Exploring co-milling of poorly water-soluble drugs with swellable polymers to enhance the dissolution rate

Abstract

Co-milling with excipients offers an effective solvent-free strategy to enhance the dissolution of drugs in the pharmaceutical industry. Nonetheless, the range of excipients available for co-milling, as well as the selection criteria, remains relatively unexplored. Therefore, this study aims to evaluate the effect of co-milling with crosslinked swellable polymers on the dissolution of poorly water-soluble drugs. A structurally diverse set of crystalline compounds (n = 13) were co-milled with the three commonly used tablet disintegrants: Croscarmellose sodium, sodium starch glycolate and crospovidone. In vitro dissolution profiles were assessed to evaluate the excipient performance and identify crucial drug descriptors relating to co-milling induced dissolution enhancement. All 39 co-milled formulations showed an increased drug intrinsic dissolution rate (IDR), with drug properties such as molecular size and polar surface area showing a positive correlation with the extent of IDR enhancement following co-milling. Moreover, co-milling consistently yielded greater initial dissolution (AUC_0-5 min) across all excipients compared to milling the drug without an excipient. On average, milling with croscarmellose sodium produced the greatest improvement in the early stages of dissolution for neutral and basic compounds, while sodium starch glycolate was more effective in enhancing the dissolution of co-milled acidic drugs. Furthermore, an assessment within the refined Developability Classification System (rDCS) revealed that co-milling was effective to overcome dissolution rate limitations for all rDCS class IIa drugs. This study establishes a practical framework for the broader application of co-milling with tablet disintegrants and demonstrates its relevance within the latest rDCS paradigm for overcoming dissolution rate-limited absorption.

Introduction

The formulation of drugs with dissolution rate-limited absorption remains a considerable challenge for the pharmaceutical industry [48]. A useful tool to predict the risk of limited oral absorption by a low drug dissolution rate for a novel compound in the development pipeline is provided by the Developability Classification System (DCS) [10]. The DCS, which was refined in 2021 (rDCS), supports formulation decision-making by assessing risk levels and categorizing compounds to guide appropriate formulation strategies [40]. For compounds with dissolution rate-limited absorption, milling-based particle size reduction remains a practical and widely used alternative to more complex bio-enabling strategies such as amorphous solid dispersions or lipid-based drug delivery systems. Within the framework of the rDCS, recent work by Dressman and colleagues has introduced an advanced approach to calculate target particle size needed to overcome dissolution rate-limited absorption [5]. The estimation of the target particle size is based on the compound’s intrinsic dissolution rate (IDR) or solubility, along with the expected in vivo dissolution behaviour under either sink or non-sink conditions.

An alternative bio-enabling approach to enhance the dissolution rate is co-milling of drugs with excipients [20, 21, 28, 31]. Previous studies showed a successful dissolution rate enhancement in vitro as well as an increase of in vivo bioavailability after applying this industrially scalable process [3, 18, 22, 46, 49, 49, 50, 50, 51, 54]. Proposed mechanisms for the enhancement of dissolution are particle size reduction, crystal lattice disorder and excipient related effects [12, 23, 26, 27, 47, 56]. Co-milling with different excipients has been applied for a variety of formulation approaches, such as co-crystals with organic acids, co-amorphous systems with amino acids, or amorphous solid dispersions with hydrophilic polymers [11, 13, 19, 32, 41]. Given the range of existing approaches, further investigation into the formulation performance of additional excipients, and their effects on processed drugs is warranted to fully realise the potential of pharmaceutical co-milling.

Croscarmellose sodium, sodium starch glycolate, and crospovidone are widely used tablet disintegrants and are typically included in orally administered tablet formulations [37]. These excipients have undergone crosslinking, which enables them to swell upon exposure to gastrointestinal fluids supporting the disintegration of tablets. [2, 17, 55]. This superior ability to promote tablet disintegration has led to their classification as “superdisintegrants” [38]. One study showed enhanced oral bioavailability of raloxifene when co-milled with crospovidone in rats [24]. Realizing the potential of superdisintegrant-based co-milling calls for further investigations involving a wider range of poorly water-soluble drugs, along with deeper insights into the mechanisms responsible for enhanced dissolution.

Therefore, this study aimed to investigate the efficacy of three superdisintegrants as co-milling aids, and applying the technique across a diverse set of thirteen poorly water-soluble drugs. In vitro dissolution data was used to assess the dissolution enhancement from both an excipient and drug properties perspective. Furthermore, the utility of co-milling with superdisintegrants to overcome dissolution rate-limited characteristics was evaluated within framework of the rDCS, and therein support the wider application of this technique as a bioenabling strategy for dissolution rate-limited drug candidates.

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Materials

Gefitinib, indapamide, meloxicam, rivaroxaban, croscarmellose sodium (Ac-Di-Sol), sodium starch glycolate type A and crospovidone (Polyplasdone XL) were provided by Zentiva k.s. (Prague, Czechia). Dipyridamole, griseofulvin, mefenamic acid, nimesulide, the dissolution medium reagents sodium hydroxide, sodium chloride and di-sodium hydrogen phosphate were purchased from Sigma-Aldrich (Prague, Czechia). Deferasirox was obtained from Neuland Laboratories Ltd. (Telangana, India), olaparib from Taizhou Crene Biotechnology Co. Ltd. (Taizhou Zhejiang, China), and apremilast, tadalafil and dasatinib from MSN Pharmaceuticals Inc. (New Jersey, USA). Simulated Intestinal Fluids powder was purchased from Biorelevant.com Ltd. (London, United Kingdom).

Pätzmann, N., Beránek, J., Griffin, B.T. et al. Exploring co-milling of poorly water-soluble drugs with swellable polymers to enhance the dissolution rate. AAPS PharmSciTech 27, 34 (2026). https://doi.org/10.1208/s12249-025-03270-w