Exploring the Excited States of a Hexa-peri-hexabenzocoronene-Substituted Dipyridophenazine Ligand and Its Metal Complexes.

A hexa-peri-hexabenzocoronene (HBC)-substituted dipyridophenazine (dppz) ligand (dppz-HBC) and its corresponding rhenium [Re(CO)3Cl] and ruthenium [Ru(bpy)2]2+ complexes were synthesized and characterized. The interplay of their various excited states was investigated using spectroscopic and computational techniques. Perturbation of the HBC was seen through a broadening and decreased intensity of the HBC absorption bands that dominate the absorption spectra. A delocalized, partial charge transfer state was shown through emission (520 nm) in the ligand and rhenium complex and is supported by time-dependent density functional theory calculations. Transient absorption measurements revealed the presence of dark states with a triplet delocalized state populated in the ligand, while in the complexes, longer-lived (2.3-2.5 µs) triplet HBC states could be accessed. The properties of the studied ligand and complexes provide insight into the future design of polyaromatic systems and add to the rich history of dppz systems.

Detection and Quantification of Adulteration in Krill Oil with Raman and Infrared Spectroscopic Methods.

Raman and infrared spectroscopy, used as individual and low-level fused datasets, were evaluated to identify and quantify the presence of adulterants (palm oil, PO; ω-3 concentrates in ethyl ester, O3C and fish oil, FO) in krill oil. These datasets were qualitatively analysed with principal component analysis (PCA) and classified as adulterated or unadulterated using support vector machines (SVM). Using partial least squares regression (PLSR), it was possible to identify and quantify the adulterant present in the KO mixture. Raman spectroscopy performed better (r2 = 0.98; RMSEP = 2.3%) than IR spectroscopy (r2 = 0.91; RMSEP = 4.2%) for quantification of O3C in KO. A data fusion approach further improved the analysis with model performance for quantification of PO (r2 = 0.98; RMSEP = 2.7%) and FO (r2 = 0.76; RMSEP = 9.1%). This study demonstrates the potential use of Raman and IR spectroscopy to quantify adulterants present in KO.

Low-Frequency Raman Spectroscopy as an Avenue to Determine the Transition Temperature of ß- and γ-Relaxation in Pharmaceutical Glasses.

In an earlier investigation, low-frequency Raman (LFR) spectroscopy was shown to detect the transition temperature of the ß-relaxation (Tß) in both amorphous celecoxib and various celecoxib amorphous solid dispersions [Be̅rzins, K. Mol. Pharmaceutics 2021, 18(10), 3882-3893]. In this study, we further investigated the application of this technique to determine Tß, an important parameter for estimating crystallization potency of amorphous drugs. Alongside commercially available amorphous drugs (zafirlukast and valsartan disodium salt), differently melt-quenched samples of cimetidine were also analyzed. Overall, the variable-temperature LFR measurements allowed for an easy access to the desired information, including the even lesser transition of the tertiary relaxation motions (Tγ). Thus, the obtained results not only highlighted the sensitivity, but also the practical usefulness of this technique to elucidate (subtle) changes in molecular dynamics within amorphous pharmaceutical systems.

Evaluating Spatially Offset Low-Frequency Anti-Stokes Raman Spectroscopy (SOLFARS) for Detecting Subsurface Composition below an Emissive Layer: A Proof of Principle Study Using a Model Bilayer System.

This work explores the potential use of spatially offset low-frequency anti-Stokes Raman spectroscopy (SOLFARS) to detect subsurface composition below an emissive surface. A range of bilayer tablets were used to evaluate this approach. Bilayer tablets differed in both the underlying layer composition (active pharmaceutical ingredient to excipient ratio, celecoxib: α-lactose monohydrate) and the upper layer thickness of the fluorescent coating (polyvinylpyrrolidone mixture with sunset yellow FCF dye). Two low- (<300 cm-1) plus mid- (300 to 1800 cm-1) frequency Raman instrumental setups, with lateral displacements for spatial analysis of solid dosage forms, using different excitation wavelengths were explored. The 532 nm system was used to illustrate how the low-frequency anti-Stokes Raman approach works with samples exhibiting extreme fluorescence/background emission interference, and the 785 nm system was used to demonstrate the performance when less extreme fluorescence/emission is present. Qualitative and quantitative chemometric analyses were performed to evaluate the performance of individual spectral domains and their combinations for the determination of the composition of the subsurface layer as well as the coating layer thickness. Overall, the commonly used midfrequency region (300-1800 cm-1) proved superior when using 785 nm incident laser for quantifying the coating thickness (amorphous materials), whereas a combined Stokes and anti-Stokes low-frequency region was found to be superior for quantifying underlying crystalline materials. When exploring individual spectral regions for subsurface composition using spatially offset measurements, the anti-Stokes LFR spectral window performed best. The anti-Stokes low-frequency range also demonstrated an advantage for models composed of data exhibiting high levels of fluorescence (e.g., data collected using 532 nm incident laser), as the Stokes scattering was masked by fluorescence. Transmission measurements were also explored for comparison and showed the best applicability for both upper and lower layer analysis, attributed to the inherently larger bulk sampling volume of this setup. From a practical perspective, these results highlight the potential adjustments that can be made to already existing (in-line) Raman setups to facilitate similar analysis in pharmaceutical industry-based settings.

Low- versus Mid-frequency Raman Spectroscopy for in Situ Analysis of Crystallization in Slurries.

Slurry studies are useful for exhaustive polymorph and solid-state stability screening of drug compounds. Raman spectroscopy is convenient for monitoring crystallization in such slurries, as the measurements can be performed in situ even in aqueous environments. While the mid-frequency region (400-4000 cm-1) is dominated by intramolecular vibrations and has traditionally been used for such studies, the low-frequency spectral region (<200 cm-1) probes solid-state related lattice vibrations and is potentially more valuable for understanding subtle and/or complex crystallization behavior. The aim of the study was to investigate low-frequency Raman spectroscopy for in situ monitoring of crystallization of an amorphous pharmaceutical in slurries for the first time and directly compare the results with those simultaneously obtained with mid-frequency Raman spectroscopy. Amorphous indomethacin (IND) slurries were prepared at pH 1.2 and continuously monitored in situ at 5 and 25 °C with both low- and mid-frequency Raman spectroscopy. At 25 °C, both spectral regions profiled amorphous IND in slurries as converting directly from the amorphous form toward the α crystalline form. In contrast, at 5 °C, principal component analysis revealed a divergence in the detected conversion profiles: the mid-frequency Raman suggested a direct conversion to the α crystalline form, but the low-frequency region showed additional transition points. These were attributed to the appearance of minor amounts of the ε-form. The additional solid-state sensitivity of the low-frequency region was attributed to the better signal-to-noise ratio and more consistent spectra in this region. Finally, the low-frequency Raman spectrum of the ε-form of IND is reported for the first time.

Rapid Quantitation of Adulterants in Premium Marine Oils by Raman and IR Spectroscopy: A Data Fusion Approach.

This study uses Raman and IR spectroscopic methods for the detection of adulterants in marine oils. These techniques are used individually and as low-level fused spectroscopic data sets. We used cod liver oil (CLO) and salmon oil (SO) as the valuable marine oils mixed with common adulterants, such as palm oil (PO), omega-3 concentrates in ethyl ester form (O3C), and generic fish oil (FO). We showed that support vector machines (SVM) can classify the adulterant present in both CLO and SO samples. Furthermore, partial least squares regression (PLSR) may be used to quantify the adulterants present. For example, PO and O3C adulterated samples could be detected with a RMSEP value less than 4%. However, the FO adulterant was more difficult to quantify because of its compositional similarity to CLO and SO. In general, data fusion improved the RMSEP for PO and O3C detection. This shows that Raman and IR spectroscopy can be used in concert to provide a useful analytical test for common adulterants in CLO and SO.

Pseudo-3D Subsurface Imaging of Pharmaceutical Solid Dosage Forms Using Micro-spatially Offset Low-Frequency Raman Spectroscopy.

A new combinatory Raman subtechnique of low-frequency and micro-spatially offset Raman spectroscopy (denoted micro-SOLFRS) is demonstrated via analysis of pharmaceutical solid dosage forms. A variety of different (multilayer/multicomponent) model systems comprising celecoxib, α-lactose (the anhydrous and monohydrate form), and polyvinylpyrrolidone (PVP) were probed to test the potency of this newly developed technique to, for example, provide qualitative and quantitative information on surface and subsurface layer characteristics, including their thicknesses as well as enable monitoring of surface-driven solid-state form transformations. A simultaneous collection of low- and, the more commonly used, mid-frequency data enabled a direct comparison between these spectral regions, where the low-frequency domain (hence, micro-SOLFRS) proved superior for every respective analysis carried out herein.

A New Frontier for Nondestructive Spatial Analysis of Pharmaceutical Solid Dosage Forms: Spatially Offset Low-Frequency Raman Spectroscopy.

A new Raman subtechnique, spatially offset low-frequency Raman spectroscopy (SOLFRS), is demonstrated via an analysis of pharmaceutical solid dosage forms. Several different model systems comprised of celecoxib (a popular anti-inflammatory drug), α-lactose anhydrous stable form, α-lactose monohydrate, and polyvinylpyrrolidone (PVP) were used to represent tangible scenarios for the application of SOLFRS. Additionally, the challenges and limitations were highlighted in relation to its real-time use, and potential solutions to address them were also provided. Lastly, the future directions for this new variation of Raman spectroscopic technique were briefly discussed, including its potential for broader application in pharmaceutical analysis and other research fields.

Can Coupling Multiple Complementary Methods Improve the Spectroscopic Based Diagnosis of Gastrointestinal Illnesses? A Proof of Principle Ex Vivo Study Using Celiac Disease as the Model Illness.

Spectroscopic methods are a promising approach for providing a point-of-care diagnostic method for gastrointestinal mucosa associated illnesses. Such a tool is desired to aid immediate decision making and to provide a faster pathway to appropriate treatment. In this pilot study, Raman, near-infrared, low frequency Raman, and autofluoresence spectroscopic methods were explored alone and in combination for the diagnosis of celiac disease. Duodenal biopsies (n = 72) from 24 participants were measured ex vivo using the full suite of studied spectroscopic methods. Exploratory principal component analysis (PCA) highlighted the origin of spectral differences between celiac and normal tissue with celiac biopsies tending to have higher protein relative to lipid signals and lower carotenoid spectral signals than the samples with normal histology. Classification of the samples based on the histology and overall diagnosis was carried out for all combinations of spectroscopic methods. Diagnosis based classification (majority rule of class per participant) yielded sensitivities of 0.31 to 0.77 for individual techniques, which was increased up to 0.85 when coupling multiple techniques together. Likewise, specificities of 0.50 to 0.67 were obtained for individual techniques, which was increased up to 0.78 when coupling multiple techniques together. It was noted that the use of antidepressants contributed to false positives, which is believed to be associated with increased serotonin levels observed in the gut mucosa in both celiac disease and the use of selective serotonin reuptake inhibitors (SSRIs); however, future work with greater numbers is required to confirm this observation. Inclusion of two additional spectroscopic methods could improve the accuracy of diagnosis (0.78) by 7% over Raman alone (0.73). This demonstrates the potential for further exploration and development of a multispectroscopic system for disease diagnosis.

Investigation on Formulation Strategies to Mitigate Compression-Induced Destabilization in Supersaturated Celecoxib Amorphous Solid Dispersions.

Compression-induced destabilization was investigated in various celecoxib amorphous solid dispersions containing hydroxypropyl methylcellulose (HPMC), poly(vinylpyrrolidone)/vinyl acetate copolymer (PVP/VA), or poly(vinylpyrrolidone) (PVP) at a concentration range of 1-10% w/w. Pharmaceutically relevant (125 MPa pressure with a minimal dwell time) and extreme (500 MPa pressure with a 60 s dwell time) compression conditions were applied to these systems, and the changes in their physical stability were monitored retrospectively (i.e., in the supercooled state) using dynamic differential scanning calorimetry (DSC) and low-frequency Raman (LFR) measurements over a broad temperature range (-90 to 200 and -150 to 140 °C, respectively). Both techniques revealed similar changes in the crystallization behavior between samples, where the application of a higher compression force of 500 MPa resulted in a more pronounced destabilization effect that was progressively mitigated with increasing polymer content. However, other aspects such as more favorable intermolecular interactions did not appear to have any effect on reducing this undesirable effect. Additionally, for the first time, LFR spectