(138c) A Novel Metrology for Polymodal Particle Size Distributions and Its Beyond Application in Twin Screw Granulation

Patient preference is for the oral administration of drugs as tablets, which also provides simply control over the dosage given. However, in the majority of the cases, the drug cannot be tabletted directly due to inappropriate powder properties and granulation to control powder properties is one of the key steps in a pharmaceutical tablet manufacutirng process. This is further complicated by the addition of excipients to modify and control physical properties but which also can influence drug release in the patient.

The most common granulation approach is the wet method which is traditionally done as batch unit operation. Currently, there is a drive within the pharmaceutical industry to adopt continuous processes and one of the most commonly used pieces of equipment for this purpose is the twin screw granulator (TSGs). TSGs provide shorter residence times, greater flexibility in granule properties and the ability to vary the required throughput without associated hazards (1).

The equipment can be described as a barrel which contains two co-rotating screws which act as agitating conveyor belts. Initially the powder is fed into the barrel, before the liquid binder is added to induce granulation. The co-rotating screws can be easily modified by configuring different screw elements or changing their position along the barrel length. Different screw configurations will modify how contact between the particles is produced and, therefore, the properties of the final granules. A broad range of outcomes can be achieved by altering these elements as well as other factors such as liquid/solid ratio, feed rate and rotation speed.

Amongst all the possible granule properties particle size is critical in pharmaceutical manufacture and currently this is studied by separating the sample into discrete size classes and measuring the relative amount of particles within a specific size interval which is expressed as particle size distribution (PSD). Unlike other properties such as friability or flowability, particle size distributions are expressed as a curve, which does not allow its direct examination as a quality attribute or a process control variable.

The most common solution to compare volume particle size distributions is the use of the d50 combined with the span calculated by gathering d10, d50 and d90 which are the intercepts for 10, 50 and 90% of the cumulative volume. The closer the span value is to zero the more homogeneous the particle size distribution. However, this analysis is only acceptable when the particle size distribution is unimodal and therefore its shape is lognormal, otherwise it will introduce a considerable error when the distributions show more than one peak and the peaks are located around the mean diameter.

Multiple peaks distributions can be very common in research before the equipment has been optimised. However, they are very difficult to compare without a numerical factor. As a solution, a methodology based in the hyperbolic tangential method (2) was developed and used for measuring homogeneity of particle size distributions. The method is able to calculate the homogeneity of PSDs with different shapes as a percentage allowing easy numerical comparison. On the contrary to span, the method responds to different modifications such as the addition of peaks, increments on the variation of the distribution or discrepancies between the main diameter and main particle size class. Using homogeneity as a quantified quality attribute leads to a better understanding of powder technology and its possible implementation as characterisation tool in the design and control of wet granulation systems.

The improvement of this method with respect to the traditional measures such as span was demonstrated through the comparison of PSD curves with different shape but similar span (3). In addition, the potential of the quantification of homogeneity was demonstrated through the application to simple wet granulation with two different excipients. In both cases, it was demonstrated that knowledge of the d50 alone does not give enough information for the ideal conditions to operate or which operational parameters have more influence on the process.

Understanding of the underlying process mechanisms of a new technology requires to be accomplished with a systematic scientific risk-based methodology. In the pharmaceutical industry, this approach is recognised as Quality by Design (QbD) and it has been recommended for adoption (4). Hence, using homogeneity as characterisation tool for PSD can be potentially advantageous. It could be used in the comparison of different batches and technologies on both a research and industrial scale as well as being a useful complement to other granule properties such as flowability or strength in the optimisation of tabletting and associated processes.

In a research context, it can be employed by defining a desired diameter operating point and controlling the homogeneity around that point. That will allow the identification of when the process is within product specifications. The benefit of this parameter has been applied to find the most homogeneous points for three different diameters (400, 600 and 800 μm) of α-lactose monohydrate and study the differences in the granular structure.

Studying the internal parameters of the granules will help to understand the formation of the granules within TSG and to compare performance with conventional batch equipment. The microporosity of the samples is determined by Quantrome Autosorb IQ2 and the granules are scanned by MULTISCALE X-ray nanotomograph SKYSCAN 2211 and processed in Matlab and Statistics Toolbox.

Despite the various advantages of twin screw granulation over batch granulation, this technology is not yet fully applicable outside the research and development phase. As a result of this, it has not been fully adopted in large scale industrial pharmaceutical manufacture. As such the current study aims to increase the understanding of this technique, it is hoped the study of the granular internal structure and the development of a homogeneity factor will enable the development of twin screw granulation as a suitable technique for widespread use both in academia and industry.

REFERENCES:

(1) Iveson, Simon M., et al. "Nucleation, growth and breakage phenomena in agitated wet granulation processes: a review." Powder technology 117.1 (2001): 3-39.

(2) Passe, T.O.R.E. "Grain size distribution expressed as tanh-functions." Sedimentology 44 (1997): 1011-1014.

(3) Torrecillas, Carlota Mendez, Gavin W. Halbert, and Dimitrios A. Lamprou. "A novel methodology to study polymodal particle size distributions produced during continuous wet granulation." International journal of pharmaceutics519.1 (2017): 230-239.

(4) ICH Expert Working Group. "ICH Harmonized tripartite guideline. Pharmaceutical development Q8 (R2)." International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2009.