Raman spectroscopy in pharmaceutical product design

Advanced Drug Delivery Reviews 89 (2015) 3–20 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Raman spectroscopy in pharmaceutical product design☆ Amrit Paudel a,1, Dhara Raijada b,1,2, Jukka Rantanen b,⁎ a b Research Center Pharmaceutical Engineering GmbH (RCPE), Graz, Austria Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark a r t i c l e i n f o Available online 11 April 2015 Keywords: Preformulation Solid-state Drug development Formulation Drug delivery Process analytical technologies Quality control Dissolution testing a b s t r a c t Almost 100 years after the discovery of the Raman scattering phenomenon, related analytical techniques have emerged as important tools in biomedical sciences. Raman spectroscopy and microscopy are frontier, non-invasive analytical techniques amenable for diverse biomedical areas, ranging from molecular-based drug discovery, design of innovative drug delivery systems and quality control of finished products. This review presents concise accounts of various conventional and emerging Raman instrumentations including associated hyphenated tools of pharmaceutical interest. Moreover, relevant application cases of Raman spectroscopy in early and late phase pharmaceutical development, process analysis and micro-structural analysis of drug delivery systems are introduced. Finally, potential areas of future advancement and application of Raman spectroscopic techniques are discussed. © 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enabling development of Raman techniques . . . . . . . . . . . . . . . 2.1. Raman sampling configurations . . . . . . . . . . . . . . . . . . 2.2. Fibre optics Raman probes, stand-off and handheld Raman spectrometer 2.3. Simultaneous and hyphenated techniques . . . . . . . . . . . . . 2.4. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Applications of Raman spectroscopy in pharmaceutical product design . . . 3.1. Early drug development . . . . . . . . . . . . . . . . . . . . . 3.2. Characterization of drug delivery systems . . . . . . . . . . . . . 3.3. Process measurements . . . . . . . . . . . . . . . . . . . . . . 3.4. Product performance testing and quality control for the final product . 4. Perspectives and future directions . . . . . . . . . . . . . . . . . . . . Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4 4 5 6 7 7 7 8 10 12 13 14 14 15 1. Introduction ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Pharmaceutical applications of Raman spectroscopy — from diagnosis to therapeutics”. ⁎ Corresponding author at: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Tel.: +45 35 33 65 85; fax: +45 35 33 60 30. E-mail address: [email protected] (J. Rantanen). 1 These authors contributed equally to this work. 2 Author's present address: F. Hoffmann-La Roche Ltd., Pharma Technical Development Actives, Grenzacherstrasse 124, CH-4070 Basel, Switzerland. Since 1928, when Raman and Krishnan discovered the new type of secondary radiation later termed “Raman scattering”, there has been a constant flow of development in the instrumentation using this principle. With the advancements in photonics and optoelectronics, as well as a rapidly expanding range of applications, Raman spectrometers, microscopes and allied analytical tools have continuously evolved over the decades [1]. Several efforts in spectrometric hardware have invested in tackling the intervention of the stronger elastic Rayleigh http://dx.doi.org/10.1016/j.addr.2015.04.003 0169-409X/© 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 4 A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 signal to the weaker Raman (inelastic) scattering signal. These efforts have resulted in the highly efficient Rayleigh line filters [2]. Historically, the developments of Raman tools were also augmented by the discoveries of various phenomena other than the basic Raman effect, such as resonance Raman (RR), coherent anti-Stokes Raman scattering (CARS) and surface-enhanced Raman scattering (SERS) [1]. Raman spectroscopy has proven to be a useful tool in a vast number of fields, including pharmaceuticals, in vivo biomedical studies, process control, environmental sciences, semiconductors, catalysts, glasses, pigments, archaeology and forensic sciences. Raman analytical techniques have been increasingly implemented at different stages of drug discovery and development. This includes chemical identification, molecular biology research and diagnostics, preformulation, solid form screening, bioanalysis, formulation analytics in late phase drug development, process analytics, quality control, raw material qualification and counterfeit identification. The analytical versatility of Raman molecular spectroscopic techniques allows for investigating a wide diversity of transparent, translucent, opaque, and coloured samples including solids, semi-solids, suspensions, and solutions. This facilitates non-invasive analysis of synthetic reaction mixtures, biological specimens, and intermediates to various finished dosage forms (such as powders, tablet/capsule, creams, heterogeneous suspensions, and syrups) with minimal or no sample preparations [3]. Spontaneous instrumental evolutions of Raman-based techniques have progressed from traditional laboratory spectrometers to a wide range of miniaturized and tunable lasers, optical filters, spectrographs, interferometers, charge-coupled device (CCD), microprocessor control and Raman probes. These have improved the mobile applications to be non-contact, process-friendly and allow for remote analysis through glass containers, well plates, and even aqueous samples [4]. Today, Raman-based tools are cheaper, smaller, smarter and faster, and the analysis of “real world samples” in-line from production lines or inside the packaged containers has gone from a concept idea to a well-established practice for different pharmaceutical products [5]. This has led to the recognition of Raman spectroscopy by regulatory authorities for innovative analysis. Spectral analysis of pharmaceuticals using Raman-based techniques presents some additional benefits over mid- or near-infrared (IR) spectroscopy. Because Raman spectroscopy is a scattering technique, there is no need for a reference light path (as needed for IR/NIR); therefore, it is amenable to fibre optics and allows for remote sampling. Higher lateral spatial and depth resolution is attainable by (confocal) Raman microscopy than by IR microscopy. In many ways, it is possible to characterize samples better than with Fourier-transform IR (FT-IR) spectroscopy. However, any possible fluorescence from the sample should be taken into consideration. A single scan of a typical Raman measurement can collect spectral data in the range of 4000–40 cm−1. In addition to the fingerprint region between 4000 and 400 cm−1, the low frequency or far IR region (400–40 cm−1) of Raman spectra covers some of the important vibration modes that are relevant for the identification of different solid-state forms [6]. Water being a weak Raman scatterer makes it possible to successfully analyze aqueous samples by Raman spectroscopy. In many cases, sharper spectroscopic contrast between API and excipients offer superior quantitative analysis capability. Raman spectrometers comprise a laser light source, focusing optics, and spectrograph(s) consisting of a dispersing element and a detector [2,7]. The diverse Raman laser sources deliver in the range of UV to NIR region, the most ubiquitous being the visible light laser [8]. As Raman efficiency is inversely related to the fourth power of the wavelength, the selection of a suitable source requires the accounts of sample nature and the spectrometer geometry. Additionally, samples with possible fluorescence interference require a longer excitation wavelength. Dispersive Raman spectrometers utilize a holographic grating monochromator as the spectrograph, whereas FT-Raman instruments typically utilize the Michelson interferometers. A Raman detector is generally a photon collecting photomultiplier tube/CCD or a germanium detector (FT-Raman). Raman microscopes are equipped with a conventional optical microscope as a sampling device and thus can perform localized sample analysis, enabling hyperspectral chemical imaging by wide field imaging or line/point mapping [1]. Furthermore, confocal Raman microscopy (CRM) can axially discriminate signals originating from selective depth within the sample using the confocal hole [9]. The fundamental working principles and components of Raman instrumentations, from conventional to advanced instrumentations, are available in many standard books and excellent review papers [1, 4,7,8,10]. We have excluded the basic quantum process associated with various types of Raman scattering phenomena, but these are also covered in many books and papers. Because the present review aims to provide a broad perspective on the application of various Raman tools in drug development, only very brief accounts are reported [11]. 