Towards Rational Excipient Selection: Assessing Lactose-Based Co-Processed Excipients with APIs of Differing Solubilities

Abstract

Purpose

This research was designed to systematically investigate the performance of three lactose-based co-processed excipients (CPEs): SuperTab^® 40LL, StarLac^®, and MicroceLac^® 100 in immediate-release tablet formulations prepared by direct compression. The objective was to evaluate their suitability with drugs of varying solubility and mechanical properties and provide practical guidance for excipient selection in tablet formulation.

Methods

Each co-processed excipient (CPE) was evaluated for flowability, tabletability, compressibility and compactibility. Formulations were prepared using four model drugs (promethazine, theophylline, hydrocortisone, and paracetamol) at drug loadings of 20 and 30% w/w. A single-punch tablet press was employed to prepare the tablets and were evaluated under harmonised conditions for strength, friability, disintegration and dissolution.

Results

Different performance profiles were observed among the excipients. SuperTab^® 40LL exhibited the strongest flow properties. StarLac^® demonstrated superior disintegration speed and dissolution performance but had the weakest tensile strength, failing friability testing at 30% paracetamol loading. MicroceLac^® 100 demonstrated enhanced mechanical strength and compactibility, coupled with consistently low friability values for all APIs tested, but generally failed British Pharmacopoeia criteria for disintegration and dissolution. Regardless of the excipient used, tablets containing hydrocortisone exhibited the poorest disintegration and dissolution. Overall, most formulations complied with friability specifications, confirming good manufacturability.

Conclusion

Excipient performance depended on API properties, drug loading, and formulation strategy. StarLac^® provides optimal performance in terms of fast disintegration and high dissolution rates, SuperTab^® 40LL improves flow, and MicroceLac^® 100 enhances mechanical strength. This comparative evaluation provides a framework for rational excipient selection and supports Quality-by-Design approaches in tablet formulation.

Introduction

Oral solid dosage forms, particularly tablets, remain the most widely used method for drug delivery due to their convenience, stability, ease of administration, and cost efficiency during industrial-scale manufacturing. Among tablet manufacturing techniques, direct compression (DC) has become increasingly popular because it eliminates granulation steps, shortens production time, and reduces costs [1]. However, successful DC technique depends strongly on the physicomechanical characteristics of the active pharmaceutical ingredient (API), especially at high drug concentrations [2]. Many APIs exhibit poor flowability and compressibility, which can lead to problems such as weight variability, capping, lamination, or poor mechanical strength [3]. Therefore, the selection of suitable excipients is a key factor influencing the final tablet’s performance.

Excipients constitute the bulk of most tablet formulations and perform multiple roles including acting as fillers, binders, disintegrants, glidants, and lubricants [4]. For DC, excipients should ideally retain key characteristics when combined with APIs, including good flowability to minimise processing issues at high tablet press speeds [5, 6]. Additionally, optimal excipients need to be stable, safe, colourless, and economically viable, while exhibiting low sensitivity to moisture and lubricants, as well as high dilution potential [2, 4, 7]. Traditional single excipients such as microcrystalline cellulose (MCC) and lactose have well-known limitations: MCC has poor flowability and lubricant sensitivity, whereas lactose, although brittle and free-flowing, has limited binding capacity [8,9,10].

To overcome these challenges, co-processed excipients (CPEs) have emerged as a promising alternative. CPEs are combinations of two or more excipients that are physically co-processed by a special particle engineering technique to create new particles with superior functional properties compared to simple physical mixtures [11]. These systems typically combine plastic and brittle components to improve compressibility, reduce elastic recovery, and enhance flow without chemical modification [12]. Since their constituents are already approved, CPEs often require less regulatory testing and offer advantages such as better dilution potential, improved machinability, and reduced sensitivity to lubricants [13,14,15]. However, co-processed excipients are associated with certain drawbacks. One of the major limitations is that they are made of a fixed ratio of individual constituents, and during formulation, this may not be a desirable choice for the dose and characteristics of the API [16]. Additionally, these excipients in many cases do not have an official monograph; consequently, they are not recognised by pharmacopoeias. This results in a longer time for regulatory approval, which makes them a less attractive choice for pharmaceutical companies [17]. Therefore, additional characterization such as physicochemical, performance, and compatibility studies is often required to support the safety and quality of a new drug product. Scaling up CPEs from laboratory to commercial manufacturing presents a major challenge, as it demands strict process control to maintain consistency in terms of quality and performance.

