Alteration of gel point of poloxamer 338 induced by pharmaceutical actives and excipients

Abstract
Poloxamer 338 is used as versatile thermo-responsive gelling agent in topical and sub-cutaneous applications. Due to application specific needs a gel point below body or even below room temperature is required. The influence of inorganic salts and active pharmaceutical ingredients (APIs) on the gel point was investigated using oscillatory rheology to identify the driving forces and predictors for gel point alteration. While most inorganic salts decreased the gel point, API salts exhibited an increase. Consistent with previous findings, the extent of gel point alteration caused by inorganic salts could be empirically described by the Hofmeister series, primarily influenced by the anion. Notably, this study revealed a concentration-dependent increase in the gel point in the presence of API salts. Moreover, this increase could be accurately predicted in a linear manner by considering the respective logP value. By utilizing the proposed prediction model, the effect of API addition on the gel point can be estimated, facilitating formulation development to achieve the desired gelling behavior for specific applications.
Introduction
Poloxamers are a type of nonionic amphiphilic block copolymers consisting of polyethylene oxide (PEO) and polypropylene oxide (PPO) blocks arranged in an ABA structure. The inner propylene oxide block (B) forms the hydrophobic part, while the outer ethylene oxide blocks (A) represent the hydrophilic segments (Fig. 1). Poloxamers have been known for several decades, with the earliest literature dating back to the 1950s [1], [2]. These triblock copolymers possess surface-active properties since they are characterized by an amphiphilic structure, self-assembly at interfaces, leading to a reduction of interfacial and surface tension. This feature enables their use in various fields, including technical, agricultural, cosmetic, and pharmaceutical applications. For pharmaceutical applications, poloxamers in high quality and compliance to major pharmacopoeias are marketed under trade names such as Kolliphor® P (BASF) or Synperonic® PE Pharma (Croda).

Poloxamers are synthesized through anionic sequential polymerization of propylene oxide and ethylene oxide using a difunctional starter such as propylene glycol at elevated temperatures. The polymerization process involves two steps: first, the difunctional starter is reacted with propylene oxide, followed by the addition of ethylene oxide in the second step. Basic catalysts like potassium or sodium hydroxide are used during the polymerization process [3]. Residual catalysts are neutralized and remain incorporated within the polymer, whereas residual monomer traces are removed by vacuum stripping down to levels below 5 ppm. It is important to note that all ethylene oxide-propylene oxide block copolymers contain unsaturated species, which typically ranges from 0.02 to 0.07 meq/g (Table 1). The unsaturation is formed as a side-reaction during the base-catalyzed polymerization of propylene oxide, resulting in the formation of allyl alcohol. This byproduct is further alkoxylated and remains as a low-molecular-weight polyethylene oxide-polypropylene oxide diblock copolymer within the final product [4]. Commercial poloxamers are often stabilized with BHT (butylated hydroxytoluene) to ensure long-term stability.
Tablet 1. Poloxamers in USP (NMT: not more than).

The variation in block lengths of the hydrophilic PEO block and the hydrophobic PPO block allows a wide range of amphiphilic polymers with specific properties. The chemical space of poloxamers is depicted by the “Poloxamer Grid” (Fig. 2), which illustrates the composition of these polymers.
![Fig. 2. Classic “Poloxamer Grid” including gel formation propensity based on literature [5].](https://www.pharmaexcipients.com/wp-content/uploads/2025/01/Fig.-2.-Classic-Poloxamer-Grid-including-gel-formation-propensity-based-on-literature-5-300x240.jpg)
A specific three-digit nomenclature has been established to name poloxamers and indicate their composition. The first two digits, multiplied by approximately 100, represent the average molecular weight of the PPO block, while the last digit, multiplied by 10, indicates the weight percent of ethylene oxide (EO) in the polymer. The molecular weight of the PPO block and the weight percent of EO in the polymer determine not only the overall molecular weight of the poloxamer, but also several other physical properties. These properties include the physical state of the poloxamers (liquid, paste, or solid), hydrophilic-lipophilic balance, water solubility, critical micelle concentration (CMC), cloud point, gel-forming properties, and more. Thus, by adjusting the ratio of PEO to PPO block length and the molecular weight of the block copolymer, the physicochemical properties of the poloxamers can be tuned. In the past, extensive investigations have provided valuable insights into the relationship between poloxamer composition and their resulting properties [6], [7].