2. Enabling development of Raman techniques 2.1. Raman sampling configurations Different existing Raman sampling geometries are schematically illustrated in Fig. 1. A traditional backscattering Raman analysis acquires data from a small spot of an analyte. Therefore, the resulting spectral output may fail to entirely represent the static and heterogeneous sample. Sample rotation during spectral acquisition and the temporal averaging of the acquired data, the spatial averaging of the data acquired by scanning different regions of sample, and simultaneous wide-angle illumination (WAI) are configurations available to overcome the issues related to sub-sampling [12–14]. Most analysis of pharmaceutical solid samples utilizes WAI, which involves the illumination of a large volume of samples using wider laser beam and selective collection of Raman scattering within the covered area. A dispersive Raman probe constituting multiple optical fibres, known as PhAT (Pharmaceutical Area Testing), measures a significantly larger sample volume [12,15]. Furthermore, the configuration enabling the collection of signals from locations laterally offset away (hundred micrometres to centimetres in some cases) from the illuminated area is called spatially offset Raman spectroscopy (SORS) [16]. Typical SORS geometry irradiates the laser at the centre of the ring and Raman collection from the circumference, the radius being the spatial offset [17]. The avoidance of surface interference with this technique can facilitate the depth profiling of the sample. Spectral acquisition representing a bulk sample can be performed using transmission Raman spectroscopy (TRS), wherein the incident and the collection beam path are separated to the extreme on opposite sides of sample [18]. TRS potentially avoids the sub-sampling problem of heterogeneous samples and yields (semi) averaged spectral data of the bulk composition for turbid or opaque materials [19–23]. Surface-enhanced Raman scattering (SERS) and tip-enhanced Raman scattering (TERS) are extensively researched and implemented surface-sensitive Raman techniques [24–27]. In brief, a SERS signal enhances via dipolar localized surface plasmon resonance originating from the interaction of visible light and a nanoscale rough surface noble-metal substrate coated with analyte [28]. The interaction of sample with the intense electric field generated from substrateincident light interaction increases the magnitude of induced dipole of the sample, thus enhancing the Raman scattering signal [24]. TERS is a high resolution SERS variant combined with atomic force microscopy (AFM) for the localization of incident light at sufficient proximity to the analyte [29–31]. The surface plasmon excited at a sharp-metal tip brought onto the sample surface initiates the SERS effect upon laser irradiation [32]. In addition to surface sensitive Raman techniques, signal enhancing Raman nonlinear techniques such as coherent anti-Stoke Raman scattering (CARS) are increasingly used for the spectroscopic imaging of pharmaceuticals [33,34]. CARS technique involves a coherent A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 5 Fig. 1. Different Raman spectroscopic configurations (Modified from [1,12,134–136]). interaction between two high energy lasers (incident and pump laser) collinearly irradiated on the sample producing strong Raman scattering. The CARS signal inherently lacks the fluorescence interference. Several recent reviews cover the details of these techniques [35–37]. 2.2. Fibre optics Raman probes, stand-off and handheld Raman spectrometer Fibre optics-based remote Raman systems are extensively used in drug discovery and development. The construction essentially consists 6 A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 of the sampling probe that is remote from the dispersive Raman spectrometer and is connected via optical fibres acting as transmitters for incident and collected light via total internal reflection [38]. The separation can be as much as 100 m and can thus benefit the remote analysis of samples [1]. The common fibre probe Raman setup consists of a single excitation fibre surrounded coaxially by a bundle of separate multiple collection fibres [39] (Fig. 1). Additionally, a double fibre probe with separate illuminating and collecting fibres as well as a single fibre probe for both the incident and collection beams is also common [1]. Both the distance and angle of incident beam fibre and collection beam fibre are very important. Overall, fibre optic arrangement provides extreme flexibility for monitoring samples that are at harsh or physically inaccessible locations, e.g., varying process environments. The fibre material should be devoid of Raman interference and resistant to solarisation, especially using UV radiation. Interested readers are referred to an excellent review published recently by Latka et al. on fibre optic Raman probes [40]. Various factors, including the collection efficiency, S/N ratio, flexibility, fibre-cladding, probe diameter, working distance, and confocality, are important for fabricating fibre-based Raman sensors [40]. The requirements can be quite different for integrating a Raman probe as a PAT tool in a particular location of a manufacturing line versus using it as an in vivo diagnostic tool or with plate readers for solid-form screening. The probe head is important in the case of immersion probes in solids, semi-solids or solutions. A bevelled fibre tip enclosed in an air window is reported to minimize the influence of the refractive index on the depth resolution [41]. The resistant window of the Raman transparent material housing collection lens is operable in contact mode with a chemically reactive or high pressure environment [42]. Optimal focal length immersion probes provide better results for the dispersive media [43]. Wide varieties of TRS probes, SORS probes and ready-made or customizable Raman probes are commercially available for in situ and real time analysis of facile transformations in solid, liquid and melt at non-ambient pressure; humidity; shear; temperature conditions during flow; levitated drying; mixing; coating; spraying; extrusion; and compression [42,44–46]. Furthermore, a recently devised Raman fibre optic microstructure light guiding hollow-core and a miniaturized sample holder for flowing gas or liquid analyte showed promising quantitative capability for picomolar drug concentration in physiological medium and for the mixture of gases in human breath [47,48]. Various fibre-based Raman systems include but are not limited to the WAI probe (PhAT), polarization Raman probes and imaging fibre probes, fibre coupled confocal Raman, video probe, and a chemical/high pressure/temperature resistant immersion probe [40]. Fibre optics-based Raman techniques are well-recognized to be versatile and elegant in situ/in process monitoring PAT tools for various pharmaceutical unit operations and processes [49–51]. Moreover, micro-Raman sensors have been extensively developed in the medical and diagnostic analysis field [52–54], in vivo analysis [55], and skin and cosmetic research and applications [56]. The other variant of the fibre-based Raman technique is a stand-off spectrometer configuration that generally physically separates the instrument from the sample [4]. This enables remote analysis using telescopic signal collecting system(s) with the stand-off distance up to 500 m [57]. The incident laser source and collecting telescopic lens are assembled together to make a probe that illuminates the sample and collects the returning signal. This assembly is connected to the dispersing and detecting spectrograph via optical fibre. Both dispersive backscattering and SORS systems are available in stand-off setup [58]. Stand-off tools are widely used for remote analysis of packaged pharmaceuticals, as well as toxic and explosive materials [59–61]. Substantial progression in miniaturization of Raman instruments can be observed by the significantly diminished size and weight of spectrometers over the last decade [62,63]. A recent report by Crocombe includes extensive details of commercial portable handheld Raman devices [64]. Major areas include the expeditious and cost-effective testing of packaged samples for quality control, incoming material inspections, at-line analysis of biopharmaceuticals, and counterfeit analysis [65–69]. Portable Raman instruments consist of a miniaturized laser source, a dispersive component, and detectors that are connected via micro-fibre optics with the Raman probe. Furthermore, the incorporation of wireless technologies such as Bluetooth, WiFi and GPS into new technologies has enabled remote operation of these handheld Raman devices. Major commercial handheld devices work with a laser source at 785 nm, whereas newer systems operate with a non-fluorescent source (1030 or 1064 nm) [64]. A recently reported portable FT-Raman analyzer and SERS system with a laser source less likely to cause eye damage (1550 nm) shows versatility for mobile outdoor application [70,71]. Hand held SORS are potentially implementable for rapid, non-invasive detection of drugs and explosives [72,73]. Although handheld Raman instruments deploy an inbuilt (partial) spectral library and chemometric data analysis, reliable calibration and relative intensity correction are important for robust material identification. Various baseline correction methodologies for handheld Raman instruments have been reported [74]. 