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Comparing the Surface Energetics and Mechanical Properties of two Potential Sub-micron Sugar
Bulking Excipients for use in Low-dose, Suspension Formulations in Metered Dose Inhalers
Jeff James,a* Clive J Roberts,a Martyn C Davies,a Richard Toon,b Phil Jinks.b
aSchool
of Pharmacy, Laboratory of Biophysics and Surface Analysis, The University of Nottingham, UK b; 3M Drug Delivery Systems, Loughborough, UK
Highly potent, low-dose active pharmaceutical ingredients (APIs) may require the incorporation of a bulking excipient within a suspension formulation in order to reduce the variability of the delivered dose between actuations from a pressurised metered dose inhaler (pMDI). This
study compares the characteristics and processing of two potential bulking excipients, anhydrous sub-micron α-lactose and sub-micron sucrose. The dispersive surface free energy and Young’s Modulus were determined for each sub-micron material, their respective parent materials
and any intermediates. The adhesive interactions of the potential sub-micron bulking excipients were then assessed against a selection of APIs. Salmon calcitonin was also investigated due to the current interest in, and the potential low dose requirements for, the pulmonary delivery
of proteins.
Method
Results
Right: Surface energy values for sub-micron sucrose
and its parent material. Sub micron sucrose has a lower
surface energy than silk grade sucrose.
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Functionalised AFM Tips
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α-Lactose
Monohydrate
Micronised α-lactose
monohydrate
Surface free energy (mJm-2)
Fig. 3. Left: Surface energy values for anhydrous submicron α-lactose and its parent materials. A significant
increase in surface energy is seen upon micronisation,
an effect which is reversed following high pressure
homogenisation
Surface free energy (mJm-2)
Surface Energy Determination
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Anhydrous Sub micron α-lactose
Silk Grade Sucrose
Sub-micron Sucrose
Fig. 2. Top: SEM image of anhydrous sub –
micron α-lactose. Bottom: SEM image of sub
– micron sucrose.
Young’s Modulus Determination
Young’s Modulus E (GPa)
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Right: Young’s modulus values for sub-micron sucrose and its
parent material. Processed sub micron sucrose is a softer
100 µm
material than silk grade sucrose.
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α-Lactose Monohydrate
•The surface energies of each sub-micron excipient, along with their
respective parent materials and any intermediates, were determined using two
Atomic Force Microscopy (AFM) methods. The results were calculated for
each material based upon the Johnson-Kendal-Roberts theory.
Micronised α-Lactose Monohydrate Anhydrous Sub-Micron α-Lactose
Silk-Grade Sucrose
Lactose Materials
Sub-Micron Sucrose
Sucrose Excipients
API – Excipient Particle Interaction
•Similar AFM based force measurements were determined to quantify
nanoscale elastic deformation and hence, Young’s Modulus.
•The adhesive interactions of each sub-micron bulking excipient were
determined with formoterol fumarate, salmeterol xinafoate, mometasone
furoate and salmon calcitonin using colloid probe AFM (salbutamol sulphate
was also assessed as this is a pulmonary API that is commonly used in the
literature).
Fig. 5. The adhesion of each sub – micron excipient to five different APIs
potentially employed in pMDI formulations. With the exception of salmon
calcitonin, sub-micron sucrose showed larger adhesive interactions to the selected
APIs than anhydrous sub–micron α-lactose.
Force of Adhesion (nN)
Fig. 1. The principle of AFM
Fig. 4. Left: Young’s modulus values for anhydrous sub-micron
α-lactose and its parent materials. A decrease in hardness is
observed following both micronisation and homogenisation
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Young’s Modulus E (GPa)
School of Pharmacy, The University of Nottingham
Introduction and Background
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Anhydrous Submicron α Lactose
Sub-micron
Sucrose
Salbutamol Mometasone
Sulphate
Furoate
Salmon
Calcitonin
Formoterol
Fumarate
Salmeterol
Xinafoate
Conclusions
•Anhydrous sub–micron α-lactose has been found to have lower adhesive interactions with a range of chosen APIs compared to sub-micron sucrose.
•This could be related to the lower surface energy of anhydrous sub-micron α-lactose as determined by AFM.
•However, the significance of these results needs to be assessed during the development phase of a real pMDI suspension formulation.
•The higher levels of adhesion of sub-micron sucrose with APIs, compared to anhydrous sub-micron α-lactose, may not be detrimental to the overall shelf-life of a suspension formulation.
•Young’s Modulus, as determined by AFM, can also offer an insight into the processing of such materials as softer crystal structures can potentially be processed more easily to give smaller particle sizes.
•Both a knowledge of the surface free energy and the mechanical properties of potential bulking excipients could provide useful information during the processing and development stages of such materials
For further information
Acknowledgements
Please contact the author*
The author gratefully acknowledges Prof. Xinyong Chen for valuable advice and
assistance regarding the use of AFM. Matt Bunker and Barry Crean (LBSA), for their help
and support, and finally 3M Drug Delivery Systems and The University of Nottingham P.
forJinks. Preparation and utility of sub – micron lactose: a novel excipient for HFA MDI suspensions formulations. Drug Del. Lungs XIV:
their financial support of this research.
Email: [email protected]
More information on this and related projects can be obtained at
URL: www.nottingham.ac.uk/lbsa
References