ATR-FTIR spectroscopic imaging to study the drying and dissolution of pharmaceutical polymer-based films

Accepted Manuscript Title: ATR-FTIR spectroscopic imaging to study the drying and dissolution of pharmaceutical polymer-based films Author: Hiroki Hifumi Andrew V. Ewing Sergei G. Kazarian PII: DOI: Reference:

S0378-5173(16)30931-0 http://dx.doi.org/doi:10.1016/j.ijpharm.2016.09.085 IJP 16127

To appear in:

International Journal of Pharmaceutics

Received date: Revised date: Accepted date:

10-8-2016 16-9-2016 30-9-2016

Please cite this article as: Hifumi, Hiroki, Ewing, Andrew V., Kazarian, Sergei G., ATR-FTIR spectroscopic imaging to study the drying and dissolution of pharmaceutical polymer-based films.International Journal of Pharmaceutics http://dx.doi.org/10.1016/j.ijpharm.2016.09.085 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ATR-FTIR spectroscopic imaging to study the drying and dissolution of pharmaceutical polymer-based films

Hiroki Hifumia,b, Andrew V. Ewinga, Sergei G. Kazariana,*

a

Department of Chemical Engineering, Imperial College London, London SW7 2AZ, United Kingdom

b

Analytical & Quality Evaluation Research Laboratories, Daiichi Sankyo Co. Ltd., 1-12-1, Shinomiya, Hiratsuka-shi, Kanagawa, 254-0014, Japan * Corresponding author at: Department of Chemical Engineering, Imperial College London, London SW7 2AZ, United Kingdom. E-mail address: [email protected] (Sergei G. Kazarian).

Abstract Pharmaceutical film dosage form have recently become of interest to pharmaceutical formulation development, particularly for patients who experience difficulty in swallowing tablets or capsules. Furthermore, formulation scientists require a reliable analytical approach to reveal vital insight and investigate the drying process of these films to consolidate suitable quality control. Since most of the polymer-based films containing a drug are produced via solution or dispersion states, an estimation of the physicochemical properties of drugs during drying and dissolution is critical to design novel formulations with the consideration to control drug release, i.e. safety and efficacy to patients. This work presents the novel application of attenuated total reflection–Fourier transform infrared (ATR–FTIR) spectroscopic imaging to study the drying process and dissolution behaviour of polymer-based films. Two types of the ibuprofen containing films, hydroxypropyl methylcellusose (HPMC) based film for immediate release and polyvinylpyrrolidone (PVP) based film for extended release, were studied in modified pH environments and changing hydrophobicity. ATR-FTIR imaging has revealed important information on water ingress into the films and the presence, distribution, and physicochemical state of the drug. ATR-FTIR imaging is a powerful technique to investigate and to deeply understand physicochemical processes for pharmaceutical polymer-based films.

Keywords: Drug delivery, polymer films, interactions, ATR, FT-IR spectroscopy, imaging, dissolution

1. Introduction Oral films used for drug delivery are recognised by many pharmaceutical reference standards (including European Pharmacopoeia, United States Pharmacopeia and Japanese Pharmacopoeia) alongside commonly employed dosage forms tablets, capsules and injections. Based on their drug delivery concepts, oral films are classified as orodispersible films by the European Medicines Agency (EMA), oral soluble films by the Food and Drug Administration (FDA) and buccal films (Borges et al., 2015; Preis et al., 2013). The recent interest in the use of these dosage forms stems from the fact that oral films may be a very important alternatives for individuals that lack the ability to consume other orally administrated medicines. Geriatric or paediatric patients who bear dysphagia or experience difficulty or discomfort in swallowing tablets or capsules would greatly receive benefit from drug administration using oral films. Despite the desirable patient compliance from the use of oral films for drug administration, there are ongoing concerns on accurate dosage uptake to ensure patient safety and efficacy (Breitkreutz and Boos, 2007). There are several reported manufacturing methods for the preparation of oral films that include solvent casting (Cilurzo et al., 2011; El-Setouhy and El-Malak, 2010; Garsuch and Breitkreutz, 2010; Mashru et al., 2005), hot-melt extrusion (Cilurzo et al., 2008; Low et al., 2013), semisolid casting, solid-dispersion extrusion , rolling (Nagaraju et al., 2013) and printing (Janßen et al., 2013) methods. It should be realised that based on consideration of the quality of products and manufacturing cost, a conventional solvent casting method is preferentially selected and widely used to prepare oral films using water or a volatile hydro-alcohol like ethanol as a solvent (Bala et al., 2013). This technique works by preparing a solution that contains the drug and polymer(s), which is cast and allowed to dry before being shaped into a desirable size. The oral films form complex polymeric matrices that control the physicochemical characteristics of the films and subsequent drug release performance. The application of a reliable analytical approach to investigate the behaviour of polymer-based film drug delivery methods during manufacture and drug release experiments is of great importance for the continued development of these formulations. Physical characteristics that include, physical strength, chemical and physical stability, disintegration time, drug release profile, dose uniformity, residual solvents content, taste and flavour, are considered critical quality attributes (CQAs) for oral films (Borges et al., 2015). However, there is still a lack of regulatory guidance in each pharmaceutical reference standard for the characterization of the films (Preis et al., 2013). Since films are usually prepared via solution state, CQAs are largely affected by physicochemical conditions of drug and polymer(s) within films. This preparation method may allow the drug and polymer(s) to form interactions not only during the drying process of manufacturing but also in the final products, while such solution state is unlikely seen in the manufacturing process for tablets. Furthermore, the requirements for a greater understanding of pharmaceutical and manufacturing sciences is a critical factor for pharmaceutical formulation development so that a company steadily provides commercial products and complies with the regulatory terms of controlling the manufacturing processes (ICH harmonised tripartite guideline Q8(R2), August 2009). Therefore, understanding the behaviour of the drug and polymer, both in the manufacturing processes, and during dissolution is important for formulation development and quality control. There have been continuous developments for analytical approaches to study the final products as a means to evaluate the physicochemical characteristics of polymer-based films containing a drug. For example, FTIR (Ishikawa et al., 2015) and Raman spectroscopy (Sievens-Figueroa et al., 2012) have been used to evaluate the crystallinity of films or drugs from localised areas in the sample. The bulk pharmaceutical films have also been assessed with other complementary techniques such as differential scanning calorimetry (DSC) and X-ray diffraction (XRD). However, these techniques cannot provide information about the distribution of the different components in the formulation. Near