2.3. Simultaneous and hyphenated techniques Cutting-edge research is moving towards the development of analytics that deploy multiple measuring principles while (quasi-) simultaneously analyzing the same sample. The complementary information on various kinetic and thermodynamic events generated using such integrated tools can provide an excellent opportunity for understanding and more deeply characterizing complex materials. One of the major challenges of integration will be avoiding the temporal lag of response based on sensing principles and problems related to data handling [75]. Thanks to the recent increasing ubiquity and portability of the probe-based and compact Raman spectrometers, the spectrometers are now more amenable to integration with many other analytical tools, thus enabling in situ spectroscopy. Attempts to integrate Raman systems with thermal analysis tools are increasing. Raman was interfaced with a commercial thermal analysis system to study dehydration and phase conversion of hydrate [76,77]. A commercial DSC-Raman is equipped with fibre Raman mounted onto a power compensation DSC furnace. A custom Raman probe-interfaced heat flux DSC is also reported for polymer curing analysis [78]. A recent study reports that a Raman system was integrated with ultrafast DSC, enabling the facile characterization of subtle intermediate structural changes of a metastable solid form [79]. Water–solid interactions are an extremely complex and important aspect in pharmaceutical systems. The chemical speciation of molecular changes occurring during moisture sorption or desorption can improve the characterization of complex product microstructures [80,81]. The relatively poorer Raman activity of water led to the coupling of a Raman fibre probe with a dynamic vapour sorption (DVS) system [82,83] to study molecular modes of moisture-API and/or excipient interactions and crystallization in solid samples [84]. Previously, a controlled humidity cell was combined with Raman microscope or a PhAT probe was implemented in DVS to minimize gravimetric influence on spectral data [85,86]. Coupling Raman systems with microscopy can enable topochemical profiling of the microscopic surface observed by optical microscopy, mesoscopic features visualized via electron microscopy or highly localized nanoscopic surface properties revealed by AFM [87]. Near-field scanning optical microscopy (NSOM) integrated with a Raman system has been developed as a high resolution system [88]. There are commercially available modular multi-microscopic configurations combining AFM, NSOM, confocal Raman and TERS [89]. These nanophotonic approaches have yet to be applied to nanoscale pharmaceutical analysis [90–92]. The Raman integrated SEM (RISE) microscope, a recent promising innovation, can enable nanoscopic molecular distribution analysis and depth profiling by generating the chemical and topographical information of the same sample area [93,94]. A tool interfacing the Raman principle with circular dichroism spectroscopy measures Raman optical activity (ROA) and is considered A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 complementary to vibrational circular dichroism [95,96]. ROA exploits the interaction of an optical activity tensor with the circular polarizability of a chiral molecule and can thus provide structural information on chirality, enantiopurity and so on [97,98]. Typical ROA samples are liquids or solutions of peptide and protein, polymers, nucleic acid, carbohydrates, oils, and biological molecules [99–105]. Simultaneous Raman-coupled X-ray and neutron techniques are some of the recent exciting developments in this field [106–108]. The concerted measurement of Raman scattering with small and/or wide-angle X-ray or neutron scattering, absorption or diffraction yields powerful multi-scale structural data [109]. Such integrations can be employed for the in situ monitoring of heterogeneous catalytic reactions with extremely high (spatio-) temporal resolution [110–113]. Most of the reported studies utilize the installation of fibre-based optics with remote Raman in the synchrotron beamline using a specially customized sample holder [114–117]. A recent study reveals simultaneous measurement using in-house small- and wide-angle X-ray scattering with a high energy laboratory source coupled to a Raman probe for complex polymers [118]. A Raman beam scanner is often used for matching the X-ray or neutron beam and Raman laser spot. Multichannel in situ assembly, including an X-ray Raman coupled with a mass spectrometer, is also reported [119,120]. The correlation data obtained from Raman vibrational changes and diffusional, crystallographic or supra-molecular surface structures can elucidate structures of complex API, excipient or delivery systems [121–123]. One ongoing area of development is towards multimodal microscopy/ spectroscopy, including Raman with other multi-techniques in fibre optics systems [124–126]. An interest in multimodal vibrational spectroscopy has emerged with the aim to integrate Raman systems with NIR systems [127]. The fusion of the separate NIR and Raman images acquired from the same area of a formulation was reported to provide additional value over individual techniques [128,129]. In contrast, attempts of Raman-NIR integration increased due to identical measurement speed and the possibility of single sampling configuration, indicating the possibility of heterospectral Raman/NIR 2D correlation analysis [130,131]. Additionally, Raman integrated with optical coherence tomography (OCT) has a potential application to pharmaceutical products [132]. Sequential or simultaneous data acquisition from the same sample area using a combined Raman-OCT probe can provide OCT-guided Raman chemical analysis [133]. Raman systems are sometimes bridged with different separation techniques to act as a detector. Separated elution of multiple components of an analyte using chromatography or electrophoresis can be detected and possibly quantified by the hyphenated Raman spectrometer [137–142]. Interested readers are referred to the relevant book for the details on the technical aspects of using infrared or Raman as a detector for chromatographic techniques [143]. 2.4. Data analysis Large datasets can be generated using Raman spectroscopy, which creates a challenge in terms of extracting useful information from these complex data. Univariate analysis is considered the easiest, most prevalent and most robust data analysis approach and, in many cases, can provide sufficient information and reliable predictability [144]. The complex and vast amount of data generated using Raman spectroscopy often demands multivariate data analysis approaches [145]. Common multivariate methods include principal component analysis (PCA), partial least square regression (PLS), classical least squares (CLS), multivariate curve resolution (MCR) and partial least square discriminant analysis (PLS-DA). Various preprocessing and variable selection methods prior to multivariate modelling, as well as validation of the model after data analysis, become crucial for deriving reliable quantitative information [144–150]. Chemometric treatments and multivariate approaches have been extensively published with regard to micro-Raman data processing [146,151,152]. 7 3. Applications of Raman spectroscopy in pharmaceutical product design 3.1. Early drug development Preformulation studies are an essential component of the drug development process and are performed to understand the physicochemical properties of candidate drugs to support formulation development for preclinical and clinical studies. Biopharmaceutics is the study of how the physicochemical properties of the candidate drugs, the formulation/ delivery system and the route of administration affect the rate and extent of drug absorption. Overall, it is important to understand the pharmacokinetic profile (absorption, distribution, metabolism, excretion) of the candidate drugs during early development. Raman spectroscopy has been used in this research area. Determination of 5-fluorouracil in saliva using SERS is reported by Farquharson et al. [153]. Moreover, it is important to interrogate the interaction potential of the candidate drug compounds with the cytochrome P450 3A4 (CYP 3A4) enzyme to predict first-pass metabolism and drug–drug interactions. Mak et al. demonstrated the application of Resonance Raman spectroscopy for understanding binding interactions of APIs with CYP3A4 [154]. An important part of preformulation is solid-form screening aiming to identify the optimal solid form of the candidate drug compound as early as possible. This can help avoid crisis during later stages of drug development [155–157]. The lattice vibrations for different solid forms results in unique and characteristic Raman spectra for each of these forms. Therefore, Raman spectroscopy has long been used in pharmaceutical industry for this task. The structural backbone of a given solid form can be examined by Raman spectroscopy because the spectral features attributable to the lattice vibrational mode (shifts typically near 200 cm−1) are discernible with the use of modern notch filters. These filters allow the data collection of spectral data within 50 cm−1 of the excitation laser (which is not possible with FTIR). In this way, the low frequency (LF) Raman region provides richer information on the solid-state of materials. Therefore, the ability of rapid and non-invasive solid form analysis via Raman spectroscopy has been integrated into different high-throughput and low quantity solid form screening platforms of APIs including microfluidic polymorph and cocrystal