Hydrophilic Lubricants in Pharmaceutical Solid Dosage Forms: Mechanisms, Current Applications, and Future Perspectives

Abstract

Lubricants are critical excipients in the production of solid pharmaceutical dosage forms, directly influencing powder flow, compaction behavior, and tablet quality. Magnesium stearate (MgSt) is widely used owing to its excellent lubrication efficiency. However, its hydrophobic surface coverage and sensitivity to shear conditions can severely reduce inter-particulate bonding. Consequently, this adversely affects tablet wetting, disintegration, and drug release, particularly under over-lubrication conditions. For this reason, hydrophilic, amphiphilic, and less hydrophobic alternative lubricant materials have gained increasing attention. In this review, these lubricants with hydrophilic, amphiphilic, or low-hydrophobicity properties are collectively referred to as “hydrophilic lubricants”, and mainly include polyethylene glycol (PEG), sodium lauryl sulfate (SLS), poloxamers, and sodium stearyl fumarate (SSF). This narrative review summarizes the physicochemical characteristics, lubrication mechanisms, formulation applications, and effects on tablet mechanical properties, disintegration, and drug release of these alternative lubricants, and discusses the influence of lubricant properties, concentration, specific surface area, and incorporation method on lubrication performance. Furthermore, this review focuses on lubrication issues in continuous manufacturing and discusses the prospects of process analytical technology and predictive modeling. However, the available evidence remains predominantly derived from MgSt-based systems, and whether the relevant conclusions can be extrapolated to hydrophilic lubricants has not yet been validated. Nevertheless, these approaches hold promise for linking the distribution of hydrophilic lubricants and process conditions to tablet critical quality attributes, thereby providing a more rational control strategy for the lubrication process.

1. Introduction

The manufacture of oral solid dosage forms, particularly tablets, relies heavily on lubricants to prevent manufacturing defects during high-speed compression. However, conventional hydrophobic lubricants, such as magnesium stearate (MgSt), are highly sensitive to blending conditions, often causing over-lubrication due to excessive coating of particle surfaces, leading to reduced tablet tensile strength and delayed drug dissolution [1,2]. Furthermore, the alkaline nature and metal ions of MgSt can lead to chemical incompatibilities with certain active pharmaceutical ingredients (API), compromising product stability [2,3]. Additionally, for specialized dosage forms such as effervescent tablets or orally disintegrating tablets, the incorporation of hydrophobic lubricants can leave insoluble residues in the oral cavity, negatively impacting palatability and patient compliance [4]. Consequently, the development and application of hydrophilic lubricants have attracted increasing attention [5,6].

It is noteworthy that the term “hydrophilic lubricants”, as discussed in this review, adopts a broad, formulation-function-based definition, referring to hydrophilic, amphiphilic, or low-hydrophobicity materials that possess higher water affinity, lower surface hydrophobic effects, or improved wetting characteristics relative to conventional hydrophobic lubricants, especially MgSt, while still capable of exerting lubrication functions during solid dosage form manufacturing. These materials include polyethylene glycol (PEG), sodium lauryl sulfate (SLS), poloxamers, and sodium stearyl fumarate (SSF), among others. This classification is intended to discuss alternative materials that can mitigate the adverse effects of traditional hydrophobic lubricants on wetting, disintegration, and drug release from a formulation and process functional perspective and does not imply that these materials share identical properties.

Previous reviews have provided important accounts of the principles of tablet lubrication, the performance of commonly used lubricants, and the effects of lubrication on manufacturing and product quality [2,6]. In particular, MgSt has received considerable attention, whereas hydrophilic, amphiphilic, and less hydrophobic alternative lubricants have generally been discussed within broader reviews rather than examined as a distinct formulation-oriented category. Although recent studies on hydrophilic lubricants have made considerable progress [7,8,9,10,11], their results are often difficult to compare directly because lubricant performance depends on formulation composition, lubricant concentration, and processing conditions. A comprehensive synthesis is therefore needed to assess the balance between friction reduction and critical tablet quality attributes, distinguish formulation-specific benefits from more generalizable findings, and identify the limitations of current evidence, particularly with respect to continuous manufacturing (CM).