infrared chemical imaging (NIR-CI) (Palma et al., 2016; Sievens-Figueroa et al., 2012) has been demonstrated to provide information about the spatial distribution of the drug in a film but due to the near infrared wavenumber range, it is does not provide information about all of the individual components or reveal any drug–polymer interactions. Thus, mid-infrared spectroscopy and spectroscopic imaging are more suitable to determine such information about the formulated polymerbased films. Interestingly, based on a primary quality risk assessment produced from available knowledge of polymer-based films (ICH harmonised tripartite guideline Q9, November 2005), as shown in Table 1, there are currently no established imaging techniques for the real-time and in situ investigation of processes such as drying and dissolution behaviour from these film formulations. A range of analytical techniques have been developed in order to study the dissolution behaviour of drugs from tablets or pure drugs; fluorescence imaging (Adler et al., 1999; Bajwa et al., 2006; Brandl et al., 2010), ultraviolet imaging (Boetker et al., 2011; Jensen et al., 2015; Østergaard et al., 2010; Østergaard et al., 2014; Østergaard et al., 2011), magnetic resonance imaging (Chen et al., 2010; Fyfe and Blazek-Welsh, 2000; Nott, 2010; Richardson et al., 2005; Tres et al., 2015a), and vibrational spectroscopy (Ishikawa et al., 2013; Tres et al., 2015b; Windbergs et al., 2009; Wray et al., 2015). Fourier transform infrared (FTIR) spectroscopy is a powerful analytical approach that can be used to facilitate the characterization of individual chemicals based on their infrared absorption bands that arise from the fundamental vibrations of the chemical bonds. A relatively recent development of this approach has led FTIR spectroscopy to be combined with a focal plane array (FPA) detector to enable FTIR spectroscopic imaging (Lewis et al., 1995). FTIR spectroscopic imaging can provide the spatial distribution of individual chemicals by plotting the absorbance of unique spectral bands as a function of the measured area. By utilising the attenuated total reflection (ATR) methodology, ATR–FTIR spectroscopic imaging has become a unique approach for studying the dissolution of pharmaceutical formulations (Ewing et al., 2015; Kazarian and Chan, 2003; Kazarian and Ewing, 2013; Pudlas et al., 2015; Punčochová et al., 2015; van der Weerd and Kazarian, 2004; Wray et al., 2014). The data produced by this approach show the spatial distribution of each component within the measured area and thus allows quantitative and qualitative information to be determined. Since ATR–FTIR imaging reveals both chemically and spatially specific information, it is possible to track the dissolution and behaviour of different domains of the drugs within the matrix. This work demonstrates the applicability of ATR–FTIR spectroscopic imaging to study the drying process and the dissolution of polymer-based films containing ibuprofen as a model drug. Ibuprofen was selected as it is one of the most commonly taken drugs. It is classified as BCS II, thus ibuprofen is poorly soluble in water and could crystallize in the acidic gastric fluid, resulting in potential irritation the lining of the gut causing stomach ulcers (Lanza et al., 1979). Several approaches have been used to improve and control its solubility and a dissolution profile that include amorphous solid dispersions (ASDs) with the introduction of a polymeric excipient (Najib and Sheikh Salem, 1987) or a usage of inclusion compounds like cyclodextrins have also been investigated (Bibby et al., 2000). This study investigates two types of model films, an HPMC-based film for immediate release and a PVP-based film for extended release. The effect of changing the conditions of the aqueous pH environment and modifying the hydrophobicity of the films, by the addition of sodium carbonates or polyethylene glycol 4000 to the matrix, was assessed, respectively. Modifying the micro pH environment is an effective methodology for adjusting a drug dissolution profile (Streubel et al., 2000; Thoma and Zimmer, 1990). Since ibuprofen is a week acid and hence is much more soluble in basic conditions, adding basic pH modifiers, such as a mixture of sodium bicarbonate and sodium carbonate, can increase the solubility of ibuprofen by dissociating protons from its carboxylic acid groups (Levis et al., 2003). ATR–FTIR spectroscopic imaging was employed to characterise the

intermolecular interactions between the drug and excipients produced during preparation. Finally, the effect of adding a pH or hydrophobicity modifiers to change the micro pH environment, ionic strength, homogeneity, hydrophilic property, and subsequent dissolution rates of the films was investigated with respect to the modality of the intermolecular interactions within the polymer-based films using this chemically specific, reliable imaging approach. This approach can help to establish a reliable investigational method by being combined with the established testing methods and provide additional insight about behaviour and physicochemical properties of each component during processes. This may be useful to identify important material attributes or critical quality attributes (CQAs) in formulation research.