screening [158–166]. Raman spectroscopy has been extensively used for understanding phase transformations such as polymorphic changes, anhydrate − hydrate transitions and amorphization [45,167–178], as well as for identifying the mechanisms of co-crystal formation [179,180]. Taylor et al. studied the influence of particle size on the dehydration behaviour of trehalose dihydrate of two different particle sizes using in situ FT Raman spectroscopy [177]. Although smaller particles (b45 μm) progressively underwent amorphization during dehydration, the larger particles (N 425 μm) led to a crystalline anhydrate form. DSC-Raman facilitates the visualization and understanding of molecular manifestations underlying transient thermal transitions, such as polymorphic transformation of crystalline pharmaceuticals [181–184]. As shown in Fig. 2, solid–solid transition between enantiotropic polymorphs of sulfathiazole can be clearly distinguished with the simultaneously recorded DSC-Raman data [184]. Transformation of form III to form I observed in the DSC thermogram is confirmed by the corresponding change in the integrated Raman peak areas of respective polymorphs. Raman spectroscopy was utilized as a real-time analytical technique to monitor the anhydrate-to-hydrate transformation of a wide diversity of APIs in an aqueous environment by Wikström et al. [178]. The transformation was found to be dependent on API chemistry and surface properties and to be strongly affected by extraneous factors such as degree of shear force and the presence of seeds. A recent publication reports the use of integrated Raman-neutron scattering to study API polymorphism [185]. In a recent study, Raman-coupled SEM was shown to identify solution-mediated polymorphic transformation of sulphathiazole at the dissolving crystal surface [186]. 8 A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 Fig. 2. DSC thermogram of sulfathiazole form III showing transition to form I and the subsequent melting event of form I. Inset shows the simultaneously measured Raman peak areas of corresponding polymorphs. Reprinted (adapted) with permission from [184] Copyright (2009) John Wiley & Sons Inc. mechanisms governing the reactions of different quercetin structures and thus enabled the understanding of structure–instability correlations. Furthermore, SERS analysis in Ag-doped sol–gel-filled capillaries was carried out to identify a nerve agent and its hydrolytic degradation products in aqueous solution [192]. The kinetics of disproportionation of a crystalline new drug candidate–citrate salt in both buffered and unbuffered aqueous slurries was measured using online Raman spectroscopy [193]. Apart from small molecules, determination of protein–complex structures using XRD alone can be ambiguous. Wen et al. demonstrated that Raman spectroscopy offers certain advantages over XRD for studies of detailed local environments and intermolecular interactions of side chains of proteins, both in solution and in crystals [194]. The authors used visible Raman, Raman optical activity and UV Raman Resonance spectroscopy to determine the conformation and local environments of a recombinant human interleukin-1 receptor antagonist. Hédoux et al. investigated the thermal denaturation behaviour of the lysozyme in aqueous solution with and without trehalose using Raman spectroscopy [195]. The spectral analysis of low frequency and amide region elucidated the dynamics of protein–solvent and protein–trehalose interactions in the native state and during the denaturation process. Trehalose addition was shown to retard protein dynamics and thus reduce aggregation. 3.2. Characterization of drug delivery systems Understanding solid state transformations as a function of humidity and temperature is quite important for investigating the storage stability of the selected solid form of the API. DVS is a frequently used method for understanding the complex transformation pathways among various anhydrate–hydrate forms as a function of humidity and temperature [187]. However, the gravimetric data in DVS need to be further correlated with the detailed structural changes. The utmost utility of the DVS-Raman technique is in monitoring moisture- or solvent sorption/desorptioninduced solid-state transformation (e.g., anhydrate/hydrate, crystallization) of pharmaceuticals [188]. Gift et al. explored the application of the DVS-Raman technique to gain a mechanistic understanding of watersolid interactions [84]. The authors studied various phenomena such as stoichiometric and non-stoichiometric hydrate formation, deliquescence, amorphous-crystalline transformations and capillary condensation. Furthermore, the authors demonstrated that quantitative information on transformation kinetics can be easily derived from the collected Raman spectra at various humidities. Feth et al. derived useful information using a DVS-Raman tool [86]. The authors identified phase transitions among non-stoichiometric hydrate forms using a combination of Raman spectroscopy and DVS (Fig. 3a to d). In another study on the same compound, Feth et al. used hot stage Raman spectroscopy to understand the behaviour of form-1 (2.25 eq. hydrate) as a function of temperature and correlated the phenomena using DSC (Fig. 3e and f) [189]. The authors observed that form-1 transforms to form-2 (1 eq. water) above 60 °C followed by melting above 90 °C. One of the important tasks during preformulation is understanding the degradation profile of the drug in the presence of various excipients under different stress conditions. Although HPLC and LC–MS analysis is needed to obtain a complete picture of the degradation profile of the API under various stress conditions, Raman spectroscopy can give useful hints of possible degradation in the API. Savolainen et al. prepared amorphous indomethacin samples using different preparation techniques from α and γ forms of indomethacin as starting material. The authors observed that Raman spectroscopy was the most sensitive technique among spectroscopic techniques for distinguishing both the molecular differences of amorphous samples prepared by different methods as well as differential degradation behaviour of differently prepared amorphous samples [190]. Sensitive Raman methods such as SERS have also been used to study the autoxidation, molecular fragmentation, dimerization and polymerization of quercetin flavonoids under alkaline conditions in an aqueous solution and on an Ag nanoparticle [191]. SERS spectra acquired at different pH unravelled the molecular Raman spectroscopy can be used for microstructural characterization of drug delivery systems, as well as to understand drug–excipient interactions in the formulation. Raman chemical imaging has been utilized to determine the size distribution of API microparticles and to determine the API distribution homogeneity in a composite formulated tablet [196,197]. This type of information can be extremely useful for the development of innovative drug products with increasingly complex and highly engineered structures [198–201]. Scoutaris et al. used confocal Raman microscopy (CRM) to study the distribution of printed drug delivery systems of felodipine–PVP mixtures [198]. Chen et al. used Raman spectroscopy to characterize nanosized PEGylatedreduced graphene oxide [202]. The latter was developed as an effective carrier for a photo-thermally controllable drug delivery system with the intention of increasing the effectiveness of tumour therapy. Hasa et al. used Raman spectroscopy to elucidate drug–polymer interactions in co-ground tablets prepared using cross-linked PVP or AcDiSol® [203]. One of the strategies for developing a modified release formulation is the use of multi-layered tablets. Choi et al. developed geometric three-layered tablets with various mechanical properties to achieve a sustained release once-a-day formulation for a model drug, tamsulosin HCl dihydrate [204]. The authors successfully used Raman imaging to understand the drug migration inside the dosage forms during dissolution, which were in turn used to obtain a mechanistic insight into the drug release profile from the complex matrix system. Amorphous solid dispersions are one of the effective solubilizing formulations available for poorly water soluble APIs. Amorphous APIs and carriers are widely characterized using Raman spectroscopy, even in the presence of moisture [205]. The nature of water molecules in hygroscopic amorphous polymer matrices such as PVP and PVP–VA was discerned using FT-Raman spectroscopic analysis as a function of moisture content [206]. Raman spectroscopy and imaging offer excellent opportunities for understanding drug–polymer interactions, miscibility and spatial phase distribution in solid dispersion formulations [151,167, 207,208]. Qian et al. performed Raman microscopic profiling on two PVP–VA-based solid dispersions of a drug candidate, BMS-A, with the same average composition (40% drug) but prepared by hot melt extrusion (HME) using screw speeds of 50 RPM (HME 1) and 225 RPM (HME 2). Despite the detection of a single identical glass transition temperature for both extrudates, the drug underwent partial crystallization from HME 1 after two months storage at ambient condition, whereas HME 2 remained amorphous. As shown in Fig. 4, the Raman chemical image of HME 1 clearly demonstrates the evidence of poorer homogeneity with A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 9 Fig. 3. Phase transitions of a non-stoichiometric hydrate (form-1) (a) water sorption gravimetric curve: sorption isotherm (b) Raman peak position vs relative humidity plot during desorption and sorption cycles, (c) distribution plots of the three hydrate forms during a water-sorption experiment determined by multivariate curve resolution (MCR) analysis of the Raman spectra, (d) phase diagram of hydrate phases as a function of humidity (Form 1 — 2.25 eq. water, Form 2 — 1 eq. water, Form 3 — 1.5 eq. water), (e) variable temperature Raman hot-stage experiment, (f) MDSC thermogram for form-1 in an aluminium pin-holed pan. (a) to (d) reprinted (adapted) with permission from [86] Copyright (2010) John Wiley & Sons Inc, (e) and (f) reprinted (adapted) with permission from [189] Copyright (2010) Elsevier. Fig. 4. Raman chemical imaging of HME 1 (50 RPM) (a) and HME 2 (225 RPM) (b) of BMS A–PVPVA (40% drug). The histogram inset shows the population distribution of different local drug concentrations. In the colour index displayed on the right, blue and red represent the lowest and highest drug concentration, respectively. Reprinted (adapted) with permission from [209] Copyright (2010) Elsevier. 