(32a) Tailored Composition of Lipid-Based Excipients for Improved Functionality in Advanced Pharmaceutical Manufacturing Processes

The key requirement for the development of innovative and robust dosage forms is the application of excipients with desired functionality. In this context, there is a growing interest in using lipid-based excipients due to their low toxicity, biocompatibility and biodegradability. The challenge is however, their unstable solid state and the high degree of crystallinity, affecting the stable performance of their products and limiting their application for certain manufacturing processes, respectively.

In previous works, we introduced polyglycerol fatty acid esters (PGFAs) available as Witepsol^® PMFs as advanced lipid-based excipients with ideal properties, such as being monophasic systems with stable polymorphic form (1, 2). In the current study, the effect of minor fractions in the composition of PGFAs has been investigated on their solid state and mechanical properties. The results have been used for tailoring the composition with defined solid state to reach ideal properties for challenging applications, such as melt extrusion and filament-based 3D printing.

Materials and methods

PGFAs are hydroxyethers of glycerol, fully or partially esterified with saturated fatty acids. As same as most other lipid-based excipients, their synthesis yields a composition of similar molecules, having defined PGFA as the main component and minor fractions of polyglycerol mono esters and free polyglycerols (PG). In this study, PG6C16p; composed of six glycerol moieties partially esterified with palmitic acid was used. Two different batches of PG6C16p with different concentrations of minor fractions were screened. The batch with higher concentrations of PG monoester and free PG was selected for further screening. A variety of free PG(n) molecules, composed of two, three, four and six glycerol moieties (n=2 to 6) were provided and systematically added to the selected PG6C16p batch, in three different concentrations; 2.6%_w/w, 8.6%_w/w and 14.6%_w/w.

Melt casted samples were provided from the PG6C16p batch (blank) and each mixture. The solid state of melt casted films in terms of thermal behavior, polymorphism, and lamellar configuration was analyzed via DSC and x-ray diffraction after preparation (T0) and after storage under long term (25°C, 65% relative humidity) and accelerated (40°C, 70% r.h.) conditions. Processability of mixtures in melt extrusion, the solid state of filaments and their quality in terms of flexibility, filament diameter and diameter distribution were investigated and compared with each other.

Results and discussion

Melt casted samples

Differential Scanning Calorimetry (DSC): The DSC data showed the similar thermal behavior of PG6C16p batch (blank) to its mixtures with different free PG. All samples displayed two endothermic peaks at T0, which were dropped to one phase after storage under both conditions. The cooling cycle also revealed two crystalline phases. The area under the curve of the cooling cycle was found to decrease with the addition of free PG, depicting less crystallinity compared to the blank (PG6C16p batch).

X-ray diffraction: The x-ray analysis in wide angle region showed a stable α-form (no polymorphism) for the blank as well as for its mixtures with free PGs. This phenomenon is typical for all PGFA molecules and described elsewhere (1).

The existence of two crystalline phases in PG6C16p batch (blank) and its mixtures with free PG was confirmed with the x-ray data in small angle region, showing two coexisting phases (hexagonal and lamellar arrangements) with two categories of d-spacing. Phase transitions toward a single lamellar phase was observed after storage, which can be explained due to existence of free hydroxyl groups with high level of polarity, triggering the system towards the phase transition. Further studies on the kinetics of phase transition showed a tempering step at 40 °C for approximately 20 minutes is sufficient for the complete phase transition to a stable lamellar phase.

Elongation of the lamellar length of PG6C16p (d-spacing) was noticed with the addition of free PGs in the following order: free PG6<PG4<PG3<PG2. Addition of free PG2 displayed the maximum elongation, whereas, free PG6 displayed the minimum elongation. This can be explained with the smaller molecular size of free PG2 compared to free PG6, providing an easier submerging of free PG2 between the lamella layers of the main component (PG6C16p) as well as the molecular similarity of free PG6 to PG6C16p. The molecular similarity was also responsible for the negligible crystal growth of main component in its mixture with free PG6 after storage under both long term and accelerated conditions. In contrary, samples of PG6C16p with additional free PG2 showed a significant crystal growth.

Melt extrusion of samples and filament quality

PG6C16p batch was processable via melt extrusion. However, upon increasing the percentage of free PG, or the number of glycerol units or both, improved processing and improved quality of the produced filaments were observed (e.g. ease of process adjustment, homogeneity and flexibility/spoolability of filaments). This can be explained by the reduced crystallinity of the main component in front of free PGs (observed in the DSC thermograms of melt casted films, explained above) and the fact that the increase of free PG in the system is associated with an increase in available sites for hydrogen bonding, which may contribute to the enhanced filament flexibility.

The WAXS analysis of filaments after manufacturing and after storage confirmed the stable α-form also in filaments. The Phase transitions toward a single stable lamellar phase also took place during the process under the effect of time, temperature, and shear.

Conclusion

A mechanistic knowledge of the composition of lipid-based excipients is essential to understand their functionality. The composition of a candidate molecule (PG6C16p) belonging to the group of PGFA excipients was successfully tailored through the fine-tuning of its minor fractions. The molecular similarity between the main component and minor fractions was essential for providing stable solid state. The smart balance between the components resulted in reduced degree of crystallinity in the main component. Adjusted degree of polarity in the system provided extra potential sites for hydrogen bonding. These two behaviors were the key parameters for improving the processability via melt extrusion. The resulted filaments showed advanced properties for 3D printing. This work is an important step towards the extending the functionality of lipid-based excipients for advanced pharmaceutical manufacturing processes.

Acknowledgement

The Austrian Research Promotion Agency (FFG)

References

1. Corzo C. et al., (2020), European Journal of Pharmaceutics and Biopharmaceutics, 148, 134–147. https://doi.org/10.1016/j.ejpb.2020.01.012
2. Salar-Behzadi S., et al., Structure - function analysis of lipids for the development of advanced excipients for pharmaceutical manufacturing, AIChE Annual Meeting 2021

Keywords

Pharmaceuticals (Chemicals & Materials), Lipid-based excipients, Structure-Function of excipients; Pharmaceutical Engineering & Drug Delivery, Pharmaceutical Development