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The Effect of Mill Type on Two Dry-Granulated Placebo Formulations
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.
The solid fraction of each ribbon sample was determined according to a relationship that can be expressed by the following equation:
in which w is the ribbon width, l is the ribbon length, t is the ribbon thickness, m is the ribbon mass, V s is the volume of the roller serrations, and ρ t is the true density of the material.
The tensile strength of the compact can be determined from the following relationship:
in which σ T is fracture tensile strength, F is the load applied at fracture, W is the width of sample, L is the distance between beams 2 and 3, and t is the thickness of the sample.
Tableting was performed using a rotary tablet press (T-100, Kilian) at a press speed of 60,000 tablets/h to produce a dwell time of ~11 ms, which approaches a production-press speed dwell time of <10 ms. A precompression force of approximately 1 kN was used for all compression runs. The tooling size was selected based on the target tablet weight of 225 mg (5/16-in. standard round concave tooling typically accommodates a fill weight of 200–250 mg). A compression profile was generated for each granulation up to approximately 80% (30 kN) of the maximum allowable force (37 kN) for the tooling size.
Compaction parameters. Ribbon solid fraction is considered to be the physical attribute with the greatest influence on the physical properties of a dry granulation. The typical compacted ribbon solid fraction range for a conventional IR tablet formulation is 0.6–0.8 (2, 3). Therefore, a target solid fraction of 0.7 was selected to evaluate mill performance. Solid fraction, or relative density, is the measure of the ribbon's apparent density (sample volume in cubic centimeters divided by its mass in grams) divided by the material's true (i.e., absolute) density.
Previous experience with the Gerteis roller compactor influenced the process parameters selected for ribbon compaction except the roll type and roll force. A ribbon thickness >1.0 mm was unobtainable for the microcrystalline cellulose (MCC)–dibasic calcium phosphate (DCP) formulation using smooth rolls. However, the target ribbon thickness of 2.5 mm was obtainable when serrated rolls were used. Therefore, serrated rolls were used to compact both formulations.
A series of compaction trials were performed for both formulations to determine the roll force required to achieve the target ribbon solid fraction. A roll force of 8 kN/cm2 was selected as the best roll force for the MCC–DCP formulation, and a roll force of 6 kN/cm2 was selected for the MCC–lactose formulation. Although two different roll forces were used, both formulations were compacted using a roll gap of 2.5 mm, a roll speed of 2.0 rpm, and a feed ratio of 250 to produce ribbon at the target solid fraction of 0.7.
Results and discussion
Ribbon bypass level. Because the level of bypass generated during the compaction process influences the fines level in the milled granulation, it was relevant to measure the bypass level before ribbon milling. Bypass is defined as uncompacted primary particles of active pharmaceutical ingredient or excipients that migrate around the rolls without being subjected to any compaction force.
The dry-granulation bypass level was measured by removing the bulk of the ribbon from the compacted material by hand and sieving the remaining material through a 100-mesh (150-μm) sieve. The material that passed through the 100-mesh sieve is mainly uncompacted primary particles and is considered bypass. Using this method, the amount of bypass measured for the MCC–DCP formulation was 2.4% (ribbon bag #10). The amount of bypass measured for for the MCC–lactose formulation was 2.1% (ribbon bag #10).
The MCC–lactose formulations produced tablets of a lower crushing strength than those of the MCC–DCP formulations for all the mills evaluated. Although all the granulations performed similarly, some differences in tabletability and compactibility were evident. One noteworthy difference was a higher tablet-crushing strength for the Gerteis-milled material. Tablets had an approximately 0.5 MPa higher strength compared with the other milled lots. The authors found no definitive explanation for these results.
Although all the granulations have a flowability rating of good, the Gerteis granulation had the lowest value of 8.0, compared with the 9.1 and 9.0 for the M5A and Comill, respectively. The lower flowability value suggests a higher level of smaller particles in the granulation and correlates with the laser-diffraction data showing the Gerteis material having the smallest D10 and D50 particle-size values. However, the Gerteis material also has the highest D90 value and the greatest breadth of particle size for the three granulations. The smaller particle size and greater breadth of this granulation may contribute to the higher tabletability and compactibility observed. Also, the difference in particle size could be attributed to the ribbon properties.
Overall, formulation composition, not mill type, had the most significant effect on compaction properties. Compression using a high-speed rotary tablet press confirmed that differences in the formulation composition had an effect on tabletability and compactibility and that mill type did not significantly influence the tabletability and compactibility of the formulations.
The authors acknowledge Barbara Spong's active support of this study.
Thomas A. Vendola* is a scientist in solids development, and Bruno C. Hancock is a research fellow in material sciences at Pfizer, Eastern Point Rd., Groton, CT 06340, tel. 860.441.4430, fax 860.441.3972,
*To whom all correspondence should be addressed.
Submitted: Jan. 28, 2008. Accepted: Mar. 20, 2008.
and we may post them to the site.
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