Introduction
Natoli Scientific, in collaboration with TaBlitz, conducted a case study to evaluate a customer’s formulation, adhering to USP <1062> principles for Tabletability, Compressibility, and Compactibility. Several additional powder characteristics were also utilized to determine root cause of capping for the assessed formulation.
By integrating the Natoli RD10A and RD30 Rotary R&D tablet presses, Natoli AIM™ data collection and instrumentation monitoring system, and TaBlitz powder analysis platform, the study identified raw material inconsistencies in the new formulation causing capping defects, ensuring robust process optimization and scalability.
Problem Presented
A customer approached Natoli Scientific after encountering persistent capping issues with their new formulation across several production batches. Despite adjusting press parameters and investigating process-related factors, the issue persisted. The customer ran multiple batches, resulting in the waste of several hundred kilograms of material, prompting an urgent need for a root cause analysis to prevent further losses and optimize the formulation process. The delay to their production lasted 2 weeks.
Methodology
The case study compared the original and new powder formulations to assess tabletability (tablet strength vs. compaction pressure), compressibility (solid fraction vs. compaction pressure), and compactability (tablet strength vs. solid fraction), as defined by USP <1062>. The following tools were used:
- Natoli RD10A R&D Tablet Press: A high-precision tablet press for small-scale production, enabling controlled compaction pressure to evaluate tablet formation.
- Natoli AIM™ (Advanced Instrumentation and Monitoring): A data acquisition system that monitors real-time parameters, including compaction pressure, and tablet weight, generating comprehensive data for analysis.
- TaBlitz Platform: A powder analysis tool that consumes all AIM data and integrates it with micromeritic properties, including particle size distribution, bulk and tap density, flowability (Hausner and Carr Index), solid fraction, porosity, and loss on drying (LOD).
Process
- Powder Assessment with TaBlitz: Both formulations were analyzed for micromeritic properties. Particle size distribution, flowability, density, and porosity were evaluated to assess their impact on tabletability, compressibility, and compactability per USP <1062>.
- Tablet Compression with RD10A: The RD10A applied controlled compaction pressure to compress each formulation into tablets, varying pressure to assess tablet quality and defect potential.
- Real-Time Data Collection with Natoli AIM™: AIM captured data on compaction pressure, and tablet weight, enabling precise monitoring of process parameters aligned with USP <1062> definitions.
- Analytical Integration with TaBlitz: TaBlitz consumed all AIM data, combining it with micromeritic analysis to evaluate tabletability (tensile strength vs. compaction pressure), compressibility (solid fraction vs. compaction pressure), and compactability (tensile strength vs. solid fraction), identifying the cause of capping in the new formulation.
Results
The integration of RD10A, AIM, and TaBlitz, with TaBlitz analyzing all AIM data per USP <1062>, revealed critical differences between the formulations.
Original Formulation (FM102 – Original)
- PSD Analysis by TaBlitz: The original formulation had a consistent PSD, with only 5% fines below 75 µm, which TaBlitz noted as unlikely to disrupt flow characteristics. However, it flagged potential segregation and flowability issues due to some particle size variation, recommending granulation or glidants if required.
- Tabletability Profile: TaBlitz reported a good Tabletability profile, with tablet strength increasing from throughout the target range based on dosage form (1.5 – 2.5 MPa).
- Compressibility Profile: The solid fraction (0.85) was within the ideal range (0.75–0.9) falling within the optimal range.
- Compactibility Profile: The compaction profile was also ideal, indicating robust tablet performance.
- TaBlitz Assessment
- Outcome: No capping or lamination issues, with consistent tablet quality suitable for scale-up.
New Formulation (FM102 – New)
-
PSD Analysis by TaBlitz: TaBlitz identified significant inconsistencies in PSD, contradicting the Certificate of Analysis (CoA). The new formulation contained a higher proportion of fines and irregular particle sizes, leading to poor flowability and segregation issues.
- Tabletability Profile: TaBlitz’s analysis of AIM data revealed poor tabletability, with insufficient tensile strength when increasing compaction pressure, resulting in capping defects prior to achieving desired tablet hardness.
- Compressibility Profile: Indicates solid fraction falls within the range of target dose but has no ideal association due to Tabletability not meeting required target.
- Compactibility Profile: Due to the poor performance of Tabletability the compaction profile shows extremely poor performance for this formulation.
- TaBlitz Assessment
- Outcome: Capping defects were prevalent, batch rejected by customer due to inconsistent and misalignment with CoA.
Identification of Issues
TaBlitz’s integration of AIM’s compaction data with particle size distribution analysis pinpointed the new formulation’s inconsistent PSD as the primary cause of capping. AIM’s detailed and accurate data collection, feeding into TaBlitz’s comprehensive analysis, highlighted discrepancies in the CoA, revealing unreliable raw material specifications for the original formulation.
Once Natoli Scientific and TaBlitz were engaged, the root cause analysis was completed in just two days, primarily due to sample shipping time. The actual analysis by TaBlitz and AIM, took only two hours and can be performed at a customer’s site if equipped with the right equipment, which Natoli Scientific can provide.
Cost Savings
By detecting the new formulation’s particle size distribution issues during R&D, TaBlitz prevented costly production failures. While exact savings were not quantified, avoiding defective batches and reformulation delays likely saved significant resources and delays.
Discussion
The synergy of the Natoli RD10A, AIM, and TaBlitz, enabled rapid identification of root cause for this formulation. The RD10A’s controlled compaction pressure ensured accurate tablet formation, while AIM’s real-time data provided critical insights into process variability. TaBlitz’s integration of this data with micromeritic analysis, particularly particle size distribution for this case study, revealed the new formulation’s raw material inconsistencies, which led to poor compactability, causing capping. The rapid two-hour analysis time underscores the efficiency of following the USP <1062> regulatory procedures as executed in this study by AIM and TaBlitz.
This case study highlights the critical role of AIM and TaBlitz in analyzing and characterizing how formulations will perform and rapidly identify root cause to resolve manufacturing issues. The original formulation’s robust performance supported seamless scale-up, while the new formulation’s issues emphasized the need for rigorous raw material verification, saving the customer from further costly production failures.
This integrated approach is not limited to capping defects but can be applied to identify and prevent a multitude of tablet defects. By leveraging TaBlitz’s analysis and AIM’s comprehensive process data alongside micromeritic properties, formulation scientist can diagnose issues like poor flowability, inadequate tablet strength, or poor scalability that contribute to various tablet imperfections or process limitations. This versatile methodology ensures robust formulation development and process optimization across a wide range of pharmaceutical and nutraceutical manufacturing challenges.
Conclusion
Natoli Scientific and TaBlitz demonstrated the effectiveness of integrating the RD10A, AIM, and TaBlitz. By identifying raw material inconsistencies in the new formulation causing capping, with only 100g of material, the study enabled targeted reformulation and ensured reliable scale-up for the original formulation. Supporting material sparing formulation assessment and development for the pharmaceutical and nutraceutical industries.
Read more on the website
Source: TaBlitz, Natoli Scientific, website https://natoli.com/tablitz/
Scale Up Your Scale Up – Optimizing Tablet Development for Production Success
