Issue link: https://www.e-digitaleditions.com/i/1267517
Tablets & Capsules July 2020 13 Proof-of-concept study Table 1 shows the composition of the proof-of-con- cept tablets. The drug loading was 35 percent in the for- mulation, and microcrystalline cellulose was used as filler/ diluent. Since the product is an immediate-release tablet, the scientists added croscarmellose sodium as a super dis- integrant. Magnesium stearate was used as a lubricant. For the dry granulation step of the proof-of-concept study, the scientists used a lab-scale Freund-Vector TFC roller compactor. Prior to tableting, they analyzed the blend's bulk density, tapped density, particle size distri- bution, and Flodex. The scientists then compressed a batch of 2,000 tab- lets using a rotary tablet press equipped with a gravity feeder and experienced no issues during the tableting process. The scientists then analyzed the tablet physical properties, compression forces, and dissolution. The physical properties of the tablets are provided in Table 2, along with the blend's Flodex. The tablet hardness was 4.46 kilopascals, the tablet thickness was 3.55 millimeters, and the friability was 0.03 percent. The Flodex of the final blend was found to be 6 millimeters, indicating a good level of flowability. The disintegration time of the tablets was found to be 31 sec- onds, with 90 percent of Compound X released within 30 minutes of the dissolution. Blend compaction during initial scale-up study For scale-up, the scientists initially manufactured an intermediate batch of 50,000 tablets using the same oped during the scale-up—from proof-of-concept scale to pilot scale—of a roller-compacted tablet formulation. The scientists had elected to manufacture the tablets using dry granulation because the formulation's active pharmaceutical ingredient (Compound X) had poor flow- ability along with the added challenge of possible water-related instability. Compound X was available in its salt form and had been formulated for the proof-of-con- cept study as 12.5-milligram, 35-milligram, and 70-milli- gram strength tablets using the common-blend approach, with 35 percent w/w drug loading. Figure 1 shows a schematic representation of the man- ufacturing process. The scientists blended Compound X with the inactive excipients microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The granules obtained from the dry granulation process were blended with extragranular excipients and then com- pressed into tablets using a rotary tablet press. The initial proof-of-concept study was conducted using a batch size of 2,000 tablets, with no problems reported during their manufacture. However, while pre- paring to manufacture a 130,000-tablet batch for the pilot-scale study, the scientists observed blend compac- tion in the tablet press feeder. To successfully scale up the process for clinical trial, they needed to identify the cause of the blend compaction and resolve the problem. Table 1 Proof-of-concept tablet composition Ingredient Percentage Intragranular Compound X 35.00 Microcrystalline cellulose 58.50 Croscarmellose sodium 2.50 Magnesium stearate 0.50 Extragranular Croscarmellose sodium 2.50 Magnesium stearate 1.00 Table 2 Physical properties of proof-of-concept batch Hardness (kilopascals) Thickness (millimeters) Friability (percentage) Disintegration time (seconds) Flodex (millimeters) 4.46 3.55 0.03 31 6 Figure 1 Tablet manufacturing process Blending Granulation (roller compaction) Milling Blending with extragranular excipients Compression API Intragranular excipients