WHITE PAPER ACETYLSALICYLIC ACID
Victoire de Margerie & Christophe Eychenne-Baron
One of the biggest challenges faced today by the pharmaceutical industry lies in enabling the delivery of poorly soluble active pharmaceutical ingredients (APIs). In addition to improving the dissolution rate in digestive fluids in order to improve the bioavailability of a molecule after oral administration, the objective is also to avoid possible precipitates in the gastrointestinal tract that could attack the tissues that constitute the intestinal wall and slowly but surely cause ulceration or other secondary effects. SEQENS is a global leader in designing, developing, and manufacturing small molecule APIs and RONDOL is a technology leader for the development and continuous improvement of drug dosage extrusion technologies. Hot-melt extrusion (HME) is a technology that disperses APIs into a polymer matrix at the molecular level to form solid dispersions and it is gaining interest due to a series of advantages (1,2): – It generates physically stable amorphous forms of APIs that can disintegrate faster into the body (relative to crystalline APIs amorphous solid dispersions improve bioavailability in more than 80 % of cases) – It is a solvent-free, low energy continuous manufacturing process (so more “green”, more simple, easier to control and less costly) – It allows for all types of downstream processing of extrudates into final dosage forms (tablets, capsules, implants, controlled release dosage forms, etc.). – Since 2012, Rondol has reduced the size of HME equipment (very necessary to process APIs worth 1.000 to 5.000 € a gram), adapted them to the Pharmaceutical standards (move from aluminum and carbon steel parts to stainless steel with precise metal surface specifications, very demanding easy clean and traceability requirements) and finally made them vertical in order to further reduce contamination risks (thanks to the use of gravity to transport the extrudate) and to bring the machine footprint down to a 5th of that of a similar horizontal machine (hugely interesting with a Capex cost of 1M € per white room m2 ). (3,4) 3 So SEQENS and RONDOL signed a technology agreement in March 2021 in order to launch faster newly discovered molecules as well as to improve the delivery of generics that could be repurposed to higher-value applications if their bioavailability and release profile were to be improved.
This white paper is the 1st result of our cooperation
AcetylSalycylicAcid (ASA better known as Aspirin) is one of the most popular NonSteroidal Anti-Inflammatory Drugs (NSAID) in the world. First used as pain killer, Aspirin also brings lesser-known benefits that can be essential to prevent cardiovascular events. Further applications are also currently being developed to prevent certain forms of cancer as well as cognitive declines. Aspirin formulation is very well documented but has not really been changed for decades. So we decided to investigate the possible improvement in bioavailability in order to foster both its known usages and its repurposing for cancer or cardio vascular applications. A recent survey done in Brazil (6) with a similar model drug confirmed extrusion as a technology that can bring important benefits by obtaining formulations with improved characteristics, such as faster disintegration, higher drug solubilization, and better stability. In the case of Aspirin, extrusion could therefore help to smoothen some of its well-known secondary effects for the digestive system (5). Even with low doses, long-term toxicity can be induced for the digestive system (7) This survey therefore proposes a method to use control parameters such as drug loading, screw configuration and process temperature to demonstrate that an extrudate with a 45% acetylsalicylic acid (ASA) – 55% Soluplus® extruded at 130°C, the ASA is completely amorphous with no tendency to recrystallize after 6 weeks.
Methods, Results & Discussion
All trials were done while using 2 ASA Novacyl grades varying only in particle size. ASA grades show endothermic melting peaks (Figure 1) at 147.7 and 150.6°C for ASA 2020 (purple) and 2080 (pink) respectively.
Pre-weighed powder formulation blends of BASF Soluplus® and ASA were mixed and two parameters, drug loading (20, 30 and 50% w/w) and HME barrel temperature (120 and 130°C) were varied to investigate their effect on the physical form. Extrusions were carried out at RONDOL using a 10mm co-rotating twin-screw ‘All in One’ Vertical (L/D 40:1, feed rate of 35 rpm). XRD analysis of both ASAs (Figure 2) demonstrates that they are both crystalline and correspond to the powder pattern reported for Acetylsalicylic acid in the JCPDS.
