Glass transitions in binary drug + polymer systems

doi:10.1016/j.matlet.2009.09.033

Materials Letters

Volume 63, Issue 30, 31 December 2009, Pages 2666-2668

https://doi.org/10.1016/j.matlet.2009.09.033 Get rights and content

Abstract

To evaluate miscibility, glass transition temperatures T_g have been determined for two binary polymer (Plasdone S-630 copovidone or Eudragit® E) + drug systems as a function of composition. Each polymer serves for encapsulation of the anti-HIV drug Efavirenz. In both systems the T_g vs. drug concentration diagrams are s-shaped. T_gs of Efavirenz + Plasdone mixtures with drug mass fraction below φ_drug = 0.6 are above linear values. This implies enhanced thermal and mechanical stability—an advantage for the drug encapsulation. In the other system, a strong negative deviation of T_gs is observed over the entire compositional range and explained by positive excess mixing volumes. Several equations are used to represent T_g vs. composition diagrams, but only one (Brostow et al. Mater Lett 2008; 62:3152) provides reliable results.

Introduction

The glass transition is the most important feature of all non-crystalline materials, including polymers [1], [2] and polymer-based composites [3]. The underlying mechanism demonstrates high sensitivity to even subtle modifications of structure and interactions. Inoue et al. [4], for example, report that in thin films of polystyrene the glass transition takes place at lower temperatures than in the bulk; more complex variations have been reported for other nanoscale confining geometries. Analysis of glass transition characteristics is indispensable, for instance, for copolymers [5], in studies of morphological changes [6], of effects of fillers on polymer dynamics [7], of results of aging [8], temperature dependence of melt viscosity [9], electron beam irradiation [10] or nanoindentation creep [11]. The nature of the glassy state is an object of a variety of studies [12], [13], [14], including representation of glass structures by the Voronoi polyhedra [12], [14]. We note that the glass transition temperature T_g is a convenient numerical representation of a glass transition region; if the required service temperature range is below T_g of a given polymer, severe limitations in usability of that polymer appear.

Increasing demand for polymer-based materials with predefined properties causes more and more polymer blends being made, and examined to assert miscibility of their constituents. Typically, fully miscible binary (A + B) blends show a single T_g value varying with the composition, say mass fraction φ_B, from T_g,A to T_g,B. Compatible (partly miscible) blends exhibit two composition-dependent transitions, while incompatible blends show two glass transitions (T_g,A and T_g,B) unaffected by the composition. Compatibilizing agents are also in use; success of a compatibilization is necessarily evaluated again in terms of T_g results.

A distinct yet related issue is that of drug encapsulation or preparation of drug + polymer matrices for controlling the rate at which the drug leaves the material. This objective can be achieved provided there is miscibility of the drug with the polymer matrix [15]. Fusion or solvent evaporation dispersion methods can be used to incorporate drugs into polymers. The use of a hot-melt extruded (HME) system has several advantages over traditional pharmaceutical processing techniques, such as the absence of solvents, few processing steps, continuous operation, and the formation of solid dispersions for improved drug dissolution and bioavailability. As already noted, miscibility can be verified by T_g(φ) determination. Along these lines, we report here results on two drug + polymer systems, with the drug Efavirenz the same in both. Both systems have shown miscibility, but unusual s-shaped T_g(φ) diagrams. With anomalous T_g(φ) plots often reported for binary blends, the best option would be representing experimental data by a single analytical equation. Then, among others, development of drug + polymer encapsulating systems would be significantly facilitated since the polymer concentration in the capsule has to be optimized. We describe below the drug + polymer pairs and the method of determination of T_g(φ) used. Accordingly, we list important T_g(φ) equations and apply them to evaluate their reliability in the representation of T_g(φ) diagrams.

Section snippets

Experimental

Efavirenz + PLS S-630 (Plasdone S-630 copovidone) and Efavirenz + Eudragit® E have been studied. The chemical formula of the drug Efavirenz is:

It is used as a part of an antiretroviral therapy for the treatment of human immunodeficiency virus (HIV) type 1. This drug is not absorbed well through the gastrointestinal tract due to its poor water solubility. The dissolution of Efavirenz can be increased by preparation of HME blends of this drug and the polymers under examination.

Chemical formulae of

T_g(φ) equations

In Table 1 we have tabulated several T_g equations for miscible binary polymer blends, ending the list with our own equation. We have discussed previously origins of the above equations [24]. The Couchman and Karasz equation requires the knowledge of changes in heat capacities, often not available (T_g values from dielectric or dynamic mechanical relaxation). Gordon–Taylor, Jenckel–Heusch, and Utracki equations can only represent either positive or negative deviations from linearity, and – as

Calculations and results

Fig. 1 presents the results for the miscible Efavirenz + Plasdone S-630 copovidone blend. The success of each representation of experimental data is judged by the coefficient of determination R² (= 1 for the perfect fit). We see clear divergence from the Fox, Gordon–Taylor and Kwei equations. The Brekner–Schneider–Cantow equation with K₁ = − 0.4 ± 0.2 and K₂ = − 0.9 ± 0.1 (R² = 0.997), provides decent description of the data—slightly inferior to that attained by our equation with a₀ = 8 ± 1, a₁ = − 32 ± 3 and a₂ = − 39 ± 7