Accordingly, this narrative review integrates material properties, formulation performance, and manufacturing considerations to compare the effects of different hydrophilic lubricants on lubrication efficiency, tablet mechanical strength, disintegration, and drug release, while discussing the influence of concentration, specific surface area, lubricant incorporation strategy, and formulation composition on lubrication efficiency. The review further considers lubricant addition, residence time distribution (RTD), and shear history in CM, as well as the potential and current limitations of process analytical technology (PAT) and predictive modeling. By integrating material-specific findings and process-related evidence, this review aims to support rational lubricant selection, clarify the conditions under which alternative lubricants may offer advantages, and identify priorities for further experimental validation.

5. Several Commonly Used Hydrophilic Lubricants

Hydrophilic lubricants are widely used in the manufacture of effervescent tablets, orally disintegrating tablets, and other dosage forms that require rapid disintegration and clear solutions after administration. Considerable research efforts have focused on identifying hydrophilic lubricants that can effectively reduce friction between the tablet and die surfaces while maintaining favorable disintegration and dissolution properties. Accordingly, a summary of commonly used hydrophilic lubricants is provided in Table 1. In addition, Table 2 summarizes representative marketed products containing these hydrophilic lubricants.

Table 1. Physicochemical characteristics, formulation applications, potential benefits, and limitations of hydrophilic and alternative lubricants used in solid dosage forms.

Table 2. Representative marketed pharmaceutical products containing hydrophilic lubricants.

5.1. Polyethylene Glycol

PEG, particularly PEG 4000 and PEG 6000, are water-soluble polymers that have been investigated as alternatives to conventional hydrophobic tablet lubricants [67,68,69,70]. Their potential value lies in providing lubrication without necessarily introducing the same degree of hydrophobic surface coverage associated with MgSt. However, PEGs generally have lower lubrication efficiency than MgSt, and their performance depends on molecular weight, concentration, particle size, and incorporation method. In particular, excessive PEG addition may increase the risk of sticking to compression tooling [71]. Consequently, PEG-containing formulations often require optimization of lubricant concentration or combination with other excipients to achieve an acceptable balance between ejection performance and tablet quality.

One strategy is to optimize the incorporation method of PEG or to combine it with other lubricants. In an optimization study involving effervescent tablets, a formulation containing 2% L-leucine and 3% PEG 6000 was selected based on responses including tablet ejection force, friability, and disintegration time [72]. Medarević et al. prepared self-lubricating lactose-based excipients by fluid-bed melt granulation using PEG 4000 as a meltable binder. At a compression pressure of 173.5 MPa, the formulation containing 20% PEG 4000 exhibited an ejection stress of 3.58 ± 0.94 MPa, compared with 18.90 ± 4.02 MPa for unprocessed lactose, representing an approximately 81% reduction in ejection stress. The tablets also showed acceptable tabletability, with tensile strength exceeding 2 MPa. However, when the PEG 4000 content was increased from 10% to 20%, the tablet disintegration time was prolonged from 1.88 min to 4.07 min [73]. It should be noted that the relatively high polymer concentrations used in these co-processed systems should not be interpreted as conventional lubricant concentrations in finished drug-containing tablets.

However, owing to its repeating ether groups, PEG is susceptible to free-radical-initiated autoxidation during manufacturing and storage. Oxidative degradation can generate reactive species, including peroxides and low-molecular-weight degradation products, which may subsequently promote the degradation of susceptible APIs. In addition, terminal hydroxyl groups and PEG degradation products may participate in drug–excipient interactions [53]. Therefore, when PEG is selected as a lubricant, particularly for oxidation-sensitive API, peroxide levels, antioxidant strategies, and compatibility with the API should be considered.

5.2. Sodium Lauryl Sulfate

SLS is an anionic surfactant that has been investigated as a multifunctional excipient capable of providing both tablet lubrication and enhanced wettability [74,75,76]. Unlike MgSt, SLS can facilitate contact between hydrophobic drug particles and aqueous dissolution media. Its lubrication efficiency is influenced by lubricant concentration, particle properties, and formulation composition.