10 A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 local drug concentration up to 50% in some regions as observed in the histogram inset. In contrast, fair compositional homogeneity was discernible for HME 2 with narrow distribution of drug concentration centred at 40%. This is in agreement with the superior physical stability of the latter dispersion [209]. Furthermore, Raman spectroscopy can also provide useful information about residual crystallinity in solid dispersion formulations and can be used to study the crystallization kinetics of amorphous API from solid dispersion formulations prepared by different techniques. The limit of detection of the Raman method for the trace crystallinity in solid dispersion is often comparable to that of XRD [210]. Time resolved Raman spectroscopy has been used to study the kinetics of crystallization of several amorphous APIs from the pure state as well as from molecular dispersions at elevated temperature and/or humidity [176,211]. Owing to the superior sensitivity of the phonon peaks of nanocrystallites (~30 Å) generated during early stage crystallization of amorphous pharmaceuticals, there is growing interest in using LF Raman susceptibility to monitor crystallization from amorphous pharmaceuticals [6]. Additionally, LF Raman spectroscopy can be used to monitor structural evolution during amorphization by cryo-grinding and pressure. Hedoux et al. obtained distinct LF Raman spectra of amorphous indomethacin generated by pressurizing and quench cooling/cryo-grinding the drug, and the authors suggested a clear distinction between their local structures, pointing to polyamorphism [167]. Raman spectroscopy can also provide useful information for the fabrication of implants. Esrafilzadeh et al. developed multifunctional conducting polymer-based hybrid fibres to achieve electrically controlled release of ciprofloxacin. The authors used Raman spectroscopy to study the electropolymerisation mechanism of the fibres [212]. The integrity and microstructure of drug eluting stents are difficult to characterize using conventional analytics because drug formulation is present as a thin coat over the wire. CRM was used to analyze the chemical morphology of rapamycin/PLGA coatings on stents, from the surface through the bulk of the coatings [213]. Biggs et al. published excellent results on the comprehensive elucidation of the sirolimus-eluting coronary stent (CYPHER™) during drug elution using CRM correlated with AFM [214]. Drug-rich regions revealed by surface and sub-surface Raman chemical images were linked with AFM topography of the coating, which indicated a link between drug release behaviour and device microstructure and pore networks. Raman spectroscopic and imaging techniques have been used for the characterization of different topical drug delivery systems with in vitro, ex vivo and in vivo studies on the cutaneous penetration of active drugs from dermatological products [54,215,216]. Lipid-based drug delivery systems have gained interest in recent years for enhancing the oral bioavailability of BCS class II and IV drugs by means of increasing solubility and permeability [217–220]. Raman spectroscopy and Raman imaging techniques have been successfully employed for the characterization of lipid-based drug delivery systems [201,221–224]. Breitkreitz et al. used Raman image spectroscopy for the homogeneity evaluation of semi-solid self-emulsifying drug delivery systems of the model compound, atorvastatin calcium [222]. Schaefer et al. used CRM to probe the temperature-controlled release of encapsulated molecules from phospholipid vesicles in liposome formulations [223]. Stillhart et al. determined drug precipitation kinetics during in vitro lipolysis of a lipid-based drug delivery system using Raman spectroscopy as a real-time monitoring tool [221]. The same group recently extended the use of in-line Raman spectroscopy to monitor in vitro drug dispersion, lipolysis and supersaturation of lipid-based formulation using in vitro lipolysis integrated with a continuous absorptive environment [225]. The characterization of spatial drug distribution on the carrier surface is challenging but highly relevant to aerodynamics and API lung deposition from dry powder for inhalation (DPI). Raman spectroscopy is also used in the analysis of respirable dosage forms [226] and to gain insight into the controlled release behaviour of inhalable polymeric microspheres for treatment of pulmonary hypertension [227]. High performance LF Raman spectroscopy was shown to exhibit an excellent ability to distinguish the solid-state (amorphous and crystalline) from small mass fractions of API (b 3% w/w) present in multicomponent respirable powders [226]. Theophilus et al. utilized Raman spectroscopy to analyze the drug (co)deposited following the aerodynamic impaction tests of a metred dose inhaler containing a salmeterol/fluticasone propionate combination, as well as the two drugs tested separately. The result implied that the drug combination in a single device significantly increased the co-deposition over using separate inhalers [228]. Raman chemical imaging using coupled Raman and optical imaging was shown to be a promising method for characterizing particle size and distribution, together with chemical identity for a representative corticosteroid in aqueous nasal spray suspension [229]. CRM is also used as a fast and convenient method for the analysis of content uniformity, homogeneity and the polymorphic form of a drug substance distributed within a spray-dried lipid-based inhalable powder [230]. Recently, Fussell et al. showed the capability of CARS imaging to identify drug particle clusters and their size on the carrier particle surface of a DPI formulation [231]. As shown in Fig. 5, CARS images, when combined with SEM images, provide information on the behaviour of morphological changes and drug distribution onto the carrier surface as a function of mixing time. Raman spectroscopy can also be informative for the characterization of protein and peptide drug delivery systems [232–234]. A Raman spectroscopy-based method for in situ monitoring of secondary structural composition of proteins during frozen and thawed storage was developed by Roessl et al. [232]. Raman optical activity (ROA) bears high potential for application towards protein characterization in the native state as well as in a formulated environment [235]. Raman chemical imaging was used to study the distribution of orally delivered parathyroid hormone within sucrose spheres beneath the entericcoating layer and to visualize the enteric coating integrity [236]. 3.3. Process measurements The concept of process analytical technology (PAT) is becoming increasingly important in the pharmaceutical industry. Raman spectroscopy is being considered a feasible PAT tool as it can provide molecular level insight into chemical and physical phenomena taking place during pharmaceutically relevant unit operations, which can be useful for obtaining real-time information from these processes. Various analytical applications of Raman spectroscopy and relevant pitfalls have been compiled in literature reviews [49,237]. These cover several processes related to the manufacturing of solid dosage forms such as synthesis, crystallization, mixing, granulation, tableting and coating. Here, we have compiled the recent advancements and selected examples from various processes. Synthesis and fermentation processes are often the source of smallmolecular and bio-macromolecular APIs. Raman spectroscopy has been used to monitor the fermentation process of antibiotics [238,239]. Raman spectroscopy has also been used to monitor mammalian cellbased bioprocesses [240,241]. The quality of the cell culture media is a crucial factor affecting bioprocess performance and the quality of the final product in biopharmaceutical manufacturing. Calvet et al. demonstrated the application of SERS to the simple and fast analysis of cell culture media degradation [242]. Crystallization is a crucial unit operation used for the separation and purification of solid products. Batch crystallization is ideally performed in an aqueous environment. Therefore, Raman spectroscopy is a very useful tool for process control and monitoring the desired polymorphic form during crystallization [147,149,237,243,244]. Pataki et al. demonstrated the application of fibre optic-coupled Raman spectroscopy for real-time monitoring of the desired polymorph of carvedilol during the cooling crystallization process. The authors successfully tested the Raman signal feedback method for the production of the desired form II of carvedilol [245]. A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 11 Fig. 5. Correlative CARS–SEM image of salmeterol xinafoate mixed with α-lactose monohydrate particle intended for DPI (0.4 wt.