(203a) The Effect of High Shear Blending on Lactose Alpha-Monohydrate

Title: The effect of high shear blending on lactose α-monohydrate

Authors: Dr Rachel Bridson, Dr Phillip Robbins, Dr Charles Gillham, Professor Jonathan Seville.  

Abstract

Introduction: Lactose α-monohydrate is a common pharmaceutical excipient used extensively in inhalable drug formulations in particular with dry powder inhaler devices (Boerefijin et al. 1998, Zeng et al. 2001).  It has two key roles in such formulations:

1. to dilute the active drug so a convenient dose size can be produced.  (A number of inhalable drugs are very potent and only a few micrograms of the active drug are required).
2. to provide a powder that can easily flow from the inhaler.  The active drug will be micronised to an aerodynamic diameter of 1 ? 5 μm to allow deep penetration into the lungs.  As powders in this size range are very cohesive, the active is mixed with an excipient of a mean particle size of ca. 70 μm to provide a freely flowing powder mixture (Zeng et al. 2001). 

The particle size distribution of the excipient is very important in how the formulation will behave when flowing from the inhaler device.  In particular, the number of fine lactose particles (in the same size range as the drug) plays a key role in determining how much drug is available to penetrate the lungs (Boerefijin et al. 1998, Zeng et al. 1998). The pharmaceutical industry has historically used high shear blenders to mix the active drug with the excipient.  Although there are numerous studies investigating how the active drug and the excipient interact (Jashnani et al. 1995, Young et al. 2005, Price et al. 2002, Zeng et al. 1998) and how the drug formulation acts on discharge from the inhaler device (Shekunova et al. 2003, de Boer et al. 2003), little information is available on how the blending process, and the way in which the excipient powder is stored before blending, affects the formulation.  This study has investigated the effect on lactose α-monohydrate only, as this will typically make up ~ 98% of the material in the formulation, and so a considerable influence on the formulation behaviour.  

Experimental Work: The work studied the effect of storage of lactose (20°C / 40% RH and 20°C / 70% RH) and changes in the high shear blender (time of blend, blade speed, design of blade, wall temperature of blender and headspace humidity of the blender) on the final particle size distribution of the lactose measured by dry powder laser diffraction (Sympatec).  The focus was on the lactose fines (i.e. particles around 1 ? 5 μm) and so a lens that allowed measurement in the range 0.1 μm to 150 μm was used. The bowl of the high shear blender was free to spin and this allows the torque on the bowl to be measured via a force transducer (Knight et al. 2001). The power input, P (W) into the powder during the blend depended on this force via

where R (m) is the distance from the central axis of rotation to the force transducer, F (N) is the force measured by the transducer and N (rpm) is the rotational speed of the blade.  The force measured will depend on the blade speed (N), with normally an increase in speed leading to a higher force.  The energy input E (J) between times t₁ and t₂, is then

Results: Storage and energy input effects dominated.  For lactose stored at 40% RH, an increase in energy input led to an increase in the d₅ size reading which indicated a reduction of fine material in the blend.  For lactose stored at 70% RH, a more variable picture was seen as the particle size of the starting lactose increased with time of storage.  After about 2 months storage blending of the 70% RH stored lactose gave a decrease in d₅ (i.e. an increase in fine mass). Blade design was seen to have some effect with the 40% RH lactose with a knife edged blade tending to give an increase in d₅, and a blunt blade a decrease.  However the variations in blade speed, blender wall temperature and headspace humidity did not have a significant effect. In addition to the experimental work, a simple model was developed to predict the temperature of the powder during the blend based on the energy input.  Being able to model the temperature rise of the powder is important, as the relative humidity of the blend has a very strong influence on how the active drug and the lactose excipient interact (Price et al. 2002).  The temperature is the key parameter for the relative humidity as there is little ?free' water in the lactose that can be released.  

Conclusions

• Storage of lactose α-monohydrate has a major impact on its blending characteristics.
• The energy input into the powder during the blend alters the particle size distribution of the lactose.
• Blade design has an effect on the particle size distribution but it is less important than the storage and energy effects.
• Wall temperature, head space humidity and blade speed did not have a significant effect.
• It is possible for a simple energy balance model to match the temperature change of the powder during blending.

 
References:

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