Dun et al. [24] systematically compared the lubrication performance of SLS and MgSt in formulations containing MCC, lactose, and their mixtures. In MCC-based placebo tablets, 1% SLS provided lubrication performance comparable to that of 1% MgSt. In formulations containing 60% MCC and 40% lactose, 2% SLS produced a slightly lower ejection force than 1% MgSt while maintaining higher tablet tensile strength. In contrast, lactose-based formulations required 5% SLS to approach the lubrication performance of 1% MgSt. This suggests that the lubrication performance of SLS depends largely on formulation composition. Furthermore, studies have shown that SLS can improve the in vitro dissolution of the poorly soluble drug celecoxib, mainly by reducing the interfacial tension between drug particles and the dissolution medium, thereby enhancing tablet wettability. This indicates that in suitable drug formulations, SLS can act simultaneously as a lubricant and a wetting agent. However, although SLS has been reported to improve the in vitro dissolution of certain poorly soluble drugs, these findings do not necessarily indicate improved in vivo absorption or bioavailability. A study of posaconazole amorphous solid dispersions reported that [77], although the SLS-containing formulation showed improved apparent in vitro dissolution, its oral bioavailability in dogs was lower than that of the corresponding SLS-free formulation. In addition, clinical pharmacokinetic findings for alectinib formulations further indicate that changes in SLS content may affect systemic drug exposure, but that this relationship is formulation-dependent [78].

Therefore, in the absence of appropriate biopharmaceutical or pharmacokinetic evaluation, SLS-associated improvements in in vitro dissolution should not be regarded as evidence of improved in vivo performance. Additionally, the favorable results reported by Dun et al. should not be generalized to all tablet systems. Zheng et al. found that in a study of lactose-based orodispersible tablets, 4% SLS was required to achieve an ejection force comparable to that of 0.25% MgSt, and sticking problems occurred even at SLS concentrations of 2%; further increasing the SLS concentration also prolonged tablet disintegration time [54]. In addition, some studies have reported that although SLS improved the wettability of some model tablets, none of the investigated formulations showed an improvement in drug dissolution rate [46]. Therefore, formulation composition, lubricant concentration, and target dosage form performance have a significant influence on the lubrication efficiency of SLS. Moreover, the incorporation method of SLS can also affect tablet performance. In a specific dry-granulated formulation studied by Moore et al., when SLS was added during initial blending, the maximum tablet hardness was 61 ± 3 N; when added immediately before tableting, it was 89 ± 5 N, representing an approximately 46% increase in hardness; and the addition of SLS immediately before tableting had no significant adverse effect on drug dissolution [79].

In addition to its lubrication efficiency and effects on tablet performance, SLS may also present certain limitations related to formulation and safety. In acidic environments, SLS may form poorly soluble complexes with basic drugs, potentially reducing dissolution performance [55]. In formulations containing super-disintegrants, its wettability-enhancing effect may be diminished, and in some cases, SLS may even delay disintegration in MCC-based tablets, possibly due to competition for available water [10,46]. Furthermore, SLS can disrupt the permeability barrier of the oral mucosa; therefore, its concentration must be carefully controlled to ensure safety [80].

5.3. Leucine

Leucine is an amino acid containing both polar functional groups and a hydrophobic side chain. Its physicochemical properties and particle characteristics both influence its performance as an alternative lubricant in tablet formulations. Leucine has been successfully used in orally disintegrating tablets to facilitate tablet ejection while maintaining adequate mechanical strength. After disintegration, leucine generally does not leave noticeable insoluble residues or a gritty sensation in the oral cavity, thereby improving patient acceptability [8]. The lubricating performance of leucine can be further enhanced through spray-drying processes. For instance, tablets containing 3.75% spray-dried leucine exhibited lubrication performance comparable to those containing 10% milled leucine, while also showing shorter disintegration times under high compression forces [44]. In effervescent tablet formulations, the combination of spray-dried leucine and PEG 6000 has proven effective. A formulation containing 2% L-leucine and 3% PEG 6000 achieved rapid disintegration (within 2 min), adequate tensile strength, and the formation of a clear solution [72].