2. Materials and methods 2.1. Materials Sodium bicarbonate, sodium carbonate, ethanol absolute, and 37% (w/w) hydrochloric acid were supplied by VWR International (Poole, UK). Polyethylene glycol (extra pure, m.w. 4000) was supplied by Fisher Chemical (USA), polyvinylpyrrolidone K15, ibuprofen, and ibuprofen sodium salt was supplied by Sigma–Aldrich (Gillingham, UK). Hydroxypropyl methylcellulose (Methocel K100 Premium LV CR EP) was supplied by Colorcon (Orpington, UK). Glycerol was supplied by Value Health (Nottingham, UK). To make a 0.1M hydrochloric acid aqueous solution, 0.833 mL of 37% (w/w) hydrochloric acid was diluted to 100 mL. 2.2. Preparation of HPMC-based films A mixture containing 10 g of hydroxylpropyl methylcellulose (HPMC) and 10 g of glycerol was prepared by adding 80 mL of water and heating to 80°C. This composition was selected based on the previous work describing the suitability of such formulations (Sievens-Figueroa et al., 2012). The temperature of the mixture was decreased to room temperature to dissolve the polymer completely. The components were mixed until a clear colourless solution was obtained. The resulting solution was then degassed. 0.3 g of the polymer solution was added to 1 mL of 100 mM ibuprofen sodium salt aqueous solution, mixed and then degassed. In the samples where pH modifier was used, a ground mixture of sodium bicarbonate and sodium carbonate with 1:1 weight ratio was added to the 100 mM ibuprofen sodium salt aqueous solution with the polymer solution. Formulations of each film are shown in Table 2. The final viscous solution was then cast onto a diamond crystal of a commercially available Imaging Golden Gate ATR accessory (Specac, UK). The film was then dried at 50°C using a Heated Golden Gate Controller (Specac, UK). 2.3. Preparation of PVP-based films A solution containing 0.5 g of polyvinylpyrrolidone (PVP), and 125 mg of polyethylene glycol (PEG) 4000 for Film E, was prepared by adding 10 mL of ethanol and heating to 50°C for 30 minutes. The polymer solution was allowed to stand at room temperature for an hour. 25 mg of ibuprofen free form was added to 1 mL of the polymer solution and dissolved. The formulations of each of the film are shown in Table 2. The final solution was then cast onto a non-sticky plastic petri dish and dried in an oven at 50°C for over 3 hours. It should be clarified that in order to achieve homogeneity in the films, ibuprofen free form and ibuprofen sodium salt were used by taking into consideration the drug solubility in aqueous HPMC solution and PVP ethanol solution, respectively.

2.4. ATR-FTIR spectroscopy ATR-FTIR spectra for all of the pure materials and formulations studied in this investigation were measured using an Alpha-P spectrometer (Bruker, UK) fitted with a diamond ATR crystal. Spectra were recorded across the range of 4000–600 cm–1, using a spectral resolution of 8 cm–1 and 32 coadded scans. This spectral resolution was chosen to match the spectral resolution used in spectroscopic imaging experiments. 2.5. ATR-FTIR spectroscopic imaging To collect ATR-FTIR spectroscopic images, a commercially available ATR accessory (Specac, UK) fitted with a diamond crystal was employed. This ATR accessory was placed in an IMAC sampling compartment that was attached to an FTIR spectrometer (Equinox 55, Bruker, UK) and the imaging data was recorded using a focal plane array (FPA) detector. OPUS software was used to record the spectra in the mid-IR region between 4000–900 cm–1 at a spectral resolution of 8 cm–1 and 16 coadded scans for all experiments. The FPA detector was setup to record an array size of 64 × 64 pixels, meaning that 4096 individual FTIR spectra were recorded in a single experiment, and resulted in an image size of approximately 638 × 525 μm2. A macro was used in OPUS to record the spectroscopic imaging at regular defined intervals during the experiments. Chemical images representing the spatial distribution of the different components during the experiment were generated based on the identification of specific absorption bands for each of the materials of interest. Subsequently, the integrated absorbance of these spectral bands was plotted as a function of the measured area. Table 3 and Figure 5 show the integration ranges used to generate the spectroscopic images of the different components of interest in this investigation. The spectral band integration method used draws a linear baseline between the frequency limits defined in Table 3 and the area above this line is integrated. It should be realised that red regions in the spectroscopic images relate to high absorbance and the blue areas relate to zero or low absorbance of the species in the Figures presented in this manuscript.

2.6. In situ drying methodology The drying process of the HPMC-based solutions was investigated using both conventional ATRFTIR spectroscopy and spectroscopic imaging. As the solution dried, it was possible to characterise hydrogen-bond interactions between the ibuprofen and the HPMC excipient. To investigate this process using ATR-FTIR spectroscopic imaging, HPMC-based solutions were cast directly onto the measuring surface of the diamond crystal of the ATR accessory and were dried without a cover by heating to 50°C using a Heated Golden Gate Controller (Specac, UK). In contrast, for conventional ATR-FTIR spectroscopy, the HPMC-based solution was cast directly onto the diamond crystal of an Alpha-P spectrometer (Bruker, UK) and was dried without a cover in ambient conditions. Spectra were recorded across the range of 4000–600 cm–1, using a spectral resolution of 4 cm–1 and 32 coadded scans. 2.7. In situ dissolution methodology The dissolution experiments were setup by cutting and positioning the film in the centre of the diamond crystal. A custom designed transparent flow cell made of poly(methyl methacrylate) was placed above the film and a spacer was used to form a seal between the ATR crystal and the flow cell

(Wray et al., 2014). Furthermore, the flow cell was used to provide sufficient pressure from the top of the film that allowed sufficient contact to be achieved between the film and the ATR crystal (Fig. 1). In the flow cell, the dissolution medium was pumped at a rate of 0.1 mL/min. It should be realised that when using this setup the film is sandwiched between the flow cell and the measuring surface of the ATR crystal, meaning that the dissolution medium only contacts the side, not the top or bottom, surface of the film. Two dissolution media were used in this study, a neutral solution and pH 1 solution that were selected to represent the assumed oral and gastric conditions, respectively.