The United States Pharmacopeia (USP) includes five listed poloxamers, covering a molecular weight range from 2000 g/mol to approximately 18000 g/mol and a weight percentage of ethylene oxide ranging from 40 to 80 % [8]. Table 1 provides an overview of the poloxamers listed in the USP-NF. Approved formulations incorporating poloxamers encompass various administration routes [9], [10], including oral, intramuscular, intravenous, topical, ophthalmic, and periodontal administration. Poloxamers find targeted applications in pharmaceutical formulations, such as enhanced solubilization [11], [12], drug and gene delivery [13], [14], [15], [16], protein stabilization [17], [18], and nano formulations [19]. Their broad range of applications highlights the versatility and potential of poloxamers in the pharmaceutical industry. In commercialized pharmaceutical formulations poloxamers are used for example as tablet and capsule lubricant [20], as surfactant to prevent protein aggregation [21], or solubilizer [22].
Reversible thermo-responsive hydrogels based on poloxamers have garnered significant interest and find diverse applications [23], [24], [25], [26], [27], [28], [29], [30]. These hydrogels are utilized across various administration routes, including (sub)cutaneous, ocular, intranasal, vaginal, rectal, intramuscular, among others. Poloxamer hydrogels offer advantages such as sustained drug release and enhanced bioavailability [31].
By encapsulating active pharmaceutical ingredients (APIs) within amphiphilic block copolymer micelles, the solubility of poorly soluble drugs can be enhanced, which increases drug bioavailability. The interaction with the block copolymer can positively impact drug stability by minimizing drug degradation [32]. Poloxamer hydrogel formulations of active pharmaceutical ingredients offer tailored release profiles and depot mechanisms. Local administration with a sustained release profile is particularly advantageous in terms of minimizing side effects and improving patient compliance. An example of this is the development of Rilpivirine extended-release formulations for long-acting HIV combination therapy based on poloxamer 338 [33], [34]: The formulation enables a once-a month instead of daily administration.
In aqueous solutions, poloxamers self-aggregate into micelles, where the hydrophobic PPO blocks form the core, while the hydrophilic PEO blocks form the outer shell, interacting with the surrounding water. The formation of micelles occurs at the CMC and the critical micelle temperature. The thermosensitive gelation of poloxamer solutions is attributed to temperature-dependent micelle formation. At room temperature or below, both types of polyalkylene oxide blocks are hydrated and relatively soluble in water. However, as the temperature increases, the solubility and hydration of the PPO blocks decrease, leading to their aggregation and subsequent micellization, which ultimately results in hydrogel formation [13]. Poloxamers with longer PPO blocks tend to aggregate into micelles at lower concentrations and temperatures [35]. When comparing block copolymers with the same ratio of EO and PO, increasing the molecular weight will shift the gel point temperatures to lower values. Poloxamers with an EO content below 40 % typically do not exhibit gelling behavior in water. The gel point temperatures of 20 % (w/w) aqueous solutions of selected compendial poloxamers range from 20 °C to 50 °C (Table 2). As presented in the ‘Poloxamer Grid’ (Fig. 2) poloxamer 407 and 388 are most favorable for gelling applications due to their gel point below body temperature at concentrations less or equal 20 %.
Table 2. Gel point for selected poloxamers at 20% (w/w) in aqueous solutions [40].