Figures 3 & 4 contain the XRD patterns for 20 and 30% w/w ASA 2020-loaded Soluplus® blends respectively at temperatures ranging from 40 to 150°C. Figure 3 5 demonstrates that above 120°C the ASA is completely amorphous and thus dissolved in the Soluplus®, which has a glass transition temperature (Tg) of 70°C. For the 30% w/w sample (Figure 4) it is similar, at 130°C ASA is completely amorphous in the Soluplus®.
The XRD diffraction patterns for 50% w/w ASA in Soluplus® at different (40 to 135°C) temperature ranges are presented in Figures 5 and 6. The trend is similar to 20 and 30% w/w with a complete loss of crystallinity for both grades of ASA at 6 temperatures above 125°C, which suggests that the ASA is completely dissolved in the Soluplus®.
DSC analysis of the 20 and 30% w/w ASA-loaded pellets manufactured by HME at 120°C (Figure 7) shows that the endothermic melting peaks at 147.7 and 150.6°C for 7 ASA in all samples has disappeared. This is due to the ASA being in its amorphous form within the Soluplus® polymer.
XRD analysis of the 30% w/w ASA-loaded pellets (Figure 8) produced diffraction patterns with a smooth halo pattern and no diffraction peaks associated with ASA. This would further suggest that the ASA is dispersed at the molecular level and its crystallinity completely removed. This is not surprising as the pellets were manufactured at 120°C and the XRD data demonstrated that at this temperature the ASA dissolves in the molten Soluplus®. Furthermore, the mixing and shear of the extruder screws adds further heat and energy to the extrudate, consequently melting the ASA into its amorphous form and mixing it into the Soluplus®. The subsequent cooling causes the Soluplus® to solidify holding the ASA in its amorphous form.
Figure 8: XRD diffraction patterns for the 30% w/w ASA-loaded pellets manufactured via hot melt extrusion at 130°C XRD analysis of 50% w/w ASA-loaded pellets (Figure 9) indicates low-intensity diffraction peaks at 5, 15 and 23 2Thếta, similar to the ASA control (Figure 2). This demonstrates that the ASA within the 50% w/w ASA-loaded pellets has lost some of its crystalline structure as a result of some ASA being dissolved within the Soluplus®, However, the Soluplus® does not have enough solvation energy to dissolve all of the ASA. Based on this data it is estimated that 45% w/w ASA in Soluplus® should result in solid dispersions that contain completely amorphous ASA.
Figures 10 contains XRD diffraction patterns for the 30% w/w ASA-loaded Soluplus® extruded pellets 6 weeks after manufacture. The lack of any diffraction peaks belonging to ASA demonstrates that it is still in its amorphous form 6 weeks after manufacture.
Vertical extrusion offers an opportunity to convert crystalline APIs into their amorphous form, stabilized by the use of a water-soluble polymer, which makes it possible to improve their solubility and thus bioavailability. In the case of ASA, we have demonstrated that it can be fully amorphous in Soluplus® at loadings of up to 45% w/w. The ASA in the 20 and 30% w/w pellets was 100% amorphous, while the ASA in the 50% w/w pellets was approximately 90% amorphous. Based on a loading of 50% w/w, this would correspond to 45% of the ASA being dissolved in the Soluplus® and 5% remaining crystalline. Finally, we demonstrated that ASA is still in its amorphous form 6 weeks after manufacture. Any recrystallization of the ASA would be expected to occur within the first few weeks after manufacture. The fact that the ASA in these pellets remains in its amorphous form after 6 weeks is promising for their long-term stability and solid dispersions. In vitro pharmacokinetic studies would now need to be performed to validate the impact of ASA amorphization and understand the interaction between ASA and Soluplus® and its impact on bioavailability and release profile.
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