Recent advances in the applications of vibrational spectroscopic imaging and mapping to pharmaceutical formulations.

Vibrational spectroscopic imaging and mapping approaches have continued in their development and applications for the analysis of pharmaceutical formulations. Obtaining spatially resolved chemical information about the distribution of different components within pharmaceutical formulations is integral for improving the understanding and quality of final drug products. This review aims to summarise some key advances of these technologies over recent years, primarily since 2010. An overview of FTIR, NIR, terahertz spectroscopic imaging and Raman mapping will be presented to give a perspective of the current state-of-the-art of these techniques for studying pharmaceutical samples. This will include their application to reveal spatial information of components that reveals molecular insight of polymorphic or structural changes, behaviour of formulations during dissolution experiments, uniformity of materials and detection of counterfeit products. Furthermore, new advancements will be presented that demonstrate the continuing novel applications of spectroscopic imaging and mapping, namely in FTIR spectroscopy, for studies of microfluidic devices. Whilst much of the recently developed work has been reported by academic groups, examples of the potential impacts of utilising these imaging and mapping technologies to support industrial applications have also been reviewed.

Infrared spectroscopy and spectroscopic imaging in forensic science.

Infrared spectroscopy and spectroscopic imaging, are robust, label free and inherently non-destructive methods with a high chemical specificity and sensitivity that are frequently employed in forensic science research and practices. This review aims to discuss the applications and recent developments of these methodologies in this field. Furthermore, the use of recently emerged Fourier transform infrared (FT-IR) spectroscopic imaging in transmission, external reflection and Attenuated Total Reflection (ATR) modes are summarised with relevance and potential for forensic science applications. This spectroscopic imaging approach provides the opportunity to obtain the chemical composition of fingermarks and information about possible contaminants deposited at a crime scene. Research that demonstrates the great potential of these techniques for analysis of fingerprint residues, explosive materials and counterfeit drugs will be reviewed. The implications of this research for the examination of different materials are considered, along with an outlook of possible future research avenues for the application of vibrational spectroscopic methods to the analysis of forensic samples.

The Combined Use of Imaging Approaches to Assess Drug Release from Multicomponent Solid Dispersions.

PURPOSE: Imaging methods were used as tools to provide an understanding of phenomena that occur during dissolution experiments, and ultimately to select the best ratio of two polymers in a matrix in terms of enhancement of the dissolution rate and prevention of crystallization during dissolution. METHODS: Magnetic resonance imaging, ATR-FTIR spectroscopic imaging and Raman mapping have been used to study the release mechanism of a poorly water soluble drug, aprepitant, from multicomponent amorphous solid dispersions. Solid dispersions were prepared based on the combination of two selected polymers - Soluplus, as a solubilizer, and PVP, as a dissolution enhancer. Formulations were prepared in a ratio of Soluplus:PVP 1:10, 1:5, 1:3, and 1:1, in order to obtain favorable properties of the polymer carrier. RESULTS: The crystallization of aprepitant during dissolution has occurred to a varying degree in the polymer ratios 1:10, 1:5, and 1:3, but the increasing presence of Soluplus in the formulation delayed the onset of crystallization. The Soluplus:PVP 1:1 solid dispersion proved to be the best matrix studied, combining the abilities of both polymers in a synergistic manner. CONCLUSIONS: Aprepitant dissolution rate has been significantly enhanced. This study highlights the benefits of combining imaging methods in order to understand the release process.

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

Pharmaceutical film dosage forms 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 films for immediate release and polyvinylpyrrolidone (PVP) based films 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.

Attenuated total reflection-Fourier transform infrared spectroscopic imaging of pharmaceuticals in microfluidic devices.

The poor aqueous solubility of many active pharmaceutical ingredients presents challenges for effective drug delivery. In this study, the combination of attenuated total reflection (ATR)-FTIR spectroscopic imaging with specifically designed polydimethylsiloxane microfluidic devices to study drug release from pharmaceutical formulations has been developed. First, the high-throughput analysis of the dissolution of micro-formulations studied under flowing conditions has been introduced using a model formulation of ibuprofen and polyethylene glycol. The behaviour and release of the drug was monitored in situ under different pH conditions. In contrast to the neutral solution, where both the drug and excipient dissolved at a similar rate, structural change from the molecularly dispersed to a crystalline form of ibuprofen was characterised in the obtained spectroscopic images and the corresponding ATR-FTIR spectra for the experiments carried out in the acidic medium. Further investigations into the behaviour of the drug after its release from formulations (i.e., dissolved drug) were also undertaken. Different solutions of sodium ibuprofen dissolved in a neutral medium were studied upon contact with acidic conditions. The phase transition from a dissolved species of sodium ibuprofen to the formation of solid crystalline ibuprofen was revealed in the microfluidic channels. This innovative approach could offer a promising platform for high-throughput analysis of a range of micro-formulations, which are of current interest due to the advent of 3D printed pharmaceutical and microparticulate delivery systems. Furthermore, the ability to study dissolved drug in solution under flowing conditions can be useful for the studies of the diffusion of drugs into tissues or live cells.