Overall, poloxamers have a beneficial safety profile. Safety must always be assessed in relation to dosage, route of administration, and the corresponding specific risks [41], [42], [43]. Within the poloxamer substance class, the variation in molecular weight and hydrophilicity can affect the toxicological profile. Poloxamer 338 was found to have only low to moderate toxicity after intravenous injection in mice, the LD50 was reported to be 1250 mg/kg body weight. Poloxamer 338 is not irritating to the eyes of rabbits. In an older study, feeding of poloxamer 338 to rats and dogs at doses of 200, 1000 and 5000 mg/kg body weight/day showed no significant effects regarding hematology, urinalysis and (histo)pathology. No mutagenic activity of poloxamer 338 was observed in the Ames test [44]. Further safety information, on poloxamer 338 in intramuscular applications can be found as reviews in FDÁs Drug Approval Package on Vocabria® and EMÁs Assessment report on Rekambys® [45], [46].
Topical applications and subcutaneous applications require gel points below room temperature or body temperature, respectively. The gel point can be influenced by the presence of salts or APIs. The effects of added salts on phase transition and micelle formation have been discussed in the literature for poloxamer 407 and other poloxamers [47], [48], [49], [50]. The presence of APIs can also affect the gel formation of poloxamer gels. For example, recent studies have investigated the impact of diclofenac on the gelation temperature of poloxamer 407 gels, as well as its effects on self-assembly and drug delivery profiles. It was found that increasing the concentration of diclofenac resulted in higher gelation temperatures, and the effects of counterions present matched the trends of the Hofmeister series [51]. The gelation, drug solubilization capacity, and release kinetics of ibuprofen-containing poloxamer 407 hydrogels have also been described. It was found that the presence of ibuprofen increased the micellar volume fraction in poloxamer 407 aqueous solutions [52]. Additionally, the applicability of gels composed of combinations of poloxamer 407, poloxamer 188, and alginate with 5-fluorouracil as an API for drug delivery has been demonstrated [53].
While there have been studies indicating a significant effect of gel point shifting upon the addition of additives in poloxamer 407 or poloxamer 407/poloxamer 188 gel formulations, no systematic investigation has been published for poloxamer 338. However, due to its favorable toxicological profile, poloxamer 338 can be a suitable alternative to poloxamer 407 for hydrogel formulations. This study investigated the influence of various additives, including salts and APIs, on the gelation temperature of poloxamer 338. The results were contextualized within the existing data on other poloxamer formulations. Additionally, a predictive model was established to elucidate the relationship between shifts in gelation temperature and the physicochemical properties of the APIs. This model provides a valuable framework for formulators of semisolid preparations incorporating P338.
Download the full article as PDF here Alteration of gel point of poloxamer 338 induced by pharmaceutical actives and excipients
or read it here
Materials
Kolliphor® P 338 was obtained by BASF (Geismar, USA). Reagents and APIs were obtained as follows: sodium chloride, potassium chloride and HPLC-grade water from Honeywell (Seelze, Germany); Sucrose, sodium iodide and salicylic acid from Sigma Aldrich (Steinheim, Germany); Sodium sulfate from VWR (Leuven, Belgium); Ammonium chloride, sodium thiocyanate and sodium dihydrogen phosphate monohydrate from Sigma (Darmstadt, Germany); Calcium chloride and sodium hydroxide from Bernd Kraft (Duisburg, Germany); Diclofenac sodium from Henan Dongtai Pharm Co., LTD. (Tangyin, China); Ibuprofen from BASF (Bishop, USA); Naproxen sodium from Zhejiang Charioteer Pharmaceutical Co., Ltd. (Jinhua, China); Ketoprofen from Midas Pharma (Ingelheim, Germany); Metformin hydrochloride from Exemed Pharmaceuticals (Luna, India); Flurbiprofen from Fluorochem (Hadfield, Great Britain).; Acetylsalicylic acid from TCI (Zwijndrecht, Belgium); Propranolol hydrochloride from Cosma S.p.A. (Ciserano, Italy). Buffer solutions were prepared by dissolving sodium dihydrogen phosphate monohydrate in HPLC-grade water and pH adjustment using sodium hydroxide.
Natalie Deiringer, Fabian Fischer, Martin Hofsäss, Meik Ranft, Sophia Ebert, Alteration of gel point of poloxamer 338 induced by pharmaceutical actives and excipients, European Journal of Pharmaceutics and Biopharmaceutics, Volume 207, 2025, 114628, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2025.114628.
Read also our introduction article on Topical Excipients here:
