(T1430-02-13) Evaluation of Compaction Properties of Several Hydrophilic Polymers and Tableting Components in the Development of a Prototype Directly Compressible Gastroretentive Extended-Release Tablet

Purpose: Utilization of special cubic designed experiment to evaluate the compaction properties of various hydrophilic polymers for their usefulness in formulation development of a directly compressible gastroretentive extended-release (ER) tablet.

Methods: Several water-soluble swellable polymers were selected as functional excipients: Polyethylene Oxide (PEO) (PolyOx WSR 303), Xanthan Gum (XG), and Hydroxypropyl Methylcellulose (HPMC) (Benecel K15M). Moreover, Microcrystalline Cellulose (MCC) (Pharmacel 101), a classic plastic material, and directly compressible Lactose Monohydrate (Flowlac 100), a representative brittle material, were chosen as fillers. For each individual excipient, tablets were compressed at a target weight of 350 mg using a NATOLI Single Station Tablet Press (Model NP-RD10A) with a 12/32” Standard Concave (SC) tooling at various compression pressures, ranging from 500 to 10,000 psi. The weight, diameter, thickness, and hardness of each tablet were measured. The tablet volume was calculated. The true density of each excipient was obtained from literature ^1-7. Tablet porosity and tensile strength were calculated. Tabletability, compactibility and compressibility profiles, as well as out-of-die Heckel plots were generated for each excipient. Moreover, to optimize the functional excipient composition, a Design of Experiment (DoE), specifically a Simplex Centroid Design, was applied to the ternary system of PEO, XG, and HPMC. The compaction properties of a total of seven formulations (360 mg/tablet) were then evaluated. These formulations contained a fixed equal amount of MCC and Lactose (90 mg/tablet each) and variable quantities of PEO, XG, and HPMC (totaling 180 mg/tablet). For each formulation, tablets were compressed at a target weight of 360 mg using the NATOLI Single Station Tablet Press with 12/32” SC tooling at various compression pressures, ranging from 500 to 10,000 psi. The true density of each formulation was calculated based on each excipient’s true density and its corresponding weight contribution. Tabletability, compactibility and compressibility profiles, as well as out-of-die Heckel plots were also generated for each formulation composition.

Results: For all excipients except Lactose, the Heckel plot analyses show an initial section of linear relationship between the natural logarithm (Ln) of inverse porosity and applied compression pressure from 500 to 2000 psi (3.45 to 13.79 mPa), indicating a consistent deformation mechanism as the applied compression pressure increases. Lactose exhibits a linear relationship over a wider compression pressure range, from 500 to 5000 psi (3.45 to 34.47 MPa). The slope of the linear portion of the Heckel plot (the Heckel parameter, 'k') is related to the material's plasticity and insight into tablet durability and quality. The classic plastic material, MCC shows the highest plasticity or k (0.0995), followed by XG (0.0941), PEO (0.094), and HMPC (0.0841). On the other hand, the classic brittle material, Lactose exhibits the lowest value of k (0.0459). Interestingly, the PEO tablets did not break during hardness testing, instead remaining deformed without any cracks. This observation indicates that PEO is a highly ductile material that can undergo significant deformation before breaking. Therefore, tensile strengths were not calculated for pure PEO. The tabletability profile analyses reveal that at the same applied compression pressure of 1000 psi, MCC has the highest tensile or mechanical strength (2.53 mPa), followed by XG (1.60 mPa), HPMC (1.41 mPa) and Lactose (0.43 mPa). Similarly, the compactibility profile analyses indicate at the same solid fraction of 0.8, MCC has the highest tensile strength, followed by XG, HPMC, and Lactose. All the 7 compositions exhibit their characteristic tabletability, compactibility and compressibility profiles. All the 7 compositions show an initial section of linear relationship between the Ln of inverse porosity and applied compression pressure from 500 to 2000 psi (3.45 to 13.79 mPa). Statistical model fitting of the Heckel plot slopes and the tablet tensile strengths (at an applied compression pressure of 1000 psi) from the seven compositions, using Stat-Ease® Design-Expert Software, derived the following polynomial equations: Heckle plot slope = 0.084(PEO) + 0.087(XG) + 0.080(HPMC) – 0.011(PEO)(XG) – 0.012(PEO)(HPMC) + 0.010(XG)(HPMC) + 0.37(PEO)(XG)(HPMC); Tensile strength = 1.76 (PEO) + 1.33(XG) + 1.57(HPMC) – 0.54(PEO)(XG) + 0.78(PEO)(HPMC) – 0.68(XG)(HPMC) – 1.74(PEO)(XG)(HPMC). The contour plots indicate the formulation with contribution of equal amounts of PEO, XG and HMPC, tends to be more plastic, and that with higher amounts of PEO and HPMC tends to have better tabletability.

Conclusion: Understanding compaction behavior is crucial in the formulation development of directly compressible products. The application of DoE to tabletability, compactibility, and compressibility profiles, as well as Heckel plots, unveiled physical interactions among the polymers which could be utilized in designing directly compressible gastroretentive ER tablets.

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