3. Results and Discussion 3.1. Drying process Oral films are commonly prepared via a solution state by a solvent casting method in order to make thin and homogenous films. In contrast, compacted tablet pharmaceuticals usually do not experience solution state except for materials that are film-coating. In the solution states it is more likely that interactions among drug and excipients will form and exist and be maintained in the final product, even after the drying process. The interaction may affect quality attributes (QAs) of films such as chemical stability of the drug, polymorphs of the drug and dissolution behaviour. Therefore, the first section of this manuscript presents the use of ATR-FTIR spectroscopic imaging to investigate films containing ibuprofen sodium salt as a model drug during the drying process that were prepared by using a solvent casting method. The Fig. 2 shows the change in distribution of the major components (ibuprofen sodium salt, HMPC, glycerol, and water) as a function of time during the drying process. Three different film formulations without pH modifier and with 1.2 and 2.4 equivalent of pH modifier with respect to the ibuprofen sodium salt moiety were used (Table 2). The characteristic spectral band used for analysis of the ibuprofen sodium salt was the carbonyl band in the range 1574 to 1537 cm–1; the band used to plot the distribution of excipients, HPMC and glycerol, was in the range 1134 to 1087 cm–1; and the band used to plot the distribution of water was in the range 1700 to 1614 cm–1 (Table 1). The red domains are areas of high concentration of the component of interest; green indicates an intermediate concentration, whereas blue indicates a domain of zero or low concentration. A significant change in the spectrum extracted from each sample is apparent in the ν(C=O) region from the ibuprofen moiety where there is the appearance and increasing absorbance of a new band at 1566 cm–1. This is shifted to a higher wavenumber compared to the same band of pure ibuprofen sodium salt that appears at 1546 cm–1 (Fig. 3). We assigned this band to the carbonyl stretch vibration of ibuprofen sodium salt that is hydrogen bonded to the O-H group of HPMC and glycerol, which was confirmed by measuring IR spectra of two samples containing ibuprofen sodium salt and HPMC or glycerol (see Fig. A1 in Supplementary materials). Furthermore, the hydrogen-bond interaction between ibuprofen and excipient has been carefully investigated using PVP as a proton acceptor (Kazarian and Martirosyan, 2002). Interaction of the proton donors, i.e. electron acceptors, with the carbonyl oxygen via H-bonding is known to decrease the frequency, i.e. increase the wavenumber, of the ν(C=O) mode due to the weakening of the C=O bond. Fig. 3 shows spectral data obtained from the ATR-FTIR spectroscopic images at 10 min during the experiment presented in Fig. 2 and the ν(C=O) at 1546 cm–1 and at 1557 cm–1 in the solid state and the solution state of ibuprofen sodium salt, respectively. During the experiment the ν(C=O) of ibuprofen sodium salt shifted to higher wavenumber at around 1566 cm–1. The shift to a higher wavenumber can be explained since the C=O bond of the ibuprofen moiety is weakened through H-bonding interaction with the electron acceptor

hydrogen of the O-H group in the HPMC and glycerol. Moreover, the ν(C=O) at 1566 cm–1 suggests that ibuprofen in the films remains in the salt form because there is no evidence of the ν(C=O) at 1703 cm–1 indicative of ibuprofen free form. This H-bond interaction between ibuprofen sodium salt and HPMC and glycerol was also independently confirmed by performing an experiment using a conventional ATR-FTIR spectroscopy (Fig. 4). The recorded spectra (Fig. 4 (A)) and a plot of the absorbance (Fig. 4 (B)) of the ν(C=O) of ibuprofen sodium salt vs the absorbance of the O-H bending vibration of water are presented and show shifts of ν(C=O) of ibuprofen moiety over the drying process, which indicates that there is a weakening of the C=O bond of ibuprofen upon interaction with the O-H group of HPMC and glycerol. This interaction directly can affect the polymorphs of the drug in the films. As a result, this can influence the stability of the drug as well as the dissolution behaviour. Thus, the molar ratio of the O-H groups contained within the excipients and C=O group of drug should be carefully considered when designing novel formulations. In conclusion, it has been characterized that ibuprofen remains stable as a sodium salt that subsequently forms H-bond interactions with the O-H group of HPMC and glycerol in the films. The interactions are maintained and detected even when prepared via an aqueous solution state that includes a drying process. However, the homogeneity of films was lowered by the addition of a pH modifier (Fig. 2), which may affect the content uniformity of the films and dissolution behaviour. Therefore, further work was conducted to study the dissolution of the drug from each film as a means to investigate how the addition of a pH modifier and homogeneity of the films would affect the drug release behaviour.

3.2. Dissolution process 3.2.1. Investigation of the behaviour of the film during dissolution The different types of pharmaceutical films, HPMC-based and PVP-based films, were studied to monitor the water ingress, dissolution behaviour of each component and the drug-excipient interaction as a function of time. Upon wetting, polymer chains will begin to disentangle as water penetrates into the matrix along the water-concentration gradient (Nair et al., 2001; Siepmann et al., 1999). As the polymer chains unravel, drug-excipient interactions can be disrupted that result in drug release from the polymer-based film. The experimental setup means that the ATR-FTIR spectroscopic images represent information from the surface of the film in contact with the ATR crystal. This means that information from the ATR-FTIR spectroscopic images directly express film characteristics such as the rate of water ingress, dissolution and stress from the film surface. There are also no preconditions such as a scale factor derived from the difference in sample size between limited measuring area and whole sample size. The data shown in Fig. 5 represents a control experiment for the two formulation concepts, a HPMCbased immediate drug release film and a PVP-based extended drug release film, with no pH or hydrophobicity modifier. The data clearly demonstrates the ability to differentiate all of the different components within the formulation and the water simultaneously in situ. The characteristic spectral bands used for analysis of the ibuprofen sodium salt and free form were the carbonyl bands in the ranges 1574 to 1537 cm–1 and 1750 to 1705 cm–1, respectively; the bands used to plot the distributions of HPMC and PVP were in the ranges 1134 to 1087 cm–1 and 1303 to 1278 cm–1, respectively; and the bands used to plot the distribution of water were in the range 1700 to 1614 cm–1 or 3700 to 3000 cm–1

