(M1530-02-14) Functional Evaluation of Disintegrants Mixed into Pharmaceutical Excipients Based on Dynamic Viscoelastic Measurements

Purpose: Disintegration functionalities of swelling-type and water-wicking-type disintegrants have been quantitatively characterized by analyzing their dynamic viscoelastic responses as a function of water content applied directly to the disintegrant powders [1]. The rheological data enabled differentiation of moisture-induced swelling behavior and particle interaction dynamics under mechanical stress conditions generated by the addition of water. This study aims to quantitatively evaluate the disintegrant functionality within mixed powder formulations composed of microcrystalline cellulose, lactose monohydrate, and disintegrants with distinct disintegration mechanisms, by performing viscoelastic measurements on samples to which water has been added.

Methods: Lactose monohydrate (LMH) and microcrystalline cellulose (MCC) were selected as model pharmaceutical excipients. The disintegrants examined included croscarmellose sodium (CCS), sodium starch glycolate (SSG), crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), and corn starch (CS). Powder mixtures containing disintegrants were hydrated with varying liquid-to-solid ratios (L/S) and subjected to frequency-dependent dynamic viscoelasticity measurements. Stress (τ) and loss tangent (tan δ) values at 1 Hz were obtained as representative rheological parameters. To quantitatively assess the influence of disintegrants on the rheological behavior of powder samples, two disintegration indices were introduced. Index 1 (I₁), representing stress reduction induced by disintegrant addition, was defined as the ratio of the maximum shear stress (τ) observed in the absence of disintegrant to that in its presence. Index 2 (I₂), reflecting modifications in viscoelasticity, was calculated as the ratio of the amplitude range of the loss tangent (tan δ) under disintegrant-containing conditions to that without disintegrant.

Results: When water was added to formulations containing water-soluble lactose monohydrate (LMH) and water-insoluble microcrystalline cellulose (MCC) as excipient bases, a consistent decrease in shear stress (τ) and a corresponding increase in loss tangent (tan δ) were observed. These rheological changes suggested a reduction in interparticle cohesive forces, primarily attributable to swelling of disintegrant particles or water penetration into the powder matrix. When LMH was used as the excipient, Index 1 (I₁) showed the highest value for CCS, while Index 2 (I₂) was relatively high for CS. In contrast, when MCC was used as the excipient, I₁ showed high values for both CCS and SSG, and I₂ was high for SSG.

Conclusion: Based on the results, variations in viscoelastic properties were observed depending on the combination of excipient and disintegrant, and it was suggested that specific formulation conditions enabled each disintegrant to exhibit its functional disintegration capacity. These findings indicated that the mechanical responsiveness varied depending on the combination of disintegrant and excipient. Moreover, the disintegration indices derived from dynamic viscoelastic measurements were suggested to serve as quantitative indicators of disintegrant functionality within excipient matrices. Application of two disintegration indices derived from shear stress variations and tan δ, which reflected the rheological response and flowability of wetted powder blends—provided a basis for quantitatively evaluating the functionality of disintegrants operating under complex disintegration mechanisms within excipient–disintegrant combinations. The results of the disintegration indices were considered to provide useful information for selecting suitable disintegrants based on excipient properties during formulation design.

References: Takayuki Terukina et al. "Characterization of the viscoelasticity of disintegrants by dynamic rheological analysis." Powder Technology 392, 150-156, (2021).

Rheological Evaluation of Powder Mixtures: Effect of Disintegrant Type on Viscoelastic Properties