(M1230-12-82) Impact of Extra Components Added to an All-in-One Coprocessed Excipient to Obtain a Better Processability of Cohesive and Poor Flowing Hydrochlorothiazide

Purpose: This study investigated the impact of adding extra granular components to an “all-in-one” coprocessed excipient to obtain better processability of a cohesive and poor flowing drug. Different lubricants and their order of addition into the formulation were evaluated. Moreover, the advantages of coating the drug with fumed silica (Si) were also studied. Flowability and tabletability were verified for each formulation and manufacturing condition, starting from a formulation predicted by ZoomLab™. This free virtual pharma assistant software uses algorithmics to predict formulations and even more. Hydrochlorothiazide (HCTZ) and Kollitab™ DC 87 L (Kollitab™) were the ingredients selected for the study. Kollitab™ is a coprocessed excipient that contains a diluent (lactose), disintegrant (crospovidone), binder (Kollicoat® IR), and lubricant, all essentials to produce a tablet. Kollitab™ was blended with HCTZ without adding any other ingredient, reporting good flowability, compressibility, and short disintegration time, indicating the outstanding functionality of this excipient in the DC process. However, the impact of adding additional common components such as sodium stearyl fumarate (SSF) and magnesium stearate (MgSt) as lubricants, and Si as drug coating glidant, is not fully understood.

Methods: Blend Preparation - ZoomLab™ was used to predict the initial formulation. HCTZ (Teva) and Kollitab™ (BASF) blends were prepared in three distinct ways with the addition or absence of extra lubricants SSF (Pruv® – JRS) and MgSt (Mallinckrodt), as described: 'Single Mix' (all materials mixed at once); 'Additional Mix' (API and Kollitab™ blended first, then an additional lubricant added and blended); 'Acoustic Drug Coating Mix' (First, the API was coated with Si in an acoustic mixer, then blended with Kollitab™ and when designated, mixed with the lubricant). All compositions and blending parameters are described in Figure 1. Flowability and Cohesion Testing - Tapped and bulk densities were measured as per USP < 616 > Bulk Density and Tapped Density of Powders. An Erweka GTB was used to measure the angle of repose. An FT4 powder rheometer (Freeman Technology) was used to determine the individual materials and mixtures' compressibility percentage (CPS%). Tabletability - Compaction simulator Styl One Evo (Medelpharm) was used to characterize the formulations regarding the tableting characteristics (tensile strength and ejection stress). The powder blends were manually fed into the tablet press XL100 (Korsch). 7 mm round tablets of 165 mg were produced at a compression force of 10 kN, with a pre-compression below 1 kN and rotor speed of 20 RPM. Tablet disintegration and dissolution - Tablet disintegration was determined via a Distek with a sample number of 6 for compression force 10kN. Tablet dissolution was performed following the USP monograph of HCTZ tablets in a dissolution Erweka, apparatus 1 at 50 rpm, 500 mL (for better dissolution discrimination), HCl 0.1N at 37 °C ± 0.5. The UV measurements were recorded via a Pion system.

Results: In comparing the impact of lubricant addition timings during blending, we found SSF did not affect flowability parameters regardless of addition timing. However, MgSt did improve flowability via Hausner ratio and angle of repose parameters. Mgst addition at the beginning of blend production showed further improved CPS%, the reduced cohesion can correlate to improved flow. Similarly, the coating of the API with Si improved blend flowability at every parameter tested (Figure 2). The introduction of SSF, regardless of timing, reduced tableting ejection stress. SSF introduced at the beginning of the blend slightly reduced tablet tensile strength. Adding MgSt early in blending resulted in almost no change in ejection stress and dramatically reduced tablet strength. Later MgSt addition resulted in a small reduction in ejection stress and generated weaker tablets. Coating the API with Si led to a higher ejection stress that was reduced by adding either lubricant. Si-coated API blends reduced CPS% and improved flowability (Figure 2) as well as produced much harder tablets (Figure 3). Adding either lubricant regardless of time and all dry-coated HCTZ blends resulted in tablets with good friability and relatively similar disintegration times. However, adding lubricant to pretreated HCTZ blends resulted in longer disintegration times. Surprisingly, the extra lubricants did not affect dissolution profiles regardless of the incorporation time. This might be due to the fast disintegrant provided by Kollitab™ (Figure 3).

Conclusion: Adding MgSt early in blend production resulted in better flowability but weaker tablets. The order of addition of the SSF did not significantly impact the tableting process. Dry coating HCTZ with Si greatly improved the flowability and compressibility of the blends at the expense of higher ejection stress, which can be relieved by adding either lubricant. Kollitab™ demonstrated great functionality by providing a robust DC process even with a cohesive and poor flowing drug. Finally, it is relevant to emphasize the reduced time saved using ZoomLab™ to predict the formulation.

Blending Methodologies and Formulation

Compressibility and Flowability Results for the Formulations Tested

Tableting and Tablet Quality Results for the Formulations tested.