in the cases of HPMC or PVP, respectively, to avoid spectral overlap from the excipients (Table 1, Fig. 6). The spectroscopic images show that the drug was released over time simultaneously with the ingress of water. The hydrophilic HPMC-based film dissolved much faster than the more hydrophobic PVPbased film, in which a slower rate of water ingress was observed. However, in the HPMC-based film, slight precipitation of crystalline ibuprofen was detected. The spectrum from the region highlighted by “(a)” in Fig. 5 (A) in the 1 min image shows a domain of crystalline ibuprofen. This is confirmed in the extracted spectrum based on comparison with the reference spectrum of a crystal state of ibuprofen free form that has a peak position of ν(C=O) of ibuprofen at 1703 cm–1 (Fig. 5 (C)). Interestingly, in regions where the crystalline deposits formed on the surface of the diamond ATR crystal, a corresponding region of low concentration of water appeared that suggests the deposits of the free form of ibuprofen displace the other components on the measuring surface of the ATR crystal. The spread of crystalline ibuprofen continues within the film during dissolution in the HPMCbased film. In contrast for the PVP-based film, no precipitation of ibuprofen was observed. The image recorded at 1 min from the HPMC-based film (Film A) shown in Fig. 5 (A) was further analysed by extracting the ATR-FTIR spectra linearly across the dissolving film (Fig. 7). The reference spectra of the solution state of ibuprofen sodium salt and the H-bonded ibuprofen sodium salt display the peak of the ν(C=O) band at around 1557 cm–1 and 1566 cm–1, respectively, as shown in Fig. 3. The spectra extracted from the dissolving film show evidence of a spectral peak at around 1555 cm–1 but without a band at 1566 cm–1. The extracted spectrum from the outside of the film has a band at around 1702 cm–1, which was assigned to the ν(C=O) of the crystalline ibuprofen as discussed above. The extracted spectra of the dissolving film indicate that the H-bond interaction between the ibuprofen sodium salt and the O-H group of HPMC and glycerol brakes and immediately turns to a solution state indicated by the ν(C=O) band of ibuprofen appearing at around 1555 cm–1 in the film matrix after the film absorbed water. In conclusion, ATR-FTIR spectroscopic imaging can provide unique information about not only the distribution of each component in the different films, but also phenomena such as the rate of water ingress, dissolution behaviour of each component and drug-excipient interactions in situ.

3.2.2. Effect of pH modifier on dissolution of immediate drug release HPMC-based film In previous studies of the dissolution of tablets containing ibuprofen using ATR-FTIR spectroscopic imaging, a large degree of recrystallization of ibuprofen free form was observed in certain conditions (Kazarian and Chan, 2003; Wray et al., 2011). Screening using this approach also revealed that the sodium salts composed of sodium bicarbonate and sodium carbonate could efficiently prevent or inhibit precipitation of the free form of ibuprofen as a pH modifier and help ibuprofen remain in its sodium salt form, subsequently resulting in desirable rapid dissolution for immediate drug release tablets (Wray et al., 2011). The data presented in Fig. 5 (A) of the HPMC-based film shows that crystalline ibuprofen formed at the beginning of the dissolution experiment and spread over the film while the ibuprofen sodium salt dissolved soon after the film absorbed water after 1 min. HPMC is well known to form a gel upon contact with water (Bajwa et al., 2006; Mitchell et al., 1990; Pygall et al., 2010), so the excipient detected in the fourth row of Fig. 5 (A) can be assigned as gelled HPMC. This was visually confirmed and observed to remain on the diamond ATR crystal, trapping some of the precipitated crystalline ibuprofen. It should be realised that the physical impact occurring in the

oral cavity or the gut may help with disintegration of such a soft gel and prevent this drug entrapment. Therefore, for BCS Class II or IV drug candidates that bear poor water solubility, preventing the precipitation of crystalline drug at the edge of the film during the initial stages of the dissolution is important to achieve the desired drug release. To find an appropriate formulation to prevent precipitation of drug at the edge of the film, the dissolution behaviour of three HPMC-based films with and without the pH modifier were studied using ATR-FTIR spectroscopic imaging. Sodium bicarbonate and sodium carbonate were physically mixed and dissolved as a pH modifier in the solution of ibuprofen sodium salt, HPMC and glycerol in water. The added levels of the pH modifier were 1.2 and 2.4 times the stoichiometry with respect to the ibuprofen sodium salt molecule. An acidic dissolution medium of 0.1M hydrochloric acid aqueous solution was used as a model solvent to represent the most severe case that films may experience if disintegrated in the mouth cavity, swallowed and then dissolved in the stomach that contains acidic gastric fluid. The data in Fig. 8 (A, B) show the dissolution behaviour of two films, Film B and Film C, deposited with 1.2 and 2.4 equivalent of the pH modifier, respectively. The ATR-FTIR spectroscopic images of Film B show rapid water ingress, leading to gradual dissolution of both of the ibuprofen sodium salt and excipients. Precipitation of crystalline ibuprofen was not observed and the drug was dissolved over the dissolution experiment. Similarly to the case of the Film A (Fig. 5 (A)), the small amount of crystalline ibuprofen detected in the 30 min image of Film B may be ignored since the soft HPMC gel could not keep its shape and would be disintegrated by physical impact in the oral cavity or the gut. One notable change in the spectra extracted from the same area of the Film B at the different time points appears in the ν(C=O) band of ibuprofen where the band at around 1566 cm–1 is shifted to the lower wavenumber at around 1557 cm–1 (Fig. 8 (C)). Same shift was observed also in Film C (Fig. 8 (D)). These two bands have been assigned above to the ν(C=O) of ibuprofen that is H-bonded with the O-H group of HPMC and glycerol and ν(C=O) of a solution state of ibuprofen sodium salt in water. In dry conditions at 0 min, the extracted spectra with the ν(C=O) at around 1566 cm–1 indicates that the interaction between ibuprofen sodium salt and the O-H group of HPMC and glycerol is present also in the film that contained the pH modifier (Fig. 8 (C, D)). The spectra extracted from the dissolving film at 1 min and 5 min show a band at around 1557 cm–1 without evidence of a band at around 1566 cm–1, which suggests that the H-bond between the ibuprofen sodium salt and the O-H group of HPMC and glycerol breaks and immediately turns to a solution state in the film matrices. This was also observed in the case of the Film A, without the pH modifier, after the film had started to absorb water. The data in Fig. 8 (D) from Film C show a different dissolution mechanism than the other films, Film A and Film B, which have been described above. In the case of the Film C, there appears to be a less organised and slower ingress of water observed in accordance with inhomogeneity of the film. Such affects can be typically caused by the abundance of pH modifier, which precipitated in the film during the drying process. Previous studies using HPMC and electrolytes demonstrated that the addition of an ionic species to HPMC may have adverse effects on the hydration of the HPMC gel and subsequent drug release (Bajwa et al., 2006; Mitchell et al., 1990; Pygall et al., 2010). The slower water ingress can be attributed to the excess amount of the pH modifier that is incorporated into the film and acts as a dehydrator for the HPMC gel upon contact with water. This results in a slower rate of water penetration and thus much slower dissolution of ibuprofen sodium salt from the gel. As for the precipitation of crystalline ibuprofen at the edge of the film, the dehydrated gel layer would form a barrier that inhibits further uptake of the dissolution medium and diffusion of the dissolved ibuprofen sodium salt, leading to precipitation of ibuprofen at the edge of the film upon contact with the acidic solution (Katzhendler et al., 2000). The extracted spectra from the edge of the film support the

