Analysis of Local Free Volume and Hydration in Pharmaceutical Polymer Films Using Positron Annihilation Lifetime Spectroscopy

Abstract

The relationship between the nanoscale free volume of pharmaceutical polymer films and their hydration behavior remains poorly understood. Eight pharmaceutical polymers were screened at three concentration levels within a quality-by-design framework; only two poly(vinyl alcohol) grades (PVA EG-30P and EG-40P), hydroxypropyl cellulose (HPC), and sodium alginate (Na-alginate) formed continuous films. These were characterized by positron annihilation lifetime spectroscopy (PALS), loss on drying (LOD), and swelling analysis.

PALS clearly differentiated HPC, Na-alginate, and PVA, whereas the two PVA grades were similar and the concentration had only a minor effect. HPC showed the largest free volume holes (86.7–89.5 ų), and Na-alginate the smallest holes (36.9–39.6 ų) together with the highest LOD (20.2–21.6%). Across the 12 polymer–concentration combinations, the free volume hole volume correlated inversely with LOD (Spearman ρ = −0.85) but not with the equilibrium swelling index, as both HPC and Na-alginate swelled considerably more than PVA.

Thus, PALS discriminates film-forming pharmaceutical polymers and reflects their residual water content, but the free volume of the air-dried films does not predict their swelling capacity.

Introduction

The organization and interactions of polymer chains, together with the amount of bound water present in the system, govern the interaction of a polymer matrix with water and thereby the properties of hydrated polymer thin films. These factors determine the local free volume available for swelling, the amount of fluid taken up during hydration, and the resulting dimensional changes. A comprehensive understanding of such systems at both the microstructural and molecular level is therefore essential for the rational selection and optimization of pharmaceutical and biomaterial polymers for a given application. Conventional macroscopic measurements, however, provide only limited insight into the microstructural mechanisms underlying the macroscopically observed water uptake, swelling, and dimensional changes.

Positron annihilation lifetime spectroscopy (PALS) is a powerful technique for probing free volume characteristics in polymeric materials at the nanoscale level [1,2]. In the PALS lifetime spectrum, the ortho-positronium (o-Ps) component, associated with the longest lifetime, is generally characterized by two parameters: its lifetime (τ3) and relative intensity (I3). By applying the Tao–Eldrup model to the o-Ps lifetime component, the mean radius and the corresponding volume of free volume cavities can be estimated, while the o-Ps intensity provides qualitative information about the relative concentration of the cavities within the polymer matrix [3,4].

The PALS technique provides insight into several aspects of the microstructural organization of polymer matrices, particularly the size, distribution, and connectivity of free volume elements. The chemical nature of the polymer, such as the presence of side chains, the rigidity of polymer chains, the density of crosslinks, and the degree of crystallinity, or amorphous nature all significantly influence the size and distribution of free volume in a polymer matrix [5,6,7]. Interpreting the PALS-derived parameters together with the loss-on-drying (LOD) and swelling data therefore allows the comparison of polymer matrices across microstructural and macroscopic levels, and may provide insight into the molecular-level mechanisms underlying their hydration and swelling behavior.

A structurally diverse yet functionally relevant set of eight hydrophilic polymers, which are commonly used in pharmaceutical applications, was selected for the initial screening in this study: two PVA grades, Poloxamer, two Carbomer grades, HPC, Na-CMC, and Na-alginate. The selected polymers comprise natural, semi-synthetic, and synthetic materials of either a nonionic or anionic character, with distinct functional groups that influence their interactions with water. Na-alginate and Na-CMC are anionic linear polysaccharides that contain carboxylate functional groups, which promote hydration and render their aqueous behavior sensitive to ionic conditions [8,9,10]. PVA and HPC are nonionic polymers with an extensive hydrogen-bonding capacity. PVA is a semicrystalline polymer, rich in hydroxyl groups, whereas HPC is a hydroxypropyl-substituted cellulose ether [11,12,13,14]. Poloxamer is a triblock copolymer, consisting of PEO-PPO-PEO triblocks. It possesses thermoreversible gelation, which is temperature- and concentration-dependent, and, owing to its amphiphilic nature, it can self-assemble into micelles in aqueous solutions [15,16]. Carbomer is a synthetic, crosslinked poly(acrylic acid) network, whose water uptake and swelling are strongly pH-dependent because of the ionization of its carboxylic acid groups [17].

The investigated polymers thus differ in polymer-chain architecture, functional group chemistry, ionization behavior, and intermolecular organization. Consequently, they are expected to exhibit distinct polymer–water interactions, hydration characteristics, and swelling behavior. To complement the comparison of chemically distinct polymer types, two PVA grades (PVA EG-30P and PVA EG-40P) and two Carbomer grades (Carbomer 971 and Carbomer 974) were included to assess grade-dependent differences in rheological and film-forming properties, as well as in PALS-derived parameters and swelling properties for the film-forming grades. If such differences are observed, they may reflect grade-dependent variations in molecular characteristics, including molecular weight, solution viscosity, and network organization. Each polymer was screened at three concentration levels. Collectively, the selected polymer set provides a basis for systematically evaluating the effects of polymer type, polymer grade, and concentration on film formation, and on free volume-related microstructural parameters, LOD, and swelling behavior in the resulting thin films.

The polymer characterization strategy was structured within a quality-by-design (QbD) framework and was aligned with the identified critical material attributes (CMAs) and critical process parameters (CPPs), and systematic risk assessment. In the present study, QbD served as a prospective framework for structuring the analyses and for identifying the factors that may influence thin film formation and film properties. It was not intended to establish a pharmaceutical design space or to conclude therapeutic performance. Initially, all eight polymers were screened at three concentration levels for apparent viscosity and film-forming capacity. Because only four of them (the two PVA grades, HPC, and Na-alginate) formed continuous films under the applied conditions (Section 2.2), a thin film thickness measurement, LOD, PALS, and swelling analysis were performed only on these four film-forming polymers, at three concentration levels.

Although PALS has been applied to a wide range of pharmaceutical excipients, drug delivery systems, and medical devices, few studies have systematically compared chemically distinct film-forming pharmaceutical polymers prepared under identical conditions while directly relating PALS-derived free volume descriptors to the residual moisture content and swelling behavior of the resulting films [1]. We hypothesized that polymer-specific differences in local free-volume descriptors are associated with distinct hydration and swelling behavior.

Accordingly, the aims of this work were (i) to investigate whether PALS is suitable for differentiating pharmaceutical polymers at the microstructural level, (ii) to relate PALS-derived parameters to macroscopic hydration behavior in terms of the underlying molecular features, including interchain interactions, crystallinity, and polymer chain mobility, and (iii) to assess whether the free volume of the air-dried films is related to their residual moisture content and whether it can predict their swelling capacity. The investigated systems did not contain an active pharmaceutical ingredient (API), nor additional formulation-specific excipients. Consequently, the API loading capacity, drug-release performance, mechanical performance, and therapeutic efficacy were outside the scope of this study.

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