International Journal of Pharmaceutics 458 (2013) 90–98

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Quantification of the types of water in Eudragit RLPO polymer and the kinetics of water loss using FTIR Chompak Pirayavaraporn a , Thomas Rades c , Keith C. Gordon b , Ian G. Tucker a,∗ a

School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, New Zealand Department of Chemistry and MacDiarmid Institute for Advanced Materials and Nanotechnology, University of Otago, Dunedin, New Zealand Research Chair in Pharmaceutical Design and Drug Delivery, University of Copenhagen, Faculty of Health and Medical Sciences, Department of Pharmacy Universitetsparken 2, 2100 Copenhagen, Denmark b c

a r t i c l e

i n f o

Article history: Received 24 May 2012 Received in revised form 29 September 2013 Accepted 4 October 2013 Available online 19 October 2013 Keywords: FTIR DRIFTs Methacrylates Eudragit Water Environment

a b s t r a c t Coalescence of polymer particles in polymer matrix tablets influences drug release. The literature has emphasized that coalescence occurs above the glass transition temperature (Tg ) of the polymer and that water may plasticize (lower Tg ) the polymer. However, we have shown previously that nonplasticizing water also influences coalescence of Eudragit RLPO; so there is a need to quantify the different types of water in Eudragit RLPO. The purpose of this study was to distinguish the types of water present in Eudragit RLPO polymer and to investigate the water loss kinetics for these different types of water. Eudragit RLPO was stored in tightly closed chambers at various relative humidities (0, 33, 56, 75, and 94%) until equilibrium was reached. Fourier transform infrared spectroscopy (FTIR)-DRIFTS was used to investigate molecular interactions between water and polymer, and water loss over time. Using a curve fitting procedure, the water region (3100–3700 cm−1 ) of the spectra was analyzed, and used to identify water present in differing environments in the polymer and to determine the water loss kinetics upon purging the sample with dry compressed air. It was found that four environments can be differentiated (dipole interaction of water with quaternary ammonium groups, water cluster, and water indirectly and directly binding to the carbonyl groups of the polymer) but it was not possible to distinguish whether the different types of water were lost at different rates. It is suggested that water is trapped in the polymer in different forms and this should be considered when investigating coalescence of polymer matrices. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Various types of acrylic polymers are used in the pharmaceutical field for pH-dependent or pH-independent controlled or sustained release of drugs as well as for site specific release of drugs in the gastrointestinal tract (Albers et al., 2009; Glaessl et al., 2010; Sauer et al., 2009; Semdé et al., 2000; Zhu et al., 2006). An important phenomenon controlling drug release from a matrix system is the coalescence of polymer particles in the matrix. The literature reports that such coalescence only occurs above the glass transition temperature (Tg ) of the polymer (Abbaspour et al., 2007; Azarmi et al., 2002, 2005; Omelczuk and McGinity, 1993). Although it is understood that moisture is likely to lower Tg (Hancock and Zografi, 1994), our previous study showed that only about 25% of the water in a sample of Eudragit RLPO (Tg = 55–70 ◦ C, Zhu et al., 2006) was ‘plasticizing’ water and that the ‘nonplasticising’ water also influenced coalescence (Pirayavaraporn et al., 2012). This raises the

∗ Corresponding author. Tel.: +64 3 479 7296; fax: +64 3 479 7034. E-mail address: [email protected] (I.G. Tucker). 0378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijpharm.2013.10.012

question about the different forms of water present in Eudragit RLPO. Water in polymers has been classified in various ways. It has been described as non-freezable bound water, which is strongly interacting with polar parts of a polymer causing Tg suppression consistent with the Gordon–Taylor prediction, and excess water, absorbed in the polymer as clusters, with no effect on Tg (Blasi et al., 2005; Cotugno et al., 2001; Jin et al., 2011). Spectroscopic techniques such as NMR, FTIR, or dielectric spectroscopy have been used to elucidate water polymer interactions and several types of water binding in polymers have been discovered (Grave et al., 1998; Jelinski et al., 1985), including H-bonding between the hydrophilic groups of water and polymer; water clusters; and the surface sorption onto free volume microvoids in the polymer (Cotugno et al., 2001). Confined into microvoids, clusters of water with no Hbonding to the polymer and water only weakly H-bonded with the polymer are likely to show high mobility but low plasticizing efficiency (Lasagabaster et al., 2006). In contrast, tightly bound water results in a high plasticizing efficiency (Cotugno et al., 2001). Others have classified water incorporation into three classes or binding species based on its thermodynamic properties:

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freezable free water, freezable bound water, and non-freezable bound water (Blasi et al., 2005; Wartewig, 2003). The freezable free water exhibits an enthalpy of crystallization and melting not much different from that of bulk water. The freezable bound water is distantly associated water with the polymer (less tightly bound water), which shows thermodynamic events different from bulk water; for example, compared to bulk water, supercooling or a decrease in the enthalpy of both melting and crystallization is often observed. The non-freezable bound water (tightly bound water) does not show phase transitions (no crystallization exotherm or melting endotherm) during calorimetric investigations. The summation of the non-freezable bound and freezable bound fraction is called “bound water content” (Hatakeyama and Hatakeyama, 1998). In order to discriminate the different types of water binding, many studies have used spectroscopic techniques, which provide molecular level information and refer to the “four stage model”, which focuses on the O H stretching vibration (the most susceptible region to H-bonding). The four stage model is generated from the decomposition of the broad O H stretching band in the IR spectrum of water by mathematical models. The position of the decomposed bands (peak frequency) relates to the strength of H-bonding, which suggests types of water present in the polymer (molecular interaction) (Cotugno et al., 2001; Lasagabaster et al., 2006; Sammon et al., 1998; Thouvenin et al., 2002). Walrafen studied the temperature effect on pure water, and decomposed the O H stretching of Raman spectra into four Gaussian components (Walrafen, 1967). He found an isosbestic point around 3460 cm−1 which divided the four components into two groups, scattering from H-bonded and non-H-bonded O H oscillators. At frequencies lower than the isosbestic point, the intensity of water components decreased upon raising temperature; while the intensity of the other two components at higher frequency increased. The four stage model has since been commonly used to decompose water spectra in the O H stretching region (Georgiev et al., 1983; Scherer, 1974). The aims of this study were to distinguish the types of water present in Eudragit RLPO polymer and to investigate the water loss kinetics for these different types of water using Fourier transform infrared spectroscopy in the diffuse reflectance mode (FTIR-DRIFTS).

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Fig. 1. Chemical structure of Eudragit RLPO [poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2].

2. Materials and methods 2.1. Materials Eudragit® RLPO (Fig. 1) (ammonio methacrylate copolymer type A, Ph. Eur./NF) was kindly provided by Evonik Industries (Darmstadt, Germany). Magnesium chloride, sodium bromide, sodium chloride, and potassium nitrate were of analytical grade and supplied from Biolab (NZ) Ltd., and Ajax Finechem (Auckland, New Zealand). 2.2. Sample preparation A few millimeters thick Eudragit® RLPO powder beds were exposed to different relative humidities of 33, 56, 75, 94%, which were generated from saturated salt solutions (Rockland, 1960), kept in tightly closed chambers. For dry samples, the same thickness of the polymer powder bed was stored over phosphorus pentoxide (P2 O5 ) in a vacuumed desiccator for a week prior to use. Temperature and relative humidity in the chambers were monitored with HOBO® data loggers (Scott Technical Instruments, Hamilton, NZ). The polymer samples were monitored for moisture content by

Fig. 2. Example of an FTIR scan over time (1–150 min) of Eudragit RLPO (stored at 94% RH) showing a reduction in intensity of the water region/OH stretching area (3100–3700 cm−1 ) upon dry air purging.

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Fig. 3. The intensity of the water region spectra decreased upon drying the sample in the FTIR chamber: (a) after normalization, (b) after smoothing, cut and baseline correction.

thermogravimetric analysis (TGA) until equilibrium was reached (100 days). 2.3. Fourier transform infrared spectroscopy (FTIR- DRIFTs) 2.3.1. Sample preparation and spectra collection For each IR measurement, 5% of the sample was geometrically mixed with ground dried KBr and filled into a cup holder. The powder surface was then leveled by using a razor blade. The sample holder was loaded into the IR chamber and the first spectrum was recorded immediately using the diffuse reflectance IR Fourier transform spectroscopy (DRIFTS) measuring mode with dry air purging (Varian Excalibur 3100 FT-IR (Varian Inc., USA) equipped with Pike Technologies Easidiff accessories (Madison, WI, USA)). Subsequent spectra were recorded every minute from 1 to 10 min, then at 15, 30, 45, 60, 90, 120 and 150 min. The average of 32 scans (from 400 to 4000 cm−1 ), at 4 cm−1 resolution was recorded in triplicate for each sample (n = 3).

2.3.2. Data manipulation OPUSTM software (Bruker Optik, Ettlingen, Germany) was used to analyze the water region (3100–3700 cm−1 ) of the spectra after converting the recorded spectra to Kubelka–Munk units and KBr background subtraction. Of the entire range of the spectrum (400–4000 cm−1 , Fig. 2), the wavenumber region from 2650 to 3750 cm−1 was manually selected to perform normalization against dominant/stable C H stretching peaks (around 3000 cm−1 ). In this study, “Min–Max normalization” was used to scale the minimum value to zero and maximum value to two absorbance units (Fig. 3a). Then the spectra were cut to the region of interest (3100–3700 cm−1 ), smoothed by a Savitzky–Golay algorithm (13 points) to reduce noise, and baseline corrected manually to be ready for the curve fitting procedure (Fig. 3b) (Wartewig, 2003). 2.3.3. Data evaluation (curve fitting procedure) The Fourier self-deconvolution and second derivative function were used to assist overlapping peak-shoulder differentiation and

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Fig. 4. Example of the appearance of the spectra after derivatization (Eudragit sample stored at 94% RH).

to guide peak positioning (Fig. 4). The Levenberg–Marquardt algorithm was used for the curve fitting of the spectra. The band parameters (peak position, intensity and width) and band shape, including Lorentzian, Gaussian, or a mixture of both functions, were

introduced to create a curve fitting model (Fig. 5) which showed the lowest residual RMS error (

Quantification of the types of water in Eudragit RLPO polymer and the kinetics of water loss using FTIR.

Coalescence of polymer particles in polymer matrix tablets influences drug release. The literature has emphasized that coalescence occurs above the gl...
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