(463f) Structure - Function Analysis of Lipids for the Development of Advanced Excipients for Pharmaceutical Manufacturing

The gradually increased expenses of global pharmaceutical R&D can be explained by: i) the rising number of new FDA approvals in the recent years, ii) increased awareness of pharmaceutical companies of the sustainability of their production (1) and iii) increased awareness of the specific requirements of patients as individuals (2,3). These trends are closely associated with the demand for innovative and robust dosage forms with stable performance. Using excipients with desired functionality is the key parameter for realizing this demand. In this context, lipid-based excipients (LBEs) have been increasingly applied for several reasons. LBEs are naturally occurring materials that are predominantly digestible and have a “Generally Recognized as Safe” (GRAS) status. They are low-toxic, biocompatible, easily available and they are used for manufacturing a broad range of pharmaceutical dosage forms. The serious challenge, however, is their unstable solid state, which affects the stability and robustness of pharmaceutical products.

In this work, the ideal properties of LBE are defined from molecular to macroscopic level. Following this definition, polyglycerol fatty acid esters (PGFAs) available as Witepsol^® PMFs are introduced as such LBEs and their structure-function relationship are analyzed with some examples for their application as advanced LBE in the development of pharmaceutical dosage forms.

Ideal properties of LBEs can be defined as:

• Direct crystallization or a fast transformation into the most stable polymorphic form (no polymorphism).
• Being a one-phase system to avoid phase separation and crystalline growth during the storage.
• Diversity in the functional groups of the chemical structure in order to offer diversity in the physicochemical properties in the macrostructure level. This limits the need for additives to the formulation and thus limits the crystal growth and alteration in the crystalline network.

Polyglycerol fatty acid esters (PGFAs) and their structure-function relationship

It is known that a polymorphic change, for example in mono- di- or triacylglycerols, is due to intermolecular non-covalent interactions between hydrocarbon chains, causing the sub-cell rearrangement toward the most thermodynamically stable geometry. Therefore, providing enough space between the chains can be a reasonable way to avoid polymorphic transition. In this context, polyglycerol esters of fatty acids (PGFAs) are promising molecules.

PGFAs are hydroxyethers of glycerol, fully or partially esterified with fatty acids (Figure 1). The larger space among hydrocarbon chains of a PGFA molecule, which is caused by the ether bonds connecting the glycerol moieties, can weaken the intermolecular interactions between the chains and thus avoid a polymorphic transformation. Analyzing the thermal behavior of selected PGFAs as received and after 6 months storage at 40 °C via X-ray diffraction and DSC revealed the crystallization of all samples into the stable monophasic α-form without transformation during storage (4-6).

Tuning the number of glycerol moieties, fatty acids chain length and free hydroxyl groups per molecule resulted in different hydrophilic-lipophilic balance (HLB) values, wettabilities, melting points, and melt viscosities (4). Structure-function relationship analysis of PGFAs showed that an increase in available free hydroxyl groups results in shifting to smaller, less dense and more disordered crystal clusters. The HLB value was also increased by increasing the number of glycerol moieties and/or available number of free hydroxyl groups (partial esterification). As expected, the HLB value was directly correlated with the wettability of molecules. An increase in the number of glycerol moieties and thereby increased number of hydroxyl groups also resulted in the increased melt viscosity of PGFAs, which is due to the lower mobility of the long chains and the availability of polar groups for hydrogen bonding. The melting temperature was directly correlated with the length of the fatty acid chain.

Application of PGFAs in the development of pharmaceutical dosage forms

Selected compounds were used as hot melt coating (HMC) excipients (5), for manufacturing of solid lipid nanosuspensions (SLN) (6), spray-dried particles for inhalation as well as for cold extrusion.

Hot melt coating: The HMC trials were performed in a fluid bed equipment. N-acetylcysteine was coated with three PGFAs with different HLB values: PG3C16/C18-partial, PG4C18-partial and PG6C18-partial (Witepsol^® PMF 1683, 184, and 186). The DSC data showed the absence of low solidification fractions, thus reduced risk of agglomeration during the coating process. The driving force for crystallization was lower and the heat flow exotherms were broader compared to conventional HMC formulations, indicating a lower energy barrier for nucleation. The API release was directly proportional to HLB and was stable during storage (5).

Manufacturing of SLN: SLN were produced via melt-emulsification followed by high pressure homogenization using PG2C18-full (Witepsol^® PMF 282) as lipid matrix and poloxamer 188 as stabilizer to encapsulate the model API dexamethasone. SLN with an API loading of 0.1%, a sharp median particle size of 242.1 ± 12.4 nm, a zeta potential of -28.5 ± 7.8 mV, an entrapment efficiency (EE) of 90.2 ± 0.7% were produced. The crystallization of the lipid matrix in the stable α-form was not affected by process conditions or material interactions. Stable EE and release profile during storage was observed. The pulmonary in vitro safety of SLN was given (6).

Manufacturing of spray-dried particles for inhalation: Lipid-microparticles for systemic delivery were loaded with ibuprofen under an organic solvent-based spray drying process. PG3C22-partial (Witepsol^® PMF 123) was used as the lipid matrix in a lipid:drug ratio of 70:30. The process resulted in high yield of solid particles (71%). Particles with unimodal size distribution, volume mean diameter (VMD) of 6.6 ± 1.1 µm and density of 0.389 ± 0.007 g/cm3 were achieved. The mass median aerodynamic diameter (MMAD) of particles was 3.57 ± 0.11 µm, indicating the inhalability of the particles. The fine particle fraction (FPF) was 45.2 ± 1.6%. Dissolution of the deposited particles in simulated lung fluid (SLF) showed stable modified release within 6 hours.

Cold extrusion: PG6C16-partial and PG2C18-full (Witepsol PMF166 and 282, respectively) were processed via cold extrusion at temperatures below their melting onset. Both materials were extrudable, resulting in filaments without die swell and a homogeneous diameter distribution. Filaments of PG6C16-partial showed improved elasticity and spoolability compared to PG2C18-full, which can be explained by higher number of glycerol moieties. These filaments can be either processed into multiparticulate systems in a further down-streaming step or can be used for printing of solid dosage forms via extrusion-based 3D-printing. Loading of API in the filaments is currently under investigation.

Conclusion

The stable release profile of API from HMC particles, SLN, and spray-dried powder for inhalation, and the stable particle size distribution and EE of SLN over storage were attributed to the monophasic crystallization of PGFAs into stable α-form and no crystallite growth. In all case studies the release profile could be tailored based on the HLB of selected PGFAs. In case of SLN, the application of PGFAs as stable lipid matrices, without the addition of oils, can pave the way for developing next generation SLN. The extrudability of PGFAs in flexible filaments plays an essential role in the extension of LBE application in pharmaceutical drug development.

Acknowledgement

The Austrian Research Promotion Agency (FFG)

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