Beyond tablet formulations, leucine is also used as a lubricant in powder systems, particularly for inhalable formulations [81,82]. Surface modification via co-spray drying with leucine is an effective strategy to reduce particle cohesion and improve powder flow properties. During spray drying, leucine preferentially migrates to the droplet surface and crystallizes into nanoscale domains, thereby altering surface morphology and reducing surface energy. These changes contribute to improved powder dispersion and lubrication performance [83,84,85].

5.4. Poloxamer

The poloxamer family comprises more than 30 amphiphilic block copolymers with varying ratios of polyoxyethylene (PEO) and polyoxypropylene (PPO). Among them, poloxamer 188 (P188) and poloxamer 407 (P407) have been investigated as alternative tablet lubricants because of their potential to reduce die-wall friction while maintaining acceptable tablet mechanical properties and aqueous wettability [86,87,88]. However, their lubrication performance strongly depends on particle size, concentration, filler characteristics, and processing conditions.

Desai et al. [88] evaluated micronized P188 and P407 in conventional and effervescent formulations. In caffeine tablets, the lubrication efficiency assessed by ejection force followed the order MgSt > P407 > P188 > stearic acid. In acetaminophen effervescent tablets, 2% spray-dried L-leucine failed to provide sufficient lubrication because the ejection force exceeded the tablet press safety limit of 1000 N, whereas P188 and P407 at the same concentration enabled successful compression; similar results were obtained in aspirin effervescent tablets. Although poloxamers improved lubrication and mechanical integrity relative to L-leucine in these effervescent formulations, they also prolonged tablet disintegration time. Mužíková et al. [57] further demonstrated the concentration- and filler-dependent nature of poloxamer lubrication. At a compression force of 17 kN, in tablets based on spray-dried lactose (Flowlac 100), the ejection force was 74.03 ± 3.88 N for 1% MgSt, compared with 239.05 ± 5.98 N for 1% P188 and 295.77 ± 19.53 N for 1% P407; increasing the poloxamer concentration to 2% reduced the corresponding ejection forces to 177.23 ± 2.35 N and 123.72 ± 4.15 N, respectively, although both remained higher than that of 1% MgSt. The study also found that, at the same poloxamer concentration, the tensile strength of lactose-based tablets was higher than that of MCC tablets. However, this result is contrary to the findings of Dun et al. [14], in which lactose-based formulations required higher poloxamer concentrations than MCC-based formulations to achieve lower ejection forces, further confirming the formulation-dependent nature of poloxamer lubrication. In addition, Dun et al. [14] observed that in tablets containing 5% ritonavir, 2% P188 or P407 produced lower ejection forces and better tabletability than 1% MgSt, and all tablets disintegrated rapidly, with disintegration times of 52 ± 4 s for MgSt, 60 ± 4 s for P188, and 57 ± 3 s for P407. In 30 min dissolution testing, tablets containing poloxamers showed higher ritonavir release, which may be related to improved wettability. However, de Backere et al. found delayed disintegration in certain MCC formulations containing P188 or P407 in a broader comparison of alternative lubricants [10].

Therefore, poloxamers should be regarded as formulation-dependent alternative lubricants that can simultaneously improve lubrication, tabletability, and drug release in specific formulations, although their lubrication efficiency is generally lower than that of MgSt.

5.5. Sodium Stearyl Fumarate

Although SSF is discussed alongside hydrophilic and amphiphilic lubricants in this review, it is practically insoluble in water and should therefore be regarded as a relatively well-established alternative to MgSt for tablet lubrication, particularly for formulations requiring preservation of tablet mechanical integrity and rapid disintegration [89]. In a systematic study using plastically deforming and brittle excipient matrices, Paul and Sun [17] found that approximately 1% (w/w) SSF achieved lubrication comparable to that of 0.5% MgSt. However, at the same lubricant concentration, SSF better preserved tablet mechanical integrity than MgSt, especially in the plastically deforming matrix. Similarly, de Backere et al. [35] reported that the reduction in tensile strength of lubricated MCC and lactose tablets followed the order MgSt > SSF > stearic acid, whereas these lubricants produced comparable ejection forces under the investigated conditions. This suggests that in certain formulations, SSF can preserve tablet mechanical properties more effectively than MgSt, although a higher SSF concentration may be required to achieve comparable friction reduction. However, the lubricating effect of SSF is also concentration- and formulation-dependent. Kapadia and Deshmukh [43] compared SSF with PEG 6000 and behenoyl polyoxyl-8 glycerides in a wet-granulated tablet formulation containing MCC, lactose, and povidone. Increasing the SSF concentration from 1% to 3% only slightly reduced the ejection force from approximately 59.25 N to 58.20 N, while the corresponding disintegration time increased from 4.13 min to 21.29 min, tablet tensile strength decreased from 1.56 MPa to 1.47 MPa, and the corresponding hardness decreased from 71.7 N to 66.3 N. Because different compression forces were used to prepare these tablets, the changes in these strength values should not be interpreted as a pure concentration effect. Nevertheless, the results indicate that increasing SSF loading does not necessarily produce a meaningful additional reduction in ejection force and may significantly delay disintegration. Tranová et al. [68] further demonstrated the formulation dependence of SSF; in three co-processed excipient systems for orally disintegrating tablets—Parteck ODT, Prosolv ODT G2, and Ludiflash—the ejection forces of 1% SSF were 36.93 ± 1.17 N, 27.74 ± 0.60 N, and 32.04 ± 1.56 N, respectively, indicating that formulation composition also has a significant influence on the lubrication performance of SSF.

In addition, SSF has also been investigated for use in orally disintegrating minitablets. Kuck and Breitkreutz [90] compared conventional 11.28 mm orally disintegrating tablets and 2 mm minitablets prepared from five co-processed excipients, using 2% SSF or MgSt as the lubricant. In 2 mm Prosolv ODT G2 minitablets compressed at 120 MPa, the disintegration times for 2% SSF and 2% MgSt were 21 ± 6 s and 44 ± 12 s, respectively. Disintegration times also differed significantly among excipient systems: at 120 MPa, minitablets containing 1% SSF disintegrated in 9 ± 2 s in Ludiflash, 6 ± 1 s in Parteck ODT, and 30 ± 2 s in galenIQ 721, whereas SuperTab 50 ODT formulations containing 1% SSF did not disintegrate within 180 s. These results further indicate that the suitability of SSF for minitablets strongly depends on formulation composition.

In addition to formulation composition, the lubricant incorporation strategy can also alter the performance of SSF. In a scale-up study, de Backere et al. [58] demonstrated that externally applied SSF, MgSt, and glyceryl dibehenate produced low and comparable ejection forces in the investigated placebo formulation without a significant loss of tensile strength. However, SSF exhibited slightly longer disintegration times than the other lubricants, which may be associated with a higher amount of SSF deposited on the tablet surface. Another study by de Backere et al. [47] also confirmed this observation. Finally, SSF should not be regarded as universally compatible with APIs. Wu Ludvigsson et al. [91] identified a degradation peak of approximately 3 area% in AZD7986 tablets stored at 50 °C/75% relative humidity and attributed the incompatibility to a reaction involving fumaric acid derived from SSF.

5.6. Sucrose Fatty Acid Esters

In addition to the commonly used hydrophilic lubricants discussed above, sucrose fatty acid esters (SEs) have also been explored as alternative lubricants in tablet formulations [47,59,92,93]. Their lubrication mechanism is primarily based on the formation of a thin film on particle surfaces via fatty acid chains, which reduces interparticle friction. Compared with MgSt, SEs generally exhibit a milder lubrication effect and are less likely to form excessive surface coatings, thereby better preserving tablet hardness and promoting faster disintegration. However, their lubrication performance is strongly influenced by the HLB value, low-HLB SEs exhibit superior lubricating efficiency by reducing inter-particulate friction and tablet ejection force [59].

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Fang, C.; Dong, Y.; Wang, P.; Gao, W.; Xian, J.; Du, R.; Hong, Y.; Wang, Y. Hydrophilic Lubricants in Pharmaceutical Solid Dosage Forms: Mechanisms, Current Applications, and Future Perspectives. Pharmaceutics 2026, 18, 1384. https://doi.org/10.3390/pharmaceutics18111384

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