Critical Excipients in Topical and Parenteral Dermatological Formulations: Novel Analytical Approaches and Risk Mitigation

Figure I. Rheological profiling of different petrolatum variants

Background & Introduction

Excipients play a crucial role in efficacy, safety and quality of medicinal products. In topical dermatological formulations, often complex excipients of natural or semi-synthetic origin with broad specifications are used (1). In parenteral drug delivery, non-ionic surfactants are key components of biopharmaceutical formulations that are playing an increasingly important role in dermatological indications such as psoriasis and atopic eczema.
Petrolatum or “white soft paraffin” is a commonly used excipient in topical and ophthalmic formulations. It consists of two solid hydrocarbon waxes and a liquid hydrocarbon fraction and can be described as an oleogel [2]. Pharmacopeial specifications are broad [3] and have little relevance to critical performance and process parameters in semi-solid formulations.
Polysorbates are widely used as non-ionic surfactants in biopharmaceutical antibody formulations. They are complex mixtures of partial esters of fatty acids with sorbitol or isosorbide with approximately 20 moles of ethylene oxide per mole of sorbitol/isosorbide. In injectables, polysorbate degradation has become a focus of attention as chemical or enzymatic degradation can lead to the appearance of sub-visible and visible particles.
The fatty acid ether lauromacrogol 400, also known as polidocanol, can be used as an emulsifying excipient, but also as an active ingredient for local anesthetics (topical) or for vein sclerotherapy (injectable).

Methods

Rheometry was performed on a MCR 102 rheometer from Anton Paar, Germany, with a CP25-1 system at 25°C. A low-stress sample application method was used; tempering time was 300 s. Amplitude sweeps were performed in oscillation mode with 0.01 to 100% deformation and a constant angular of frequency of 10 rad/s.
Polysorbate analysis was performed with a UPLC system (ACQUITY UPLC H-Class PLUS, Waters). Eluents were aqueous 10 mmol/L ammonium acetate and acetonitrile containing 0.1% formic acid at a flowrate of 0.5 mL/min. A gradient from 5 v% to 85 v% organic phase was used. Peaks were detected with a single quadrupole mass spectrometer (QDa, Waters, mass range 30–1250 m/z). For details see [4]

Results

a) Impact of Petrolatum Variability on Topical Formulations

By means of oscillatory rheology, 14 different Pharm. Eur. compliant petrolatum variants from three different suppliers (blue) and four batches of one variant (red) were investigated. The complex modulus (G*), a measure for the rigidity of the material, showed a variability of factor four between the least and most rigid variant. For the flow point (τF), a measure for the structural strength ofpetrolatum, even a variability of almost factor ten was observed (Fig. I).

This high variability renders different variants differently well suitable for different purposes of application. Often, they are not mutually interchangeable without affecting the properties of the resulting product. Rheological analysis can
support a rational selection of petrolatum variants suitable for their respective purpose.

b) Analysis of Polysorbate 20 in Biopharmaceutical Formulations

In the USP, polysorbate 20 is still referred to as ‘polyoxyethylene 20 sorbitan monolaurate’. However, Evers et al. identified 676 subspecies of the excipient (4) with only a few percent of polyoxyethylene 20 sorbitan monolaurate (Fig.II)

c) Batch to Batch Variability of Lauromacrogol 400

According to the European Pharmacopeia monograph for the drug substance, the number of moles of ethylene oxide reacted per mole of lauryl alcohol is 9. As shown in Figure IV, the number of ethylene oxide moles per mole lauryl alcohol with the highest incidence may also be 10 (supplier 1, blue) or 12 (supplier 2, green). The differences can affect the performance of the compounds both as excipient (emulsifier) and as active.

Conclusions

Oscillatory rheology provides important insight into the physical properties of complex topical drug delivery excipients such as petrolatum. UHPLC-MS analysis allows identification and quantification of subspecies of highly complex surfactant-type excipients used in parenteral delivery.
Identifying and understanding the differences in complex excipients from supplier to supplier, batch to batch, or fresh to aged materials enables risk mitigation and product optimization.

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