(W0930-07-38) An Efficient Strategy to Overcome Poor Flow and Compressibility Issues of Lamivudine for a Robust Tablet Formulation Using a Coprocessed Excipient

Purpose: Tableting is the process of consolidating powder blends to create tablets. During the consolidation phase, an applied compression pressure displaces entrapped air to reduce the volume of a powder bed while creating interparticle bonds, mainly generated by particle rearrangement, plastic deformation, and fragmentation. While direct compression increases formulation efficiency, most active pharmaceutical ingredients (API) lack inherent binding characteristics, requiring intermediate steps, such as dry or wet granulation, increasing complexity and manufacturing costs. The solution to overcome API tableting deficiencies might lie in using coprocessed excipients, a combination of two or more excipients created through mild pharmaceutical processes without significant chemical change. Their capabilities exceed conventional physical excipient mixtures, enabling formulators to streamline production processes without compromising tablet quality. Kollitab™ DC 87 L (Kollitab™) is an all-in-one coprocessed excipient containing lactose as filler, crospovidone fine as disintegrant, Kollicoat^® IR as binder and sodium stearyl fumarate, as a lubricant. Lamivudine is a slightly sticky high-dose drug with poor flow and compressible characteristics. Its formulations typically require a granulation step to enhance the tableting properties, aiming to produce strong tablets with low mass variability. Most marketed formulations are produced by roller compaction or top spray granulation because it is challenging to formulate a lamivudine tablet by direct compression (DC). This study examines the feasibility of formulating lamivudine tablets by direct compression with Kollitab™, evaluating the initial physiochemical properties, and performing a 6-month stability study.

Methods: Lamivudine (Styrax Lifesciences) and Kollitab™ DC 87 L (BASF) were selected as the drug and the coprocessed excipient, respectively, aiming to obtain 150 mg of lamivudine tablets by DC. Three formulations were proposed with drug loads ranging from 40 to 50%, as presented in Table 1. Manufacturing process: Weight the required quantity of lamivudine and sift through 40 mesh. Over the same mesh, sift the required amount of Kollitab™. Co-sift both materials through the same 40 mesh and repeat the sifting process twice for uniform mixing. Load the sifted material into a double-cone blender. Blend the sifted material for 13 min at 24 rpm. SEM images were used to study the particle morphology of individual materials and the final blend. Figure 1 presents the SEM images and photos of the individual components and the blend of batch LAMI_150-003. Tableting: Unload the blended material and manually feed it into a rotatory compression tablet press Kalavati with eight stations using 9 mm flat punches at a turret speed of 12 RPM. The target tablet weight was defined in accordance with the drug load (Table 1), and the compression force was set at 10 kN for all experiments. Tablet Analysis: Tablet hardness, friability, thickness, and mass variation were completed following USP standard procedures. The criteria for passing results at initial and stability conditions samples for dissolution, assay, and related substances were based on the USP method for lamivudine tablets. All test results were determined using a validated HPLC-UV method.

Results: The manufacturing process was streamlined using a coprocessed excipient by reducing the dispensing, weighting, and extra blending steps. Different lamivudine formulations were prepared to optimize the drug-to-coprocessed excipient ratio to have good flowability for the direct compression process. Based on the bulk-tapped density ratio, Carr index, and Hausner Ratio, the flow behavior of batch LAMI_150-003 with a 40% drug load was characterized as good. Batches LAMI_150-001 (50% API) and LAMI_150-002 (45% API) did not have good flow properties and thus did not compress, as shown in Table 1. Regarding the tableting process, batch LAMI_150-003 presented good results for tablet weight variation, hardness, friability, and thickness, as reported in Table 2. Additionally, drug assay and dissolution were in accordance with the established limits. Uncoated tablets from the batch were packed in HDPE bottles and kept in long-term (25°C/ 60% RH) and accelerated (40°C/ 75 %RH) stability conditions for six months. As observed in Table 2, all results were satisfactory and acceptable for both conditions. There were no changes in dissolution or assay after stability storage. Similarly, the concentration of lamivudine-r-sulfoxide and S-Sulfoxide impurities were below detection limits, if present. The lamivudine structure includes a primary amine, and indications of a Maillard reaction were not reported, even with the 87% lactose in the Kollitab™.

Conclusion: Lamivudine tablets (40% API) formulated with Kollitab™ showed good flowing and tableting properties, suitable for a DC process. Initial and 6-month stability data showed no concerning incompatibilities. These results demonstrate that this “all-in-one” coprocessed excipient has significant benefits and processing advantages to overcome DC issues and provide simple, reliable, and efficient drug formulations.

Table 1: Lamivudine and Kollitab™ DC 87 L formulations, flow properties of drug blends and individual components, and tableting parameters


Figure 1: SEM images (upper) and photos (down) of lamivudine drug, Kollitab™ DC 87 L and their blend (batch LAMI_150-003 with 40% API)


Table 2: Initial and 6-months stability results for tablets from batch LAMI_150-003