% drug loading) after mixing times of 0.5 min (left) and 600 min (right). Reprinted with permission from [231] Copyright (2014) John Wiley & Sons Inc. Tablets and capsules are still considered the preferred dosage forms. The manufacture of tablets involves several unit operations such as milling, powder blending, granulation, drying, compaction and coating. It is crucial to control the quality of the intermediate products generated during various unit operations to manufacture the final quality product. Raman spectroscopy has been found to be a very useful PAT tool for inprocess monitoring to test for the desired intermediate product after each unit operation [246]. De Beer et al. applied Raman spectroscopy as a PAT tool for the end-point control of a powder blending process [247]. The authors demonstrated that Raman spectroscopy enabled inline and real-time monitoring of the blend homogeneity and also led to a better understanding of the process. The effect of particle size, shape, density and/or light absorption capability on the Raman sampling depth during in situ monitoring of API-excipient blending by wide area illumination (WAI) was recently studied by Allan et al. [248]. Poutiainen et al. developed a mechanistic understanding of the evolution of granule structure and drug content homogeneity during fluidized bed granulation using X-ray microtomography and confocal Raman spectroscopy [249]. Wikström et al. studied the effect of various process parameters on the rate and extent of theophylline anhydrate to monohydrate conversion during high-shear wet granulation using inline Raman spectroscopy [250]. A solvent-mediated transformation model was shown to estimate the time scale of the transformation onset for this compound. The higher sampling volume and improved robustness against sampling distance fluctuation was obtained for monitoring phase transformation using large spot Raman optics compared to the standard immersion Raman probes. Christensen et al. studied the influence of excipients on the process-induced transformation of piroxicam anhydrate to monohydrate during wet granulation using Raman spectroscopy [148]. Raman spectroscopy is also a valuable tool for monitoring the coating process [251–253]. Knop et al. recently published a literature review on PAT-tools for process control in pharmaceutical film coating applications. The authors suggested that in-line Raman spectroscopy is a promising PAT tool for monitoring the coating process of solid dosage forms, irrespective of the coating apparatus or the core type (tablets or pellets) [252]. Wirges et al. successfully implemented Raman spectroscopy on a production scale to monitor the coating process. The authors also validated the Raman spectroscopic method at a production scale according to the European Medicine Agency (EMA) guidelines with respect to the special requirements of the applied in-line model development strategy [251]. Hot melt extrusion (HME) has gained significant attention in the pharmaceutical industry in the last five years for the rapid production of solid dispersions [254]. Raman spectroscopy has also been used as a PAT tool for inline and real-time monitoring of the concentration of APIs in the extrudate or of the solid state of the extrudates, as well as to provide information about drug–polymer interactions during the hot melt extrusion process [254,255]. Saerens et al. demonstrated an application of Raman spectroscopy for in-line monitoring of the solid state of the hot melt extrudates of Celecoxib–Eudragit E PO formulations prepared with varying drug loads (30%, 40%, 50%), temperatures (130 °C, 140 °C, 150 °C), and screw configurations. A Raman probe was inserted into the die head to monitor the solid state of the extrudates before they were forced through the die. The temperature at the Raman measurement point was kept constant at 110 °C. As shown in Fig. 6a, the in-line Raman measurements can easily distinguish glassy solid solutions (red), crystalline solid dispersions (blue) and partially crystalline solid dispersions (green). Furthermore, Raman spectra also provided useful information on the process history of the samples. As shown in Fig. 6c and d, a large variation in the average die pressure was noticed between different experiments. The authors suggested that this variation was caused by two factors: (i) higher processing temperature, which may reduce the viscosity of the melt and lower the die pressure; and (ii) higher drug load, which leads to a plasticization effect. Higher pressure at the measurement point resulted in a decrease in Raman intensity [256]. In addition to solid-state analysis, transmission Raman spectroscopy (TRS) and CRM was used to investigate the process-induced degradation of spironolactone during the preparation of solid dispersion with Eudragit E by HME [257]. The correlation of TRS results of the ratio of drug to degradation product, to that obtained by Raman chemical imaging and to the results of chromatographic analysis indicated the application of TRS as a rapid and non-invasive quality control technique. Recent advancements in the field of bio-macromolecules have opened a new avenue in the development of protein drug delivery systems. Freeze drying /lyophilization is often used in the manufacturing of protein drug delivery systems. Physical stability of proteins plays a crucial role in the quality of final protein formulations [258–260]. Raman spectroscopy can be applied as a non-invasive technique for the in-line monitoring of crystallization and polymorphic transformation of APIs and/or excipients during freeze-drying [261]. De Beer et al. proposed a strategy for the implementation of a PAT system in freeze-drying processes using in-line Raman spectroscopy and mannitol solutions as a model system for the freeze-drying process [262]. Waard et al. developed a novel process, “controlled crystallization during freezedrying”, using in-line Raman spectroscopy during the freeze-drying process to understand the crystallization behaviour of solvent and solute components during various phases of the freeze drying process [263]. Hedoux et al. used micro-Raman spectroscopy for in situ monitoring of proteins during lyophilization. The authors investigated the influence of the lyophilization parameters on the degree of protein denaturation [260]. 12 A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 Fig. 6. In-line Raman measurements of Celecoxib — Eudragit E PO formulations (varying drug loads, 30%, 40%, 50%; temperatures,130 °C, 140 °C, 150 °C; and screw configurations, FF, FB, 2 F); (a) PCA scores plot (red cluster, glassy solid solutions; green cluster, partially crystalline solid dispersions; blue cluster, crystalline solid dispersions); (b) PCA loadings plot for PC1 scores in (a); (c) PCA scores plot from in-line collected raw Raman spectra at 110 °C (different score values reflect process history); (d) Raman spectral intensity with mean melt temperatures and varying die pressures (varying intensities is due to differences in viscosity at different processing temperatures (130 °C, 140 °C, 150 °C)). Reprinted (adapted) with permission from [256] Copyright (2014) Elsevier. 3.4. Product performance testing and quality control for the final product Quality control of finished pharmaceutical products is often considered to be a challenging task due to the complexity of the dosage form and the presence of multiple excipients in the final dosage form [264]. Mostly, APIs give very sharp and significant Raman spectra, whereas excipients do not give very intense Raman signals [265]. This makes Raman spectroscopy a very useful tool for performance testing of the final product and to correlate the results of performance testing with the changes in crystal structure or morphology. Additionally, Raman spectra are almost entirely free from interference of water bands. This allows monitoring of the solid form changes during dissolution testing. However, the detection of API solid-states in the presence of solvent media is limited by the Raman signal strength and spectral bandwidths, which are significantly broader in solutions. Drug content assays and impurity profiles are two critical quality attributes of a finished dosage form. A low resolution Raman device is useful for rapid and on-line content uniformity determination in solid oral dosage forms such as tablets [266]. Owing to the multicomponent nature of finished dosage forms, various multivariate data treatment and chemometric methods are useful for the rapid detection and quantification of drug and excipients [267]. Therefore, the accuracy of content uniformity analysis and quantification also depends on