hypothesis that there is indeed coexistence of crystalline ibuprofen having the ν(C=O) at around 1705 cm–1 and HPMC gel matrix having broad peaks at around 1050 cm–1 (Fig. 8 (E)). Further investigations into this phenomenon are ongoing. Overall, the ATR-FTIR spectroscopic imaging approach demonstrates the ability to assess the dissolution behaviour of polymer-based films upon addition of appropriate pH modifiers. It is clear that careful selection of the pH modifier and its loading quantity is vital for formulation research as pH modifiers can regulate the micro pH environment and ionic strength in gel matrices. This work has demonstrated that the added level of pH modifier may be a critical quality attribute (CQA) for HPMC-based films since excess modifier was detrimental to the dissolution of ibuprofen sodium salt.

3.2.3. Effect of hydrophobicity modifier on dissolution of extended drug release PVP-based film The comparative analysis of the different films in Fig. 5 shows that the less hydrophilic PVP-based film allows much slower water ingress than the HPMC-based film. This results in a slower rate of drug release without precipitation of crystalline ibuprofen. This dissolution behaviour is suitable for an extended drug release system that allows the drug to be released over prolonged time periods. To further investigate the relationship between the hydrophobicity of the films and speed of water ingress and subsequent rate of drug release, the hydrophobicity of the films was varied by adding PEG 4000 as a hydrophobicity modifier with the aim to increase the hydrophilic character of the PVP-based film. In this study, we employed ibuprofen free form as a low solubility drug, BCS class II drug (FDA Draft Guidance for Industry, May 2015), PVP and PEG 4000 as excipients for the films, and ethanol as a solvent for the preparation by solvent casting method. The ATR-FTIR images in Fig. 9 show the changing distributions of the three major components (water, PVP and ibuprofen) as a function of time following contact between the side of the film and water used as a dissolution medium. These two films are composed of ibuprofen free form and PVP, and one of the formulations contains PEG 4000. Previous work has verified that there was H-bonding between ibuprofen and PVP and the ν(C=O) of ibuprofen shifted to a higher wavenumber at around 1724 cm–1 compared to the corresponding band of solid ibuprofen (Kazarian and Martirosyan, 2002). The characteristic spectral band used for analysis of the ibuprofen bonded to PVP was the carbonyl band in the range 1750 to 1705 cm–1; the band used to plot the distribution of PVP was in the range 1303 to 1278 cm–1; and the band used to plot the distribution of water was in the range 3700 to 3000 cm–1 (Table 1). The data shown in Fig. 9 were obtained in a neutral pH film environment and water, which was selected as assumed oral conditions. The data of ATR-FTIR spectroscopic imaging clearly shows that it is possible to differentiate all components of the system simultaneously in situ. The images in Fig. 9 show that there is similar dissolution behaviour between the two films with and without PEG 4000, Film D and Film E, respectively. Firstly, the ibuprofen free form, which forms Hbonds with PVP, gradually dissolves from the polymer matrix. Furthermore, the polymer matrices then dissolve simultaneously with the water ingress. Although the free form of ibuprofen has significantly low solubility in water, 2.5 mg/mL in pH 6.8 (Potthast et al., 2005), PVP-bonded ibuprofen was not detected to convert to the crystalline ibuprofen that could be characterized by the ν(C=O) at around 1703 cm–1. It can be considered that the slower water ingress over a long dissolution period gives sufficient water fraction to ibuprofen in the polymer matrices, leading to gradual, or controlled, ibuprofen dissolution. The data in Fig. 9 also suggest that the speed of the water ingress and subsequent rate of drug release are increased by the addition of hydrophilic PEG 4000 as

designed. The spectra extracted from the different points highlighted in the ATR-FTIR spectroscopic images of the film recorded at 30 min, confirmed that PVP-bonded ibuprofen, which has the peak of the ν(C=O) at around 1724 cm–1, remained in the polymer matrices even after the film absorbed water (Fig. 9 (C)). Overall, ATR-FTIR spectroscopic imaging has been employed to demonstrate that the slow water ingress can prevent precipitation of a low solubility drug. Moreover, the drug release rate can be controlled by simply changing the hydrophobicity of films with the addition of hydrophilic polymers such as PEG 4000. Moreover, ATR-FTIR spectroscopic imaging provides useful insight about characteristics such as water ingress, dissolution of each component and physicochemical properties of drug in the different formulations.

