(M1230-06-40) Leveraging the Digital Tool HyperStart C2C for the Development of Low Dose API Formulation and Comparative Analysis of Tablet Coatings

Purpose: HyperStart C2C is a unique digital self-service platform designed to enhance the formulation development process for oral solid dosage forms. It offers interactive formulation development from the dosage Core to its outer Coating (C2C), providing significant value to customers by increasing R&D productivity, accelerating formulation development and speeding up time to market. This study explores the utilization of the algorithm-based digital tool HyperStart C2C to develop a formulation for the low dose (4 mg, i.e., 2.67%), crystalline active pharmaceutical ingredient (API) chlorpheniramine maleate (CPM) and determining the ideal coating agents and procedures for this dosage form.

Methods: The digital tool HyperStart C2C was employed to generate formulation composition for the low dose API (Table 1A), along with a detailed procedure to prepare the tablets. The tablet blend incorporates StarTab®, known for its superior flow and direct compression application, combined with microcrystalline cellulose (MCC), as a diluent to prepare tablets. To prepare the powder blend, CPM and one-half the quantity of StarTab was bag blended, followed by passing the mixture through a 30-mesh (600 micron) screen to deagglomerate the API powder. The screened mixture was transferred to a twin shell V-blender (Patterson Kelley, USA) along with the remaining quantity of StarTab and microcrystalline cellulose (MCC) and blended for 10 minutes. Magnesium stearate was passed through a 40-mesh (425 micron) screen, added to the blender and mixed for an additional two minutes. The blended tablet formulation was evaluated for content uniformity by evaluation of CPM assay from four different locations in the blender. Tablets were prepared per the procedure recommended by HyperStart C2C using a rotary tablet press (Piccola, Riva, Argentina) with 8 mm round standard concave tooling at different compaction pressures at 50 rpm turret speed. Prepared tablets were coated at 3% weight gain with the recommended Opadry® QX formulation, and with the suggested Opadry TiO2 Free (277U) as an alternative coating agent when opting to avoid titanium dioxide. Tablets were manufactured and coated as per the procedures given by the digital tool and subjected to a series of evaluations including tensile strength, friability, disintegration time and in-vitro dissolution for both coated and uncoated formulations. The in-vitro dissolution study was performed using USP II apparatus in 500 mL of 0.1N HCl as a dissolution medium, and samples collected at predetermined time intervals followed by evaluation of drug content. The properties of coated tablets were compared with those of uncoated tablets. Additionally, the results predicted by the digital tool were compared with the actual results obtained from the evaluations.

Results: The uniformity of drug content throughout the powder batch demonstrated that the blending process was effective in achieving a consistent API distribution within the mixture (Table 1B). The dose uniformity remained consistent despite the low dosage and larger particle size (D50 of 163 microns) of the crystalline API. The digital tool predicts specific results for powder and tablet properties as “starting parameters” (Table 2). The prepared blends and tablets were subsequently evaluated for these properties and compared against the predicted results. The actual results obtained for these properties are presented in Table 2 for comparison. Overall, the actual results obtained closely matched the results predicted by HyperStart C2C, demonstrating the accuracy and reliability of the proposed parameters. This similarity is crucial to ensure the quality and effectiveness of the final product. The tabletability profile for the formulation showed excellent tensile strength at various compaction pressure with low ejection forces < 70N (Figure 1A). The presence of the StarTab-MCC combination as a diluent enhances flow properties and tabletability, making it an excellent choice for direct compression applications. The tablets prepared at 250 MPa compaction pressure were coated and evaluated for tablet properties. The recommended Opadry QX and Opadry TiO2 Free (277U) coatings provided better mechanical properties, with an increase in tensile strength and 0% friability compared to uncoated tablets, whereas disintegration time for coated tablets increased compared to uncoated tablets (Table 1C). Along with that, both uncoated and coated tablets rapidly dissolved with over 80% of the drug dissolved in less than 10 minutes (Figure 1B). These results closely matched the predictions made by the digital tool, demonstrating its reliability and accuracy in formulation development.

Conclusion: The integration of the digital tool HyperStart C2C in the formulation development process for low dose APIs like CPM offers significant advantages. The use of StarTab and MCC in combination enhances R&D productivity, accelerates formulation development and ensures the production of high-quality tablets with optimal properties. Opadry QX provides quick and flexible film coating that enhances tablet appearance and reduces coating time. The use of alternative coating agents like Opadry TiO2 Free (277U) provides additional flexibility in formulation design, catering to specific regulatory and market requirements.


Table 1:
A) Formulation Composition of CPM Tablets
B) Blend Uniformity Results (n=3)
C) Coated Tablet Parameters (at 250 MPa)


Table 2: Powder and Tablet Properties


Figure 1 A) Tabletability Profile of CPM Tablets;
B) In-vitro Dissolution Profile of CPM Tablets (n=6)