The Effect of Mill Type on Two Dry-Granulated Placebo Formulations - Pharmaceutical Technology

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The Effect of Mill Type on Two Dry-Granulated Placebo Formulations
The authors evaluate the effect of various mill types on particle-size distribution, flowability, tabletability, and compactibility.

Pharmaceutical Technology
Volume 32, Issue 11, pp. 72-86

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.

Roller compaction

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

Table III: Ribbon characterization.
Ribbon properties. Three ribbon samples were collected from each formulation and characterized for solid fraction, tensile strength, and thickness for each ribbon portion collected (~1.0 kg) during the compaction run. A total of 11 sample points were collected for the MCC–DCP formulation, and 13 sample points were collected for the MCC–lactose formulation, corresponding to process times of 84 min and 113 min, respectively. Table III lists the ribbon bag number and corresponding measured solid fraction, tensile strength, and thickness values for each 1.0-kg portion collected.

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).


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