Particle size shapes up

Stefanie Christian and Dr Karl Wagner, chair of pharmaceutical technology, university of Tuebingen, Germany, show how the uniform release of active substances is a function of particle size and shape, by using the CAMSIZER digital imager processing system.

Pharmaceutical granules are, from a technical point of view, agglomerates that usually consist of a mixture of an active ingredient and various excipients. The granules can be prepared by different methods, one of which is dry granulation, a simple and rapid method.Powder mixtures containing the active substance are compressed with tablet presses or roller compactors to form larger units and are then reduced to the required granule size by using mills or sieve granulators. The different granule sizes produced in this way naturally have irregular shapes.

Granulation is often used for obtaining a particular mixture quality as well as for improving the flow and compression properties of the powder mixture. A more recent application is the use of dry granules as an independent form of drug, which release the active substances as uniformly as possible throughout a certain period (8-12 hours). These so-called retard drug-forms benefit the patient by having longer administration intervals and accordingly a reduced administration frequency when compared with conventional drug forms.

shape and size

The greater the surface area in relation to the volume of the individual particles, the quicker the active substance will be released from the matrix. Small granules have a large surface area in comparison with their volume.

This means that, in comparison with large granules, more solvent molecules can attack and the active substance will be released more quickly.

In order to be able to predict this release behaviour knowledge of the surface area and volume of these irregularly shaped particles together with their distribution is required.

The individual granule fractions are inhomogeneous particle collectives that are very different as regards their shape and size. This means that classification using a simple spherical model (sphere diameter = class midpoint of the sieve fraction) or conventional image analysis systems is not possible. Compared with these, the Camsizer dynamic image analysis system from Retsch Technology is an efficient alternative and allows a rapid, non-invasive determination of the particle size and shape for pourable bulk goods (Manufacturing Chemist April 2005, p17). In the Camsizer, a vibratory feeder transports the granules to a free-fall feed shaft equipped with a light source and two high-resolution CCD cameras with different image scales.

During the free fall of the sample the individual particles of the granule fractions are recorded by the cameras and evaluated in real time. This is a non-destructive method; the measuring time per run is about five minutes. In addition to image analysis, parameters such as mean particle size, length, width, length/width ratio, roundness, symmetry and convexity, a surface/volume ratio (Sv) can also be determined. For the calculation of the Sv ratio various calculation models are available: the sphere and various ellipsoids (Figure 2).

The example given below uses dry granulation to granulate the antiasthmatic agent theophylline together with ammonium methyl methacrylate copolymer (Eudragit RS PO) and ethyl cellulose (Ethocel Standard 10 FP Premium).

Their in vitro theophylline release behaviour was studied as a function of their particle size and shape. The aim is to correlate these parameters to develop a model for predicting release profiles from unknown granule fractions. In order to investigate the predictability of the system described, the granules obtained are separated into five different fractions with the following sizes: 2-2.8mm / 1.4-2mm / 1-1.4mm / 0.71-1mm / 0.5-0.71mm.

The Eudragit RS PO and the Ethocel Standard 10 FP Premium are used to form a matrix that is inert to physiological liquids, in which the active substance theophylline is embedded. The quality-determining parameter of the granules obtained in this way is the amount of active substance released from the granules per unit time. This release takes place in two steps: first water wets the active substance located on the surface and dissolves it. Then the dissolved active substance molecules leave the matrix system by diffusion.

Initially, the diffusion paths are short as the active substance is close to the surface. In time these diffusion paths become longer as the diffusion front moves toward the interior of the particles so that the amount of active substance released per unit time decreases. Figure 1 shows the diffusion front after 10 hours release.

The measuring and evaluation of the studied theophylline matrix granules produced elongated and symmetric particles, so that the calculation of the Sv ratio was based on an ellipsoid, figure 2. This ratio was determined for all size classes and represents the granule fraction with respect to these two parameters.

relationships

There is a mathematical relationship between the rate of active substance release and the surface/volume ratio of the granules. If the cumulative amount of released theophylline is considered as a function of time then different release profiles are obtained for the various size fractions. These can be described by using the Weibull function. The reference parameter (k_63.2%) is the time at which 63.2% of the active substance that it originally contained has been released from the granule.

The release profiles and their associated k_63.2% values are shown for the five different size fractions in figure 3 and table 1. As the release from large particles is slower than that from small particles because of the smaller surface/volume ratio, the value for the parameter k_63.2% increases as the size of the granule increases.

A requirement for the model validity is that the surface area and volume of the individual particles do not change during the release process. This is ensured by the added excipients.

By determining the Sv ratio, see table 2, with the Camsizer for the various fractions it is possible to make a correlation between the release parameter k_63.2% and the image analysis data.

As shown in figure 4, there is a linear relationship between k_63.2% and the surface/volume ratio. With this straight-line equation and the Weibull function the release profile can be predicted for any granule fractions, provided that the size and surface/volume ratios are known. The Camsizer digital image processing system is an efficient and time-saving alternative to conventional image analysis for characterising the size and shape of inhomogeneous particle collectives.

By determining the surface/volume ratio it is possible to describe the individual granule fractions exactly.

Data obtained in this way can be correlated with the release parameter k_63.2% and in future will permit a prediction to be made about the release profile of unknown granule fractions.