the selection of a sufficiently predictive multivariate model for a particular dosage form [145]. Raman spectroscopic content analysis and the quantification of powder blend formulations and heterogeneous samples require due consideration of the influence of variations in optical path length on the Raman signal due to particle size and shape distribution and the implementation of suitable corrections and chemometric techniques [268,269]. TRS is found to be well suited for content analysis for formulations such as bulk tablets (even coated) with minimal error and for accurate compositional analysis of drug suspension in turbid media [13,270–272]. TRS mode was also recently implemented for the quality control of cocrystal tablets [273] and the analysis of solid dispersions [274]. Successful quantitative application of TRS was demonstrated for multi-component pharmaceutical capsules in intact forms owing to the absence of interferences from capsule shell signal and insensitivity to the capsule fill weight and size [275,276]. A recent publication reported the use of Raman for the quality control of drug products that are carried by astronauts into space [277]. The space-induced degradation of acetaminophen was monitored using Raman spectroscopy by measuring the API and its toxic degradation product (aminophenol). Another recent study reported the quantification of aminophenol at concentrations of 0.025% to 0.2% in an acetaminophen tablet using a SERS chemical imaging approach [278]. In addition to drug content and impurity profiles, detection of drug counterfeiting has been a serious challenge for pharmaceutical dosage forms [279,280]. Raman spectroscopy, especially handheld devices and portable units, enables analysis through a container such as a blister pack or coloured vial without sample preparation, thus allowing rapid and non-invasive material identification [281,282]. Spatially offset Raman spectroscopy (SORS) has been applied for rapid and non-invasive identification of pharmaceutical raw materials as well as for the characterization of genuine and fake tablets through blister packs [283,284]. Furthermore, Raman microscopy and two-dimensional correlation spectroscopy have been employed for the analysis of counterfeit pharmaceutical tablets enclosed within the packaging [285–287]. However, the identification and quantification of falsified medicines in complex, multi-component dosage forms using low resolution Raman spectroscopic data necessitates strong and reliable chemometric data analysis models [286,288]. One of the strengths of solid-state Raman spectroscopy is the ability to produce a unique signature of vibrational bands representing the 3-D arrangement of a particular polymorphic form of a crystalline solid. Therefore, subtle alteration in the solid-state structure, including conformational state changes due to polymorphic modifications, can provide quantitatively specific Raman signals owing to the diverse phonon vibration of crystals. Likewise, a hydrate can often be readily quantified in the presence of an anhydrate in the mixture using Raman spectra. Bulk amorphous form presents a broader spectra or loss of different peaks present in its crystalline counterpart. Extensive studies are available on the quantification of solid forms using Raman spectroscopy, microscopy and chemical image analysis in static, multicomponent mixtures or during various pharmaceutical processes as aforementioned, often accompanied by suitable statistical or chemometric treatment of data and multivariate calibration model development [147,171]. The readers are referred to a review by Strachan et al. on the application of Raman spectroscopy for the quantification of pharmaceutical solid forms [289]. Proper matching of the particle size distribution of calibration mixtures with that of the actual mixture is necessary to avoid the influence of particle size on Raman intensity, thus avoiding quantitative prediction errors [290–292]. Appropriate sample preparation A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 and homogeneity of the calibration sample is necessary to develop an accurate calibration model [293]. Sampling volume and data processing are important factors relating to the productivity and quantification power of Raman-based polymorphic and hydrate/anhydrate analysis methods [144]. Raman spectroscopy has been used to quantify binary or ternary polymorphic and/or pseudopolymorphic forms of APIs in powder mixtures, crystallinity in amorphous/crystalline mixtures, polymorphic forms and amorphous mixtures of excipient, solid forms of APIs, and excipients in tablet form [150,294–299]. Various studies report the superiority of the TRS method in terms of speed of analysis, sampling statistics, peak sharpness and low wavenumber region (solid-state lattice modes) for the facile quantification of different polymorphs of APIs in binary mixtures as well as in the presence of excipients in tablets (in blister packages) or capsules [19,271,300–303]. In situ Raman spectroscopy was used to monitor and quantify intermediate to final solid forms generated during the dehydration of hydrate forms of piroxicam and carbamazepine, and the quantitative models built were exploited by solid state quantification during fluid bed drying [304,305]. Drug release from solid dosage forms such as tablets and capsules is a complex process that is accompanied by concomitantly occurring physicochemical, solution-mediated solid-state transformations at the surface and the bulk of solids in contact with the aqueous media. Raman spectroscopy can enable the understanding of the solid-state manifestation via dissolution by analyzing formulations before dissolution and the residual solids remaining during dissolution. Moreover, the lack of water signal interference and inherent capability of data collection in aqueous systems have led to the increasing popularity of fibre optic Raman probes or Raman microscopy as powerful tools for in situ monitoring of various solution-mediated phase transformations, which includes monitoring during drug dissolution and the release testing of powder or compacts in various in vitro dissolution apparatuses and flow-through dissolution devices, even in biorelevant media [306–308]. Recent studies also showed the utilization of Raman spectroscopy orthogonally coupled with UV imaging for dissolution monitoring [309,310]. Interested readers are referred to a review on real-time Raman analysis for studying solution-mediated phase transformations by Greco and Bogner [311]. The choice between Raman spectroscopy versus microscopy depends on the type of investigation and dosage form (compact versus powder). For example, Raman microscopy is suitable for the system undergoing relatively slow transformations monitored in one single crystal or on a small portion of a compact [312]. Raman spectroscopy is better for quantitative purposes in fast conversions with a large sample volume. Various solution mediated phase transformations accompanying drug dissolution can be monitored by Raman spectroscopy/microscopy, including anhydrate to hydrate transformation [309], crystallization kinetics of amorphous pharmaceuticals [313,314], disproportionation of salt forms of API [310,315,316] and polymorphic transformations [317]. Strong hydrogen bonding interactions between carbamazepine and sodium taurocholate, a component of fasted state simulated intestinal fluid (FaSSIF), were inferred from in situ Raman spectroscopic data collected during dissolution of carbamazepine in FaSSIF [307]. This is related to the inhibition of anhydrate to dihydrate transformation in FaSSIF owing to the formation of needle anhydrate. This implies that in situ Raman spectroscopy can be a powerful tool for monitoring solid formdissolution media interaction. In addition to conventional Raman systems, Hyperspectral CARS microscopy has been increasingly used to monitor in vitro drug dissolution from different solid oral dosage forms and to relate dissolution with drug distribution in formulation [318–322]. CARS was used for the real-time spatial visualization of the change in the solid-state of theophylline from anhydrate to the less soluble monohydrate during dissolution from the lipid-based oral dosage form [323]. Haaser et al. employed Raman microscopy to chemically image the component distribution and structural changes during dissolution testing of sustained release extrudate formulations of theophylline anhydrate in a tripalmitin matrix with polyethylene glycol [324]. 