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Amorphous-state characterization of efavirenz-polymer hot-melt extrusion systems for dissolution enhancement
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Citation Excerpt :
The observed Tg values were significantly lower than the theoretical values, suggesting the free volume in the homogenous phase is larger than that in the ideal mixture. The presence of longer lateral groups in Eudragit EPO compared with those found in Plasdone S-630 explains the dissimilar Tg dependences.27 Other phenomena may also have contributed to this behavior.
The aim of this study was to improve the dissolution rate of efavirenz (EFV) by formulating a physically stable dispersion in polymers. Hot-melt extrusion (HME) was used to prepare solid solutions of EFV with Eudragit EPO (a low-glass transition polymer) or Plasdone S-630 (a high-glass transition polymer). The drug–polymer blends were characterized for their thermal and rheological properties as a function of drug concentration to understand their miscibility and processability by HME. The solid-state stability of extrudates was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and dissolution studies. Thermal and rheological studies revealed that the drug is miscible with both polymers, and a decrease in melt viscosity was observed as the drug concentration increased. XRD and DSC studies confirmed the existence of amorphous state of EFV in the extrudates during storage. The dissolution rate of EFV from the extrudates was substantially higher than the crystalline drug. FTIR studies revealed an interaction between the EFV and Plasdone S-630, which reduced the molecular mobility and prevented crystallization upon storage. EFV and Eudragit EPO systems lack specific interactions, but are less susceptible to crystallization due to the antiplasticization effect of the polymer.
A novel approach for analyzing glass-transition temperature vs. composition patterns: Application to pharmaceutical compound + polymer systems
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In medicine, polymer-based materials are commonly used as excipients of poorly water-soluble drugs. The success of the encapsulation, as well as the physicochemical stability of the products, is often reflected on their glass transition temperature (T_g) vs. composition ( $w$ ) dependencies. The shape of the $T_{g} (w)$ patterns is critically influenced by polymer's molecular mass, drug molecule's shape and molecular volume, the type and degree of shielding of hydrogen-bonding capable functional groups, as well as aspects of the preparation process. By altering mixture's T_g the amorphous solid form of the active ingredient may be retained at ambient or body temperatures, with concomitant improvements in handling, solubility, dissolution rate and oral bioavailability. Given the importance of the problem, the glass transitions observed in pharmaceutical mixtures have been extensively analyzed, aiming to appraise the state of mixing and intermolecular interactions. Here, accumulated experimental information on related systems is re-evaluated and comparably discussed under the light of a more effective and system-inclusive $T_{g} (w)$ equation. The present analysis indicates that free volume modifications and conformational changes of the macromolecular chains dominate, over enthalpic effects of mixing, in determining thermal characteristics and crystallization inhibition/retardation. Moreover, hydrogen-bonding and ion-dipole heterocontacts – although favorable of a higher degree of mixing – appear less significant compared to the steric hindrances and the antiplasticization proffered by the higher viscosity component.
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The present study explores the applicability of a three-parameter equation: T_g = φ₁T_g,1 + (1 − φ₁)T_g,2 + φ₁(1 − φ₁)[a₀ + a₁(2φ₁–1) + a₂(2φ₁–1)²] (where φ_i and T_g,i are, respectively, the weight fraction and the glass transition temperature of the ith neat component), recently proposed for describing the T_g vs. composition dependencies in miscible binary polymer blends and copolymers (Brostow et al. Mater. Lett. 62 (2008) 3152 [16]). Its efficacy is postulated here also for mixtures of polymers with low molecular mass organics (solvent, plasticizer or semicrystalline drug molecule phases) and very strongly/weakly associating polymer blends, including interpolymer complexes. Binary systems where entropic factors overcome the enthalpic ones were also considered. For several complicated (asymmetric or sigmoid) dependencies a description with better accuracy was achieved, compared to the common theoretical or semi-empirical functional forms, some of which require parameters that are not always readily available to the experimentalist or contain a superfluous number of fitting parameters. First- (linear) or second-order (parabolic) polynomial dependencies are established among its prime parameter a₀ and “interaction terms” of common T_g(φ) functions, which are used as semi-quantitative measures of the strength of intermolecular interactions (e.g., parameter k_GT of Gordon–Taylor, b of Jenckel–Heusch, and q of Kwei). Changes in the shape of the T_g(φ) plots, and the corresponding a_i fitting parameter estimates, are discussed in relation to important physicochemical phenomena and properties of the mixtures, such as, the strength of the hetero-contact forces and their composition dependence, irregular excess free-volume effects, as well as nanoscale effects arising from variation of components molecular mass, chains’ branching or organization in crystalline phases.
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Glass transitions in binary drug + polymer systems

Abstract

Introduction

Section snippets

Experimental

Tg(φ) equations

Calculations and results

Mater Sci Eng

Polymer

Bull Am Phys Soc

Mater Lett

J Polym Sci Phys

J Polym Sci Phys

Polymer Physics

Fundamentals of Fibre Reinforced Composite Materials

Macromolecules

Polym Eng Sci

Express Polymer Letters

Polym Eng Sci

Macromolecules

T_g(φ) equations