4. Conclusion This work presents the use of ATR-FTIR spectroscopy and spectroscopic imaging to investigate the behaviour of model polymer-based films containing a drug during the drying process and in dissolution experiments. This is the first time that this reliable spectroscopic imaging approach has been applied for the investigation of these emerging film dosage forms. A series of polymeric films were prepared using a solvent evaporation method that contained ibuprofen in its free acid and ionised salt form as a model drug. Different polymer-based films, prepared with HPMC or PVP, were investigated and the formulations were designed to control drug release. ATR-FTIR spectroscopic imaging demonstrated the ability to determine the characteristics of films in situ and provided unique information about not only the distribution of each component in the different films, but also phenomena such as the rate of water ingress, dissolution behaviour of each component and drug interactions with the excipients. Furthermore, it was also shown that the drug release behaviour could be regulated by the addition of a pH modifier to control micro pH environment and ionic strength to the HPMC-based films and a hydrophobicity modifier to the PVP-based films. As a result, the information revealed using ATRFTIR spectroscopic imaging can contribute to more thorough understanding of the processes of polymer-based films. This is a good example to show that ATR-FTIR spectroscopic imaging can potentially be used as a robust investigative method to assess the quality of pharmaceutical polymerbased film products during development. In addition, this approach can provide vital insight that is complementary to results obtained by the established end-product test methods, such as USP testing. It is proposed that the highly-chemical and spatial information collected using ATR-FTIR spectroscopic imaging may lead to further information about the stress ingress into films being reported in the future that will result in more reliable pharmaceutical polymer-based film products. Further, from the point of view of improving the drug administration compliance of patients with dysphagia, this work can provide platform for comparative studies of films with other dosage technologies such as orally disintegrating tablets.

Acknowledgements The authors thank Daiichi-Sankyo Co. Ltd. for their support.

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Figure captions (Figure number, brief title, description of figure)

Fig.1. Schematic diagram of the in situ experimental setup A transparent flow cell, designed to be combined with the ATR accessory, was placed above ATR crystal and the sample is placed in between, separated by using a rubber spacer. The film sample is positioned to cover at least half of the diamond ATR crystal. The dissolution medium can be flowed through the cell such that it will contact the edges of the film. The diamond ATR accessory allows the interfacial area of the film and the medium to be investigated.

Fig. 2. ATR-FTIR images during the drying process of the HPMC-based films The ATR-FTIR images show the change in distribution of the major components of HPMC-based films containing ibuprofen sodium salt, HPMC and glycerol (A) without pH modifier and with (B) 1.2 or (C) 2.4 equivalent of pH modifier. The labels (a), (b) and (c) in the ibuprofen images at 10 min during the drying process represent the location of the extracted spectra that are shown in Fig. 3. Size of the spectroscopic images are approximately 638 × 525 μm2.

Fig. 3. Comparison of the ATR-FTIR spectra during the drying process The ATR-FTIR spectra were extracted from the films at 10 min during the drying process (Fig. 2) and reference spectra of ibuprofen sodium salt in solid state and in aqueous solution state and ibuprofen free form where the ν(C=O) band is observed at 1546 cm–1, 1557 cm–1 and 1703 cm–1, respectively. The broad band at around 1640 cm–1 corresponds to the bending mode of water. Every spectrum extracted from the films at 10 min during the drying process shows the ν(C=O) at around 1566 cm–1, which is higher than the ν(C=O) obtained from ibuprofen sodium salt in solid state and in aqueous solution state.

Fig. 4. (A) ATR-FTIR spectra during the drying process of the HPMC-based film (Film A) and (B) plot of the absorbance of the ν(C=O) peak of ibuprofen sodium salt. The ATR-FTIR spectra were obtained during the drying process of the HPMC-based film without pH modifier (Film A), and (B) the plot was made from the absorbance of the peak top of the ν(C=O) of ibuprofen sodium salt from the range of 1555 cm–1 to 1567 cm–1 vs the absorbance of the O-H bending vibration of water at 1636 cm–1.

Fig. 5. ATR-FTIR images of the dissolution behaviour of the (A) HPMC-based film (Film A) and (B) PVP-based film (Film D) The ATR-FTIR images show the major components of (A) HPMC-based film (Film A) and (B) PVPbased film (Film D) containing ibuprofen sodium salt and ibuprofen free form, respectively, without pH modifier and hydrophobicity modifier. Size of the spectroscopic images are approximately 638 × 525 μm2. The comparison of the spectra extracted from the Film A at 1 min during the dissolution and reference spectra of ibuprofen sodium salt in an aqueous solution state and ibuprofen free form where the ν(C=O) band is observed at 1557 cm–1 and 1703 cm–1, respectively are shown (C). The broad band at around 1640 cm–1 corresponds to the bending mode of water. The extracted spectrum at 1 min during the dissolution shows the ν(C=O) at around 1705 cm–1, which can be assigned to ibuprofen free form.

Fig. 6. Representative ATR-FTIR spectra and specific integration absorbance ranges. Size of the spectroscopic images are approximately 638 × 525 μm2. The ATR-FTIR spectra and specific integration absorbance ranges used to generate ATR-FTIR spectroscopic images for the different components of interest in (A) HPMC-based film and (B) PVPbased film are shown.

