windows by the client. Production staff were forced to repeatedly adjust pH, feeding ratios and stirring speeds for every batch, eliminating standardized operating procedures and drastically reducing production efficiency.
Adhering to the principles of minimal disruption to the client’s core process, low-cost implementation and long-term stability, HiSiaddi developed a full set of solutions covering four dimensions: raw material calibration, formulation system optimization, production parameter adjustment and standardized on-site operation specifications. Multi-batch pilot verification was completed within 25 days with all issues fully resolved.
Collaborated with partnered GMP-certified domestic manufacturers to optimize post-treatment procedures: adding weak polar solvent washing and low-temperature recrystallization steps to selectively remove polar residual impurities. Tightened internal control standards for raw material water content and residual solvents, unified crystal morphology and particle size distribution to narrow batch-to-batch physical property differences and reduce downstream reaction interference at the source.
1. Composite acid-binding agent replacing single-agent system On the basis of the original formulation, the single organic alkali was replaced with a composite acid-binding agent system precisely matched to the intermediate’s reaction activity, effectively blocking polymerization side reactions and chloride impurity generation without modifying core reaction routes.
2. Improved mixed solvent system A weak polar solvent was proportionally blended into the primary solvent to adjust overall system polarity, enhancing dissolution and dispersion of intermediate powder and completely eliminating agglomeration and sedimentation. Filtration material loss was simultaneously reduced by 8%.
Combining raw material thermal stability data and continuous-flow equipment characteristics, new process windows were defined: core reaction temperature lowered with gradient temperature control modes implemented. Material residence time and stirring speed were precisely optimized to eliminate pyrimidine ring-opening degradation, controlling degradable impurities below detection limits. Floating parameter ranges were formulated to accommodate normal batch fluctuations of raw materials.
Full English process operation manuals, parameter comparison tables and abnormal early warning protocols were compiled based on optimized formulations and parameters, clarifying adjustment rules for different raw material batches. Technical specialists provided remote on-site guidance for two trial production batches to familiarize workshop operators with the updated workflow.
1. All production indicators restored to compliance standards After implementation of the optimization scheme, reaction conversion rebounded to standard values. Polymeric, degradable and chloride impurities were stably controlled within EMA limits. Uniform material dissolution eliminated agglomeration and sedimentation, enabling smooth operation of the full production workflow.
2. Standardized production line operation With fixed process windows and operating specifications, parameter readjustment for individual batches became unnecessary. More than ten consecutive mass production batches operated stably with production efficiency increased by 10%.
3. Successful compliance audit clearance Fully traceable optimized process data, impurity traceability reports and batch records enabled unobstructed passage of the EMA quarterly on-site audit with zero rectification items required.
The client’s Production Manager commented: “HiSiaddi accurately identified the core mismatch between formulation and raw material properties. The optimization scheme aligns closely with our existing production line, delivers rapid implementation and stable results, and effectively mitigates dual risks of production disruption and quality non-compliance.”
Cooperation was further deepened: the client raised annual procurement volume of this intermediate to 260kg and entrusted HiSiaddi with technical support and supply of three other Ticagrelor series intermediates, establishing a long-term technical collaborative partnership.
Ticagrelor advanced pyrimidine-ring intermediates feature complex structures and high sensitivity to reaction formulations, solvent systems and temperature parameters, representing common technical challenges for mass production at mid-to-high-end European and American pharmaceutical enterprises. The root cause of the issues in this case was not substandard raw material quality, but mismatching between raw material physical properties, traditional formulations and mass production processes.
Drawing on in-depth expertise in physicochemical properties of pharmaceutical intermediates, heterocyclic and peptide synthesis processes, and production models of European and American pharmaceutical manufacturers, HiSiaddi avoided blind raw material replacement or full process reconstruction. Instead, the team adopted an "adaptive optimization" core strategy, adjusting raw materials, formulations, parameters and operating procedures end-to-end to completely resolve technical challenges while controlling transformation costs. The solution preserved normal operation of the client’s existing production lines, equipment and workforce while safeguarding quality and compliance benchmarks for high-end pharmaceutical products, fully demonstrating the core value of integrated "supply chain + technical service" foreign trade service providers.
If you need further formulation optimization consulting services, please contact HiSiaddi customer service.
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