13 In situ Raman spectroscopy can also provide deeper insight into the dissolution behaviour of amorphous APIs or dispersions. Alonzo et al. investigated the crystallization behaviour of felodipine and indomethacin from the slurry of amorphous forms exposed to the dissolution medium at 25 °C and 37 °C in the absence and presence of externally added polymers such as PVP, HPMC or HPMC-AS using a fibre-optic Raman system equipped with an immersion probe [325]. As observed in Fig. 7a, the conversion of amorphous indomethacin to α-indomethacin at 37 °C could be evidenced with the disappearance of a peak unique to the amorphous form (at 753 cm−1) and the appearance of the characteristic peak of α-indomethacin (at 1648 cm−1). A univariate quantification model was applied based on the peak attributable at 1648 cm−1 and thus for correlating crystallization kinetics with the dissolution profile (Fig. 7b). Amorphous felodipine crystallized rapidly at 37 °C and slowly at 25 °C, whereas indomethacin crystallized much slower at both temperatures, generating a certain extent of supersaturation. Upon addition of polymer in the solution phase, the supersaturation was maintained due to the drastic reduction in overall crystallization rates for both the APIs. Likewise, crystallization of APIs from piroxicam–PVP amorphous solid dispersion prepared by cryo-milling from the slurry in simulated gastric fluid was monitored using a Raman spectrometer coupled with two coaxial fibre optic probes [326]. Induction of crystallization into piroxicam monohydrate occurred within 1 min for amorphous solid dispersion with PVP K25 and within 3 min for PVP K90 with no further spectral change appearing after 15 min. Ferreira Molina et al. recently published study on the drug release mechanism from cisplatin-loaded polymeric xerogel using a setup that combines Raman spectroscopy with synchrotron X-ray absorption spectroscopy and UV–Vis spectroscopy [327]. 4. Perspectives and future directions Raman spectroscopy and associated analytics have had a long development and many applications. Several specialized innovations are continuing to evolve within pharmaceuticals as a central focus. With relatively cost-effective fabrication, extensive varieties of Raman instruments are available today. This includes highly sophisticated Raman-integrated assemblies, from high performance instruments applicable to high end research to low resolution portable instruments for quality control, screening and material qualifications. This bifurcated trend of technological development will continue to support a wide diversity of multi-stage pharmaceutical research. Dedicated Raman spectroscopic installation at the synchrotron beamline holds novel application potential for multi-methodological monitoring of complex phase transitions in pharmaceutical product design and engineering. Raman integrated optical levitator cell design can be used to understand the genesis of unique microstructure and physical states of APIs and excipients in formulation while drying a single droplet levitated under varying temperatures and pressure environments [46]. Thanks to the flexibility of Raman devices, the incentives of interfacing various analytical tools with Raman have led to a booming area of pharmaceutical nanotechnology. The field of material engineering will also benefit from these developments. Simpler adaptation of sophisticated Raman experiments such as SERS, TERS and CARS will appeal to untrained professionals [328]. Even the fields of diagnostics, theranostics, and medical and in vivo research will benefit from multi-microscopic platforms that include Raman microscopy as an integral part. For example, a recently fabricated disposable Raman probe head for use with magnetic resonance imaging (MRI) has shown potential as a new avenue of in vivo diagnostic application [329,330]. Furthermore, multimodal image-guided Raman endoscopy techniques hold promising future potential for the real-time, in-vivo diagnosis of oesophageal cancer [331]. Raman spectroscopy can also be considered to be a future diagnostic tool for non-invasive glucose monitoring through skin [332]. Potential pharmaceutical research applications can demonstrate the 14 A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 Fig. 7. (a) Raman spectra of indomethacin slurries showing, from top to bottom, amorphous indomethacin after exposure to buffer (37 °C) for 120 min, 90 min and 20 min, unexposed amorphous indomethacin and α-indomethacin. (b) Normalized peak intensity (■) of α indomethacin at 1648 cm−1 as a function of time and dissolution of amorphous indomethacin at 37 °C as a function of time (□). Reprinted (adapted) with permission from [325] Copyright (2010) Springer Link. commercial economic viability of transferring customary laboratorydeveloped technologies into the real world. Innovative fibre optics-based Raman probes with operational flexibility will further incentivize the field of pharmaceutical PAT applications. The anticipated future megatrend of continuous pharmaceutical manufacturing within the Quality by Design (QbD) framework may embrace the tailored Raman probe hardware that is adaptable to a wide variety of unit operations [257,333,334]. Process monitoring for blue-sky mini-manufacturing technologies that are envisioned as personalized/individualized drug delivery techniques, such as medicine printing, dripping, film casting, microfluidics, and coacervation, reckon the use of versatile Raman sensors as an intelligent PAT system in coming years [335]. In addition, advancements in the biomedical and diagnostic application of Raman techniques will further facilitate personalized drug delivery. One such example is the use of carbon nanotubes in advanced diagnostic tools [336,337]. Portable Raman devices with improved practicalities such as unconstrained size and shape as well as simple optics are mountable in several inaccessible parts of production lines. Another possible important application in the pharmaceutical industry is the coupling of Raman to detect (in situ) extrinsic or intrinsic mobile micro-particles that are optically trapped, known as Raman tweezers spectroscopy, in products or the manufacturing process [338]. Furthermore, the simplicity and compactness of handheld and portable Raman devices will further increase their application for anti-counterfeiting and quality control purposes [339]. Eventually, a juvenile field for future application will develop around small, handheld Raman instruments that can enable the tracking of drug products from factory to pharmacy shelves or provide quality control at outpatient clinics and hospitals. As an example, a recent proof-of-concept study showed that the accuracy of quantitative analysis of hospital compounded ganciclovir by Raman spectroscopy is comparable to that by chromatographic analysis [340]. In addition to hardware, novel data handling and chemometric methods, Raman libraries and algorithms will further support the emerging instrumental development and their pharmaceutical application. Extremely large volumes of data collected during PAT monitoring or complex Raman chemical imaging require data analysis models to achieve efficient trending and meaningful interpretation. Moreover, multimodal and integrated spectroscopy generates data that are interesting for heterospectral 2D correlation treatment and extract maximum information. Multi-dimensional correlation Raman spectroscopy studies are dominant in chemical characterizations using timeresolved measurements or as the function of various types of perturbation such as temperature and composition [341–343]. This implies that there are enormous opportunities in applying 2D correlation Raman spectroscopy with different external perturbations and correlation formalism for pharmaceutical analysis, which has not been very common [344–346]. For example, such an experiment could be very useful for probing heteromolecular interactions in complex formulations, such as amorphous solid dispersions. Abbreviations AFM API CARS CCD CD CLS CRM DPI DVS DSC FT-IR HME LF MCR NIR NMR NSOM OCT PAT PCA PhAT PLS PLS-DA PMT ROA RRS SAXS SEM SESORS SORS SPM SRS STM TERS TRS UV WAI XRD Atomic Force Microscopy Active Pharmaceutical Ingredient Coherent Anti-stokes Raman Scattering Charge-Coupled Device Circular Dichroism Classical Least Squares Confocal Raman Spectroscopy Dry Powder for Inhalation Dynamic Vapour Sorption Differential Scanning Calorimetry Fourier-Transform Infrared Hot Melt Extrusion Low Frequency Multivariate Curve Resolution Near-IR Nuclear Magnetic Resonance Near-field Scanning Optical Microscopy Optical Coherent Tomography Process Analytical Technology Principal Component Analysis Pharmaceutical Area Testing Partial Least Square Regression Partial Least Square Discriminant Analysis Photo-multiplier Tube Raman Optical Activity Resonance Raman spectroscopy Small-Angle X-ray Scattering Scanning Electron Microscopy Surface-Enhanced SORS Spatially Offset Raman Spectroscopy Scanning Probe Microscopy Stimulated Raman scattering Scanning Tunnelling Microscopy Tip-Enhanced Raman Scattering Transmission Raman spectroscopy Ultraviolet Wide Angle Illumination X-ray Diffraction Acknowledgements Acknowledgement Ioan Notingher is an EPSRC Fellow (EP/ L025620/1) and acknowledges the support from the National A. Paudel et al. / Advanced Drug Delivery Reviews 89 (2015) 3–20 Institute for Health Research (NIHR) under its Invention for Innovation (i4i) Programme (grant numbers II-AR-0209-10012).The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. • http://www.controldevelopment.com/products/probes/productprobes-raman-probe.php • http://www.augustus-pharmaceuticals.com/alt.php?content=about • http://www.azonano.com/article.aspx?ArticleID=1538 • http://pharmacy.ku.dk/research/section-of-pharmaceutical-tech nology/ • http://wallpoper.com/wallpaper/pills-tablets-406870 References [1] Y.-S. Li, J.S. Church, Raman spectroscopy in the analysis of food and pharmaceutical nanomaterials, J. Food Drug Anal. 22 (2014) 29–48. [2] A. Mahadevan-Jansen, Raman spectroscopy: from benchtop to bedside, in: T. Vo-Dinh (Ed.)Biomedical Photonics Handbook 2003, pp. 759–786. [3] S.E.J. 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