Fig. 7. (A) ATR-FTIR spectroscopic image of the HPMC-based film (Film A) and the extracted spectra. Size of the spectroscopic images are approximately 638 × 525 μm2. (A) The ATR-FTIR spectroscopic image of the HPMC-based film (Film A) was recorded at 1 min during dissolution. The circles indicate positions where spectra were extracted in a linear arrangement in the image across the interface of the film and the water. (B) The extracted spectra from the outside and inside of the HPMC-based film (Film A) at the 1 min image from the experiment shown in Fig. 5 (A). The extracted ATR-FTIR spectra show the presence of the absorbance band indicative of Hbonded interactions at 1555 cm–1 inside the film where water is yet to penetrate. In contrast, the spectra at the position 1 shows evidence of crystalline ibuprofen at 1702 cm–1 as a result of H-bonds breaking during hydration.

Fig. 8. ATR-FTIR spectroscopic image of the dissolution behaviour of the HPMC-based films (Film B, Film C) and the extracted spectra. Size of the spectroscopic images are approximately 638 × 525 μm2. The ATR-FTIR images show the major components of HPMC-based films containing ibuprofen sodium salt, HPMC, and glycerol with (A) 1.2 (Film B) or (B) 2.4 (Film C) equivalent of pH modifier, and comparison of the spectra extracted from (C) Film B and (D) Film C at the different time points over dissolution experiments and the reference spectra of ibuprofen sodium salt in solid state and in aqueous solution state and ibuprofen free form where the ν(C=O) band is observed at 1546 cm–1, 1557 cm–1 and 1703 cm–1, respectively. The extracted spectrum of (E) Film C at 5 min during the dissolution shows the ν(C=O) at around 1705 cm–1, which can be assigned to ibuprofen free form. The broad band at around 1050 cm–1 is derived from the excipients, HPMC and glycerol.

Fig. 9. ATR-FTIR spectroscopic image of the dissolution behaviour of the PVP-based films (Film D, Film E) and the extracted spectra. Size of the spectroscopic images are approximately 638 × 525 μm2. The ATR-FTIR images show the dissolution behaviour of the major components of PVP-based films containing ibuprofen free form and PVP (A) without PEG 4000 (Film D) or (B) with PEG 4000 (Film E). (C) shows a comparison of the spectra extracted from the image (B) of Film E at the different locations labelled in the image at 30 min and the reference spectrum of the film separately prepared with PVP and ibuprofen free form, which has the ν(C=O) of PVP-bonded ibuprofen at around 1724 cm–1.

Table 1 Primary quality risk assessment specific for polymer-based films Quality concern (QC) Crystallinity of drug

Quality attribute that could be affected Physicochemical stability*1 Dissolution rate

Timing when QCs could rise

Analytical method

Risk identification*2 Severity Occurrence

Detection

RPN

Drying --3 2 3 18 Dissolution End product test, DSC, XRD, 3 2 1 6 Test in stability Raman study spectroscopy Interaction Physicochemical Drying --3 2 3 18 among stability Dissolution drug and Dissolution/Disintegr End product test, DSC, XRD, 3 2 1 6 excipients ation rate Test in stability Raman study spectroscopy Distribution Dosage uniformity Drying NIR-CI imaging 3 2 2 12 of drug Dissolution and End product test, IR 3 2 1 6 excipients Test in stability spectroscopy, study NIR-CI imaging *1: Physicochemical stability: assay, related substances, polymorphs, *2: Severity rates the severity of the potential effect of the failure on product quality. Occurrence rates the likelihood that the failure will occur. Detection rates the likelihood that the quality concerns will be detected. Rating scales for Severity (S), Occurrence (O) and Detection (D) are set at 1, 2 and 3 with the higher number representing the higher seriousness or risk. For example, 3 points on an occurrence scale indicate that the failure is very likely to occur and is worse than 1, which indicates that the failure is very unlikely to occur. 3 points on a detection scale indicate that the analytical method very unlikely detect quality changes. The risk priority number (RPN) is calculated by multiplying Severity x Occurrence x Detection to identify high risk concerns. We set a simple RPN criteria of 8, which can be calculated with 2 points for each rating scale (S, O, D), to identify potentially high risk concerns.

Table 2 Formulations of HPMC-based and PVP-based films

Drug

Excipient

Ibuprofen sodium salt Ibuprofen free form HPMC

Film C 100 mg (38.5 %) --30 mg (11.5 %) 30 mg (11.5 %) 100 mg (38.5 %) ---

PVP-based film*1 Film D Film E ----25 mg (33.3 %) ---

25 mg (28.6 %) ---

---

---

---

--50 mg (57.1 %) 21.5 mg (24.6 %) --1 mL

pH modifier*2

30 mg (18.8 %) 30 mg (18.8 %) ---

PVP

---

30 mg (14.3 %) 30 mg (14.3 %) 50 mg (23.8 %) ---

PEG 4000

---

---

---

50 mg (66.7 %) ---

Water Ethanol

0.24 mL ---

0.24 mL ---

0.24 mL ---

--1 mL

Glycerol

Solvent

HPMC-based film*1 Film A Film B 100 mg 100 mg (62.5 %) (47.6 %) -----

*1: Percentage is calculated by weight percent for drug and excipients. *2: A mixture of sodium bicarbonate and sodium carbonate with 1:1 weight ratio

Table 3 The specific absorbance range that was integrated and used to generate ATR-FTIR spectroscopic images for the different components of interest and the respective peak position of the spectral bands. Component HPMC-based film Ibuprofen sodium salt aqueous solution Hydrogen-bonded Ibuprofen sodium salt Crystalline ibuprofen (free form) Excipients (mixture of HPMC and glycerol) Water PVP-based film Crystalline ibuprofen (free form) Hydrogen-bonded ibuprofen Excipient (PVP) Water

Integrated absorbance range/ cm–1

Peak position of spectral band/ cm–1

1574 – 1537 1574 – 1537 1726 – 1697 1134 – 1087 1700 – 1614

1557 1566 1703 1111 1635

1705 – 1680 1750 – 1705 1303 – 1278 3700 – 3000

1703 1724 1284 3287