Lactose-based CPEs are among the most widely adopted in the pharmaceutical industry for direct compression tablet production. Examples include MicroceLac® 100 (≈ 90% α-lactose monohydrate + ≈ 10% microcrystalline cellulose), StarLac® (≈ 85% lactose monohydrate + ≈ 15% maize starch), and SuperTab® 40LL (≈ 75% spray-dried lactose + ≈ 25% microcrystalline cellulose/lactitol). MicroceLac® 100 integrates brittle and plastic deformation mechanisms to enhance binding and flow [18]; StarLac® improves flow and compressibility while promoting rapid disintegration [19]; and SuperTab® 40LL provides excellent flowability and lubricant insensitivity suitable for high-speed tableting [20].

Despite their increasing use, there is a lack of systematic, comparative data to guide excipient selection. Many studies focus on a single co-processed excipient (CPE) or compare only two, often under varying APIs, compression conditions, or analytical protocols, which limits the ability to directly compare results across studies. Moreover, investigations are frequently restricted to a single model API, typically at low drug loadings, providing little insight into how CPEs perform with drugs of differing solubility and mechanical properties.

To address this limitation, model APIs were selected to represent a wide range of aqueous solubilities and mechanical characteristics. According to the British and European Pharmacopoeias, paracetamol is classified as sparingly soluble in water and is known to exhibit poor flowability and low compressibility. Theophylline is a crystalline powder classified as very slightly soluble in water. Promethazine hydrochloride is freely soluble in water, while hydrocortisone is a hydrophobic drug classified as practically insoluble in water. These drugs therefore provide a representative spectrum of solubility behaviour relevant to direct compression formulation challenges.

The present study addresses this gap by providing a direct, head-to-head comparison of three commonly used lactose-based CPEs StarLac®, SuperTab® 40LL, and MicroceLac® 100 using a unified experimental framework. Four model APIs with distinct properties were incorporated at 20% and 30% loadings to evaluate excipient performance across realistic formulation conditions. The study integrates assessment of flowability, compressibility, compactibility, tabletability, friability, disintegration, and dissolution.

By systematically evaluating these excipients under comparable conditions, this work provides practical data to support rational excipient selection for DC tablet formulations and informs Quality-by-Design (QbD) development strategies for oral solid dosage forms.

Download the full article as PDF here Towards Rational Excipient Selection: Assessing Lactose-Based Co-Processed Excipients with APIs of Differing Solubilities

or continue reading here

Materials

The model drugs promethazine hydrochloride, acetaminophen (paracetamol; USP grade, 98.0–102.0%), hydrocortisone (≥ 98%, HPLC), and anhydrous theophylline (> 99%) and reagents such as sodium hydroxide (NaOH) and potassium dihydrogen phosphate (KH₂PO₄) were purchased from Sigma-Aldrich (St. Louis, MO, USA). The directly compressible excipient SuperTab® 40LL was supplied by DFE Pharma (Goch, Germany), while other co-processed excipients, StarLac®, and MicroceLac® 100, were obtained from MEGGLE GmbH (Wasserburg, Germany) and sodium stearyl fumarate (PRUV®) from JRS Pharma (Rosenborg, Germany). All materials were used as received without further modification.

Al-Dujaili, Z., Roberts, M. Towards Rational Excipient Selection: Assessing Lactose-Based Co-Processed Excipients with APIs of Differing Solubilities. J Pharm Innov 21, 292 (2026). https://doi.org/10.1007/s12247-026-10467-4

Are you looking for excipients in commercial quantities?