The particle-size distribution of a pharmaceutical granulation is an important physical characteristic that influences several aspects of a drug (e.g., mechanical properties, content uniformity, compression characteristics, and dissolution performance). Therefore, it is important to control the particle size of the final granulation to ensure drug-product manufacturability and quality. Various mill types currently are available for the size reduction of dry- and wet-granulated pharmaceutical products. To evaluate these milling technologies and their influence on dry-granulated (roller-compacted) formulations, four different mill types were selected for comparison.
Conventional milling is a mechanical process that passes material through a screen or plate to reduce its size into a uniform particle-size distribution. It has been proposed that mill type directly influences particle-size distribution and, consequently, the quality of the final product. However, other variables also influence the milling process. Engineering design differences such as screen size and thickness, impeller and rotor style, and mill-chamber size and shape all affect material-size reduction. Formulations' physical properties determine how well materials maintain their bonds or shear under stress. Operational variation such as impeller and rotor speed and material feed rate may also influence the final particle size.
The ideal pharmaceutical granulation process should provide short residence time in the mill chamber and pass granules quickly through the mill screen while maintaining the integrity of the granule. The strength of the material being milled has an effect on the final granulation particle-size distribution. Hard granules may increase residence time within the milling chamber and produce an excess of large granules in combination with smaller fine particles, thus creating a bimodal particle-size distribution. Minimizing fines in the final granulation enhances the flow properties of the final granulation and improves weight variation during tableting. An ideal particle-size distribution should minimize the level of granules >840 μm (retained on a 20-mesh sieve) and the level of particles <74 μm (passing through a 200-mesh sieve). Most modern mills have variable-speed drives, and are considered low-energy mills when operated at low speeds (i.e., <1000 rpm). Such mills produce granulation within this desired particle-size range and are commonly used within the pharmaceutical industry for granulation-size reduction.In this experiment, two immediate-release (IR) dry-granulation placebo formulations were selected to evaluate mill performance. Roller-compaction conditions were established using a roller compactor (Mini-Pactor, Gerteis Maschinen + Processengineering, Jona, Switzerland) to produce ribbon at a target solid fraction of 0.7. Ribbon was manufactured from both formulations and characterized for solid fraction, tensile strength, and thickness. Roller-compaction bypass was measured to establish the fines level within the compacted ribbon before milling. Three well established conventional milling options and one unconventional milling operation were compared head-to-head, and the resulting granulation was evaluated for particle-size distribution, flowability, tabletability, and compactibility.
Materials and methods
Mill types. Three established attrition mill types, an oscillating granulator (integrated with the Gerteis roller compactor), a conical mill (Comil model 197, Quadro Engineering, Waterloo, ON, Canada), and a hammer mill (FitzMill model M5A, Fitzpatrick, Elmhurst, IL), were selected to compare size-reduction performance. In addition, the authors selected a less conventional nonattrition roller mill (Gran-U-Lizer, Modern Process Equipment [MPE], Chicago) to be evaluated.
Oscillating granulator (mill integrated with roller compactor). The principle of an oscillating granulator is to mechanically pass compacted material through a wire mesh screen or plate using an oscillating rotor. The rotor speed and rotation time are variable in the clockwise or counterclockwise directions. Particle size is controlled through mill-screen size, rotor speed, and the rotor's rotation angle (1).
Conical mill. The conical mill is an attrition-type mill and performs size reduction using a rotating wedge-shaped impeller inside a conical screen. Particle size can be changed using interchangeable screens and impeller styles. The impeller selected for this study was a high-throughput, round, leading-edge impeller, and particle-size reduction was controlled with screen size and impeller speed (1).
Comminutor hammer mill. Comminutor hammer mills are also considered attrition-style mills and reduce the particle size with several rotating hammers or knives or a rotor bar. The blade type, speed, and screen size are the important variables that influence the milling process (1). The rotor bar was used for this study, and particle size was controlled by screen size and rotor speed.