New insights into the mechanism of interaction between CO2 and polymers from thermodynamic parameters obtained by in situ ATR-FTIR spectroscopy.

This work reports new physical insights of the thermodynamic parameters and mechanisms of possible interactions occurring in polymers subjected to high-pressure CO2. ATR-FTIR spectroscopy has been used in situ to determine the thermodynamic parameters of the intermolecular interactions between CO2 and different functional groups of the polymers capable of specific interactions with sorbed CO2 molecules. Based on the measured ATR-FTIR spectra of the polymer samples subjected to high-pressure CO2 (30 bar) at different temperatures (300-340 K), it was possible to characterize polymer-polymer and CO2-polymer interactions. Particularly, the enthalpy and entropy of the formation of the specific non-covalent complexes between CO2 and the hydroxy (-OH), carbonyl (C[double bond, length as m-dash]O) and hydroxyimino ([double bond, length as m-dash]N-OH) functional groups of the polymer samples have been measured. Furthermore, the obtained spectroscopic results have provided an opportunity for the structure of these complexes to be proposed. An interesting phenomenon regarding the behavior of CO2/polymer systems has also been observed. It has been found that only for the polyketone, the value of enthalpy was negative indicating an exothermic process during the formation of the CO2-polymer non-covalent complexes. Conversely, for the polyoxime and polyalcohol samples there is a positive enthalpy determined. This is a result of the initial polymer-polymer interactions requiring more energy to break than is released during the formation of the CO2-polymer complex. The effect of increasing temperature to facilitate the breaking of the polymer-polymer interactions has also been observed. Hence, a mechanism for the formation of CO2-polymer complexes was suggested based on these results, which occurs via a two-step process: (1) the breaking of the existing polymer-polymer interactions followed by (2) the formation of new CO2-polymer non-covalent interactions.

Comparison of pharmaceutical formulations: ATR-FTIR spectroscopic imaging to study drug-carrier interactions.

Attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopic imaging has been used in combination with UV detection to study the release of a model poorly water-soluble drug, indomethacin, when formulated with selected drug carriers. Firstly, formulations of indomethacin and nicotinamide in varying weight ratios were studied since novel tablet dosage forms containing multi-drugs are of industrial interest. The in situ spectroscopic imaging measurements of the dissolving tablets showed that as the loading of indomethacin was increased, the rate of drug release changed from one that expressed first-order drug release to one which showed zero-order drug release. Two drug release mechanisms have been identified from the recorded spectroscopic images and UV dissolution profiles. To further validate these mechanisms, specific formulations containing the model drug and two other excipients, urea and mannitol, were studied. The formulations with urea showed similar first-order release, indicative of the drug-carrier interactions. Whereas, the indomethacin/mannitol formulations showed a zero-order release curve explained by disintegration of the tablet. ATR-FTIR spectroscopic imaging provided highly chemically specific information as well as the spatial distribution of the components during the dissolution process which has demonstrated the potential of this combined analytical setup to determine the mechanisms of drug release.

Evaluating drug delivery with salt formation: Drug disproportionation studied in situ by ATR-FTIR imaging and Raman mapping.

Two different vibrational spectroscopic approaches, ATR-FTIR spectroscopic imaging and Raman mapping, were used to investigate the components within a tablet containing an ionised drug during dissolution experiments. Delivering certain drugs in their salt form is a method that can be used to improve the bioavailability and dissolution of the poorly aqueous soluble materials. However, these ionised species have a propensity to covert back to their thermodynamically favourable free acid or base forms. Dissolution experiments of the ionised drug in different aqueous media resulted in conversion to the more poorly soluble free acid form, which is detrimental for controlled drug release. This study investigates the chemical changes occurring to formulations containing a development ionised drug (37% by weight), in different aqueous pH environments. Firstly, dissolution in a neutral medium was studied, showing that there was clear release of ionised monosodium form of the drug from the tablet as it swelled in the aqueous medium. There was no presence of any drug in the monohydrate free acid form detected in these experiments. Dissolution in an acidic (0.1M HCl) solution showed disproportionation forming the free acid form. Disproportionation occurred rapidly upon contact with the acidic solution, initially resulting in a shell of the monohydrate free acid form around the tablet edges. This slowed ingress of the solution into the tablet before full conversion of the ionised form to the free acid form was characterised in the spectroscopic data.

Identifying the mechanisms of drug release from amorphous solid dispersions using MRI and ATR-FTIR spectroscopic imaging.

The dissolution mechanism of a poorly aqueous soluble drug from amorphous solid dispersions was investigated using a combination of two imaging methods: attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging and magnetic resonance imaging (MRI). The rates of elementary processes such as water penetration, polymer swelling, growth and erosion of gel layer, and the diffusion, release and in some cases precipitation of drug were evaluated by image analysis. The results from the imaging methods were compared with drug release profiles obtained by classical dissolution tests. The study was conducted using three polymeric excipients (soluplus, polyvinylpyrrolidone - PVP K30, hydroxypropylmethyl cellulose - HPMC 100M) alone and in combination with a poorly soluble drug, aprepitant. The imaging methods were complementary: ATR-FTIR imaging enabled a qualitative observation of all three components during the dissolution experiments, water, polymer and drug, including identifying structural changes from the amorphous form of drug to the crystalline form. The comparison of quantitative MRI data with drug release profiles enabled the different processes during dissolution to be established and the rate-limiting step to be identified, which - for the drug-polymer combinations investigated in this work - was the drug diffusion through the gel layer rather than water penetration into the tablet.

Stability of indomethacin with relevance to the release from amorphous solid dispersions studied with ATR-FTIR spectroscopic imaging.

This work presents the use of attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and spectroscopic imaging to study the stability and dissolution behaviour of amorphous solid dispersions (ASDs). ASDs are employed to improve the bioavailability of drugs which are poorly soluble in aqueous solutions. Selecting the appropriate polymeric excipients for use in pharmaceutical tablets is crucial to control drug stability and subsequent release. In this study, indomethacin was used as a model poorly-aqueous soluble drug since the amorphous-form has improved dissolution properties over its crystalline forms. ASDs of indomethacin/polyethylene glycol (PEG) and indomethacin/hydroxypropyl methylcellulose (HPMC) in a 1:3 wt ratio were compared. Firstly, ATR-FTIR spectroscopy was employed to monitor the stability of indomethacin in the ASDs over 96 h. While the indomethacin/HPMC ASD showed the ability to maintain the amorphous indomethacin form for longer periods of time, ATR-FTIR spectra revealed that indomethacin in the drug/PEG ASD crystallised to the stable γ-form, via the α-form. Secondly, ATR-FTIR spectroscopic imaging was used to study the dissolution of ASD tablets in a phosphate buffer (pH 7.5). Crystallisation of amorphous indomethacin was characterised in the spectra collected during the dissolution of the indomethacin/PEG ASD which consequently hindered release into the surrounding solution. In contrast, release of amorphous indomethacin was more effective from HPMC.

Swellable, water- and acid-tolerant polymer sponges for chemoselective carbon dioxide capture.

To impact carbon emissions, new materials for carbon capture must be inexpensive, robust, and able to adsorb CO2 specifically from a mixture of other gases. In particular, materials must be tolerant to the water vapor and to the acidic impurities that are present in gas streams produced by using fossil fuels to generate electricity. We show that a porous organic polymer has excellent CO2 capacity and high CO2 selectivity under conditions relevant to precombustion CO2 capture. Unlike polar adsorbents, such as zeolite 13x and the metal-organic framework, HKUST-1, the CO2 adsorption capacity for the hydrophobic polymer is hardly affected by the adsorption of water vapor. The polymer is even stable to boiling in concentrated acid for extended periods, a property that is matched by few microporous adsorbents. The polymer adsorbs CO2 in a different way from rigid materials by physical swelling, much as a sponge adsorbs water. This gives rise to a higher CO2 capacities and much better CO2 selectivity than for other water-tolerant, nonswellable frameworks, such as activated carbon and ZIF-8. The polymer has superior function as a selective gas adsorbent, even though its constituent monomers are very simple organic feedstocks, as would be required for materials preparation on the large industrial scales required for carbon capture.

Applications of Fourier transform infrared spectroscopic imaging to tablet dissolution and drug release.

INTRODUCTION: Solid oral dosage forms are the most commonly used method for administering active pharmaceutical ingredients to patients. Understanding the mechanisms and processes of drug release is essential for improving the design of pharmaceutical tablets. AREAS COVERED: In this review, recent approaches where attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic imaging has been applied to study tablet dissolution and drug release have been investigated. Drug release studies of model pharmaceutical systems composed of drug/polymer mixtures in the presence of aqueous solutions have been discussed, as has the subsequent combination with UV/Vis spectroscopic detection to quantify the amount of drug dissolved as a function of time. The use of a single-reflection ATR accessory with a diamond crystal allows for in situ FTIR imaging of tablet compaction and dissolution. EXPERT OPINION: ATR-FTIR imaging can address the challenges of investigating the mechanisms of drug release from a range of innovative new delivery systems. Unlike standard dissolution tests, this spectroscopic imaging method obtains insight and information about changes within the tablet during dissolution. Areas where ATR-FTIR imaging has shown further potential to be particularly useful are for the study of multi-layered solid tablets, high-throughput analysis, use of microfluidic devices and for surface-enhanced ATR-FTIR spectroscopy.