Periodic Reporting for period 1 - SMART (Smart Crystal Nucleation near Interface Dynamics in Active Pharmaceutical Ingredients)
Período documentado: 2023-07-01 hasta 2025-06-30
Pharmaceutical development faces a persistent challenge in that many active pharmaceutical ingredients (APIs) exhibit low aqueous solubility, limiting their bioavailability and therapeutic effectiveness. One of the most critical and least understood factors influencing these properties is crystal nucleation at interfaces. This process governs the transition from the amorphous to the crystalline state and impacts long-term stability, manufacturability, and drug release performance. Despite advances in solid-state chemistry, predictive control over interfacial nucleation kinetics in APIs remains limited due to the complexity of molecular interactions, the influence of thermodynamic and kinetic parameters, and the variability introduced by processing environments. The SMART project (“Smart Crystal Nucleation Near Interface Dynamics in Active Pharmaceutical Ingredients”) addresses this challenge by integrating molecular dynamics simulations, advanced kinetic modelling, and experimental electrochemical characterisation to establish a predictive framework for API crystallization. The project explores explicitly heteropolar graphene (HG) smart interfaces as a green, low-energy platform to control nucleation, enabling programmable crystallization kinetics with minimal environmental impact and aligning with EU strategic priorities in sustainable manufacturing, digitalisation, and the development of advanced materials for healthcare. The project’s objectives are to design dynamic models of API crystallization through simulation and modelling of API–interface interactions under varied thermodynamic and kinetic conditions, to identify and quantify kinetic models using both classical and adapted multivariate analysis methods, to experimentally validate theoretical predictions through non-isothermal and sub-glass-transition crystallization experiments correlating macroscopic crystallization rates with microscopic crystal growth patterns, and to develop smart analytical tools for predictive stability by combining in silico and experimental techniques to create reliable, low-carbon-footprint protocols for monitoring and controlling crystallization. The pathway to impact is based on a closed-loop model in which computational insights inform experimental design, reducing trial-and-error, resource consumption, and time-to-market for stable drug formulations. Outcomes from SMART are expected to advance scientific understanding of interfacial dynamics in pharmaceutical crystallization, enable sustainable manufacturing by introducing green synthesis routes and low-energy crystallization control methods, enhance drug stability and bioavailability through interface-engineered control over crystallization. The scale and significance of these impacts extend across pharmaceutical research and development, manufacturing efficiency, and patient outcomes, as predictive, programmable control of crystallization will help reduce development costs, minimise waste, and accelerate the delivery of effective medicines to market. Given the project’s inherently multidisciplinary nature, social sciences and humanities perspectives, particularly in the context of sustainable innovation and regulatory acceptance play a role in framing the adoption of green materials and advanced manufacturing methods in the pharmaceutical industry, ensuring that the technical advances align with societal expectations, ethical considerations, and health policy priorities, thereby maximising real-world uptake and long-term benefits.
SMART project focused on developing and validating a predictive framework for interfacial crystal nucleation and growth kinetics in active pharmaceutical ingredients (APIs) through a combined computational–experimental approach. In silico studies using DFT and molecular dynamics simulations established optimal API configurations, quantified kinetic and thermodynamic parameters, and revealed the influence of molecular arrangement and packing density on nucleation behaviour. Sensitivity analyses of Avrami/JMAK models set precision thresholds for subsequent experimental validation. Experimentally, amorphous APIs and API–heteropolar graphene (HG) interfaces were synthesized via a green melt-quench method, and their crystallization behaviour was analysed using DSC across multiple heating rates. Theoretical predictions were confirmed through multivariate kinetic analysis, achieving excellent correlation with experimental data and reliably extracting activation energies and growth parameters via Kissinger and Matusita–Sakka methods. Microscopic nucleation patterns at API–HG interfaces were characterised by optical, SEM, TEM, AFM, CV, LSV, EIS, and GCD methods, enabling direct correlation between microscopic growth rates and macroscopic crystallization rates. FTIR and UV–Vis spectroscopy identified key vibrational and electronic transitions influencing nucleation, while systematic studies on solvent polarity and temperature elucidated their roles in crystal growth dynamics near Tg. The project delivered a robust predictive kinetic model, demonstrated programmable crystallization kinetics in multi-component APIs, validated heteropolar graphene as a smart nucleation interface, and established reproducible synthesis and characterisation protocols, providing a scientific foundation for designing interface-engineered API formulations with enhanced stability, bioavailability, and low energy requirements, achieved with an overall project carbon footprint of approximately 2.5 kg CO2eq.
he SMART project has achieved results that advance well beyond the current state of the art in understanding and controlling interfacial crystal nucleation in active pharmaceutical ingredients (APIs). By integrating in silico molecular dynamics (MD) and density functional theory (DFT) modelling with high-precision experimental techniques such as DSC, the adapted multivariate kinetic analysis, CV, LSV, EIS, GCD, FTIR, UV-Vis, and advanced microscopy (SEM/TEM/AFM, XPS), the project has developed a predictive, low-carbon-footprint crystallization framework applicable to complex pharmaceutical systems. Key outcomes include the first integrated kinetic crystallization model linking macroscopic crystallization rates to microscopic growth rates for APIs at heteropolar graphene interfaces, validated predictive tools with correlation coefficients up to r ≈ 0.999 and programmable crystallization kinetics for dual- and multi-component APIs at sub- and near-Tg temperatures. Atomic-level DFT analyses have provided unprecedented insight into charge distributions, vibrational modes, and molecular orientations, guiding the design of green-synthesized, API-compatible heteropolar graphene interfaces that catalyse nucleation with stability and reproducibility. These advances promise significant impacts in pharmaceutical manufacturing by enabling rapid and precise control of crystallization pathways, improving solubility, stability, and bioavailability of poorly soluble drugs, while reducing waste and accelerating formulation timelines. The approach aligns with EU Green Deal and SDG objectives through sustainable production methods and has generated strong IPR positions, including patents on the SMART API Nucleation Model and Net-Zero HG materials. To ensure wider uptake and success, key needs include expanding validation to broader API classes, scaling heteropolar graphene interface production to GMP standards, securing financing for pilot-scale demonstration, forming commercial partnerships with the pharmaceutical industry, protecting intellectual property globally, fostering international collaborations, and working with regulators to incorporate predictive interfacial crystallization modelling into recognised drug approval frameworks.