Influence of Processing and Stabilizer Selection on Microstructure, Stability and Rheology of Emulsion-Based Semisolid Formulations

Abstract

Background/Objectives:

Emulsion-based semisolid formulations are important delivery systems for many applications, including pharmaceuticals, cosmetics and food. The manufacturing process for such formulations typically involves a series of heating, cooling, mixing and emulsification steps. Stabilizing agents are usually included in such formulations, as emulsions are intrinsically unstable and are prone to various destabilization mechanisms. Precise control of each processing parameter and the selection of an appropriate stabilizing agent are essential for delivering products with long-term stability and the desired properties. In this study, the effects of emulsification temperature and the selection of the stabilizing agent on key product attributes were investigated to enable improved design and optimization of both the formulation and manufacturing process.

Methods:

Model emulsion systems containing propylene glycol (PG) as the dispersed phase and mineral oil as the continuous phase were prepared at different emulsification temperatures to cover both pre-crystallization and post-crystallization regimes. Three stabilizing agents, namely mono-and-diglyceride (MDG), neat monoglyceride (MG) and neat diglyceride (DG), were studied. Their crystallization behavior was first examined to determine crystallization temperatures and crystal morphologies. The resulting emulsion samples were then characterized in terms of their microstructure, physical stability and rheological properties.

Results:

The emulsions prepared under post-crystallization conditions exhibited better physical stability, higher rheological parameters (crossover stress and viscosity) and a more rigid microstructure compared to those formed under pre-crystallization conditions, regardless of the stabilizer used. Rheological properties were found to corelate well with physical stability. In the pre-crystallization regime, poor stability could partially be mitigated by lowering the emulsification temperature. MG was generally more effective than DG in stabilizing the emulsions and led to higher rheological properties, despite both crystallizing into the same polymorph within the system. This difference in performance was attributed to variations in the crystal morphology and spatial distribution within the emulsion. Notably, the MG-stabilized emulsions also displayed a self-hardening effect during storage.

Conclusions:

The selection of the appropriate stabilizing agents and processing conditions tailored to the specific system is critical for the successful manufacture of emulsion-based semisolid products with an optimized performance.

1. Introduction

Semisolid dosage forms such as ointment, creams and gels are used for the topical administration of active pharmaceutical ingredients (APIs), and such delivery systems offer various advantages, including ease of application, better patient compliance, targeted delivery, long residence times and reduced systemic toxicity [1,2,3,4]. Many of these semisolid dosage forms are either water-in-oil (w/o) or oil-in-water (o/w) emulsions, which offer the flexibility of delivering APIs with different hydrophobicity. Simple emulsions contain two thermodynamically immiscible liquid phases (the oil phase and the aqueous phase), with one phase being the continuous or the external phase and the other the dispersed or internal phase [5]. Emulsion-based semisolid dosage forms are more complex systems that contain many components. The microstructure of these systems is often complex with multiple phases. Given that emulsion systems are intrinsically unstable, stabilizing agents such as surfactants or solid crystals are often added to semisolid formulations to kinetically stabilize the dispersed droplets and allow other key product attributes to be tuned at the same time [6,7,8,9]. There are two widely recognized mechanisms for kinetic stabilization: network stabilization, where stabilizing agents form a viscoelastic network throughout the continuous phase [10,11], and Pickering stabilization, where interfacially adsorbed solid particles reduce droplet coalescence [10]. Several studies have argued that Pickering stabilization is more effective than network stabilization [12,13], although they can occur in the same system at the same time [13].
Many studies have shown that microstructure of topical formulations can influence various essential physical properties, including rheology, physical stability and sensory properties [14,15,16,17,18]. This study will focus on how processing parameters, specifically emulsification temperature and the choice of stabilizer, can affect important physical properties of emulsion-based topical formulations. Other than these physical properties, microstructure has also been shown to influence active release, usually measured from in vitro release tests (IVRTs) of topical formulations. Active release is a key product attribute for semisolid dosage forms, as it is necessary to demonstrate Q3 (microstructure) similarity [19]. Factors that can affect IVRTs include viscosity, polymorphism, API particle sizes when dispersed as particles and the size of the dispersed phase in the emulsions, to name a few [20,21], and both the formulation and processing conditions have been shown to affect the structure. Wan et al. reported that by formulating pseudolaric acid B (PAB) as a microemulsion, the amount of API retained on the skin and its permeation rate both increased compared to those for the gel formulation. This was due to the reduced size of the dispersed phase [22]. Xu et al. reported that the drug release from an ointment formulation of acyclovir followed a logarithmic kinetic model and the release constant in the model was dependent on the drug loading, API particle size and composition of mineral oil in the ointment base [20].

Yuan et al. showed that addition of hyaluronic acid as a permeation enhancer reduced in vitro drug release, although skin permeation and retention were both increased [23]. Raghavan et al. reported that for emulsions, the drug release rate varied depending on the sequence of oil phase addition and aqueous phase addition [21]. Chow et al. reported that a higher amount of lidocaine was released from an emulsion cream when additional shear was applied at 35 °C compared to that for samples where additional shear was applied at 25 °C [24]. The rationale was that more severe disruption of the microstructure would occur when shear was applied at a lower temperature, as the emulsifying wax will already have crystalized and encapsulated the active phase [24]. However, in another study on lidocaine ointment, it was reported that despite the differences in bulk viscosity and crystallite (encapsulated by MDG) sizes, the drug release for samples prepared with different processing parameters was similar [25]. This was suggested to be due to the direct diffusion of the API from free droplets into the receptor compartment in the in vitro release test setup [25]. Dong et al. reported am inverse correlation between the cumulative amount of drug release and viscosity for an emulgel formulation of terpinen-4-ol [26]. Wong et al. formulated poly (ethylene oxide) (PEO)-based hydrogels using different methods of drug loading, which affected the drug release profiles. Immediate release occurred when the API was incorporated into microporous spaces, and prolonged release occurred when the API was embedded into the polymer matrix [27]. Fanse et al. studied the drug release from two commercial levonorgestrel intrauterine systems (LNG-IUSs) and an in-house LNG-IUS. Differences in drug release were observed, and the release kinetics correlated well with their microstructures, characterized using advanced imaging techniques [28]. In another study on LNG-IUSs, higher polymer crosslinking density and lower crystallinity were correlated with faster drug release [29].

Mono-and-diglyceride (MDG) is a commonly used stabilizer in many pharmaceutical and cosmetic topical formulations and other food products [30,31]. Commercially available MDG is a mixture of mono, di and triglycerides (trace amounts) produced through esterification of glycerol and fatty acids. The fatty acids used are often a mixture of stearic acid and palmitic acid. As per the United States Pharmacopeia-National Formulary (USP-NF), MDG should contain no less than a 40% monoglyceride content. Furthermore, based on the ester bond position, monoglycerides (MGs) and diglycerides (DGs) can exhibit positional isomers such as 1-MG, 2-MG, 1,2-DG and 1,3-DG [32]. The crystallization behavior of neat glycerides and that in oleogels have been widely studied [33,34,35,36,37,38,39]. Different polymorphs are reported for neat glycerides [40]. Upon cooling, the first liquid-to-solid transition occurs at a temperature named the Krafft temperature when the isotopic fluid is converted into an inverted lamellar phase (Lα), where the glycerol head groups are packed in a hexagonal way and the acyl chains remain largely amorphous. Upon further cooling to below the Krafft temperature, the inverted lamellar phase is converted into the sub-α phase (also referred to as the β’ phase or α gel) with orthorhombic subcells [33]. Both phases are unstable and can transform into the stable β crystalline form with a triclinic subcell type over time. Destabilization of MG-stabilized emulsions is often associated with a transition from the metastable phases, including both the inverted lamellar and sub-α phases, to the stable β crystalline phase [33]. Controlling the polymorphic form of the stabilizing agent in emulsion formulations is essential, as it can affect important product attributes such as textural properties [41], appearance [41] and physical stability [42].
Despite various studies on the crystallization of neat glycerides [33,34,35,36,37,38,39], there are limited reports on the crystallization behavior or crystal structure of MDG as a mixture. Kushwah et al. [32] studied the effects of aging and lot-to-lot variability on the crystalline structure of MDG. It was found that different batches contained different percentages of the sub-α and β phases, and the percentage of the β phase tended to increase with aging. Ali et al. [12] studied the crystallization of commercial MDG from paraffin oil and reported that the MG component mainly crystalized into the 𝐿𝛼 phase, with a plate-like morphology, whereas DG directly crystallized into the stable β crystalline form, with a spherulite morphology. In a polyethylene glycol 400 (PEG 400)/paraffin oil emulsion, MG crystals mainly adsorbed onto the PEG droplet surface, whereas DG crystals resided in the bulk oil phase. Other studies have focused on the effects of the manufacturing process and formulation parameters on the product attributes for semisolid formulations that contain MDG [25,43,44,45]. Chow et al. [25] reported that the long-term stability of a model ointment stabilized with MDG could be enhanced by adding the dispersed phase into the continuous phase at a lower temperature.

It was hypothesized that a lower addition temperature led to better encapsulation of the dispersed phase by the MDG crystals. Saremnejad et al. [44] developed an aerated nonaqueous foam by using MDG as the surfactant and achieved the desired formulation attributes with an MDG content of 10 wt%. It was reported that foamability and foam stability increased with increasing MDG content. Wang et al. reported that MDG promoted the crystallization of anhydrous milk fat and increased the solid fat content of aerated emulsions [45]. However, the existing literature has mainly focused either on the crystallization behavior of MDG from melts or solutions [12,32], without investigating its role as a stabilizer in emulsions, or on the macroscopic properties of MDG-stabilized emulsions, without addressing the underlying mechanism of emulsion stabilization by MDG [25,43,44,45]. In addition, the individual contributions of MG and DG, specifically how each component crystallizes and stabilizes the emulsions under different processing conditions, have not been thoroughly studied. Here, the effects of processing and formulation factors on macroscopic product attributes were studied in MDG-containing emulsions, with a focus on the microscopic behavior of MDG, and its stabilizing mechanism was also proposed.

In this study, the model system used was an emulsion system consisting of propylene glycol (PG) droplets dispersed in mineral oil, with MDG as the stabilizing agent. Crystallization of MDG from mineral oil was investigated to determine the crystallization temperature of the individual components, namely MG and DG, and their crystal morphologies and polymorphic forms. Emulsions were then prepared with different Te values selected based on the crystallization temperatures that were determined previously. The effect of Te on the resultant emulsion microstructure was analyzed using optical microscopy and correlated with the formulated product attributes, including rheology and stability. Finally, the effects of Te on the stabilization efficiency of neat MG and DG were investigated separately to determine their individual contribution towards the emulsion stability. The findings reported here will help formulation scientists to design emulsion-based topical formulations better with optimized formulations and manufacturing processes tailored to different systems.

2. Materials and Methods

2.1. Materials

Light mineral oil (NF/FCC, CAS No. 0842-47-5) and propylene glycol (CAS No. 57-55-6) (Ph. Eur-grade) (PG) were purchased from Thermo Fisher Scientific (Loughborough, UK). Mono-and-diglyceride (Geleol™) (CAS No. 85251-77-0) (MDG) was purchased from Gattefosse (Saint Priest, France). Distilled monoglyceride (CAS No. 122-94-4) (MG) was supplied by Chemsino Industry Co., Ltd. (Zhengzhou, China).

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Yang, R.; Tee, X.Y.; Poornachary, S.K.; Simone, E.; Chow, P.S. Influence of Processing and Stabilizer Selection on Microstructure, Stability and Rheology of Emulsion-Based Semisolid Formulations. Pharmaceutics 2025, 17, 1221.
https://doi.org/10.3390/pharmaceutics17091221