Effects of Co-Processed and conventional excipients on content uniformity

Abstract

Silicification of microcrystalline cellulose (MCC) has previously been shown to have positive effects on the powder’s flowability and tabletability compared to plain MCC or physical blends of colloidal silicon dioxide (CSD) and MCC [1]. A further characteristic of silicified MCC (SMCC) is its specific surface area, which is approximately five times larger than that of plain MCC [1]. It was hypothesized, therefore, that SMCC might have beneficial effects in terms of blend and content uniformity via effects of interactive blending.

This study was designed to compare the blending efficacy of silicified microcrystalline cellulose and a co-processed SMCC-based multifunctional excipient to that of physical blends comprising the same nominal components. Near infrared spectroscopy (NIRS) was used to probe blend uniformity during the blending process of the excipients and a model active pharmaceutical ingredient (API), caffeine, presenting morphological and electrostatic challenges with regard to content uniformity. In addition to NIRS, both particle size analysis and scanning electron microscopy (SEM) were used to investigate the resulting blends. Content uniformity on the tableted blends, obtained by caffeine dissolution, was used to investigate the effects of differing blend uniformity on a final oral solid dosage form.

For this non-optimized formulation with a challenging API, use of SMCC and a co-processed SMCC-based multifunctional excipient yielded formulations with significant benefits over using standard MCC, or MCC blended with colloidal silicon dioxide (CSD). These benefits included a faster blend uniformity, prevention of particle attrition, and a reduced impact of blender type and materials. Additionally, use of silicified microcrystalline cellulose yielded formulations with increased tablet hardness and reduced ejection forces.

Introduction

Oral solid dosage forms, such as tablets and capsules, are widely used due to their efficiency in manufacturing patient convenient dosage forms, ease in packaging and transport, etc. Many active pharmaceutical ingredients (APIs) present challenges to formulation in oral solid dosage forms, including cohesiveness, compressibility, solubility and particularly, in the case of low dosage forms, their content uniformity. Manufacturing efficiency and the performance of the final product (i.e., bioavailability, content uniformity) largely depends on the formulation process. Approaches can include direct compression (DC), encapsulation, wet or dry granulation [2].

While direct compression is favorable in terms of ease of manufacturing, basic equipment requirements, low energy consumption and absence of water or solvents, it poses particular challenges with regard to content uniformity, especially in the case of low-dose formulations. Careful selection of excipients and blending patterns, such as geometric dilution, can have a significant impact on content uniformity [3]. In particular, co-processed multifunctional and high functionality excipients can mitigate these well-known challenges [4].

Silicified microcrystalline cellulose (SMCC) is produced by co-processing microcrystalline cellulose (MCC) with colloidal silicon dioxide (CSD) [5], leading to a significant increase in the powder’s flowability, tabletability, and specific surface area [1,6].

Based on the silicified MCC technology [7,8], JRS Pharma developed PROSOLV® RX 90 as an all-in-one co-processed excipient composite. Beyond SMCC (acting as a filler, binder, and flow aid), it comprises sodium starch glycolate as disintegrant and sodium stearyl fumarate as lubricant [9]. It maintains much of the increased surface area found in SMCC.

It was hypothesized that SMCC and SMCC-based excipients might have beneficial effects in terms of blend and content uniformity via interactive blending [10], which is a term for the ordered mixing of fine, cohesive powders onto the surface of coarse powders [11,12]. A number of years ago, JRS Pharma compared the effectiveness of co-processed SMCC with a physical blend of its individual components. A blue pigment was used as a model, fine particle size API, and the two formulations were tableted and compared visually (Fig. 1). Use of SMCC dramatically reduced the presence of darker blue “hot spots” and led to a more homogeneous distribution of the pigment. This effect was attributed to interactive blending but could not be quantified.

Fig. 1. Tablets with blue pigment as model, fine particle size API, primary excipient

In this study, we aimed to characterize tablets made from co-processed SMCC and the corresponding physical mixtures with regard inter-tablet uniformity (i.e. content uniformity) as well as intra-tablet uniformity. As a surrogate for the latter, we analyzed blend uniformity at different time points before tableting. Caffeine was used as the model API due to its unfavorable, needle-like morphology and tendency to develop high static charge [13]. Additionally, caffeine was well suited to tablet dissolution.

A series of four blending experiments evaluated the uniformity of caffeine in blends with SMCC and PROSOLV® RX 90 versus microcrystalline cellulose and a physical blend of MCC and the glidant colloidal silicon dioxide. Blends were prepared in duplicate, using both a free-fall tumble blender and a mixer with a more vigorous motion. The blending process was monitored with near infrared spectroscopy (NIRS), which has been shown to be a practical measuring tool for blending efficacy [14,15,16,17,18,19]. The effects of mixing on particle size attenuation were investigated by measuring the particle size distribution of each of the resultant blends via laser diffraction, and the particle morphology was imaged with a scanning electron microscope (SEM). The blends were tableted and, in addition to the determination of caffeine content uniformity, the manufacturability of tableting and resulting ejection forces were compared for the four formulations.

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Materials

The primary excipients studied in this work are: PROSOLV® RX 90, a co-processed composite of four functional excipients, (RX) (bulk density: 0.36 g/mL), silicified microcrystalline cellulose (SMCC) PROSOLV® SMCC 90 (bulk density: 0.36 g/mL), and microcrystalline cellulose (MCC) EMCOCEL® 90 M (bulk density: 0.33 g/mL). They were sourced from JRS Pharma (Germany). These materials are DC grades, and have similar particle sizes. The commercial lots were chosen to have bulk densities that were as similar as possible to reduce density effects on blending.

EXPLOTAB® sodium starch glycolate (SSG) and PRUV® sodium stearyl fumarate (SSF) were sourced from JRS Pharma (Germany), and were used as the disintegrant and tableting lubricant, respectively. CAB-O-SIL® M−5P colloidal silicon dioxide (CSD) was purchased from Cabot (United States) and used as a glidant.

USP grade Caffeine (CAF) was purchased from Spectrum Chemical (United States) and was used as the model API.

Stephanie Stewart, Jenna Reinhard, Anthony Carpanzano, Emil Ciurczak, Gernot Warnke, Effects of Co-Processed and conventional excipients on content uniformity, European Journal of Pharmaceutics and Biopharmaceutics, 2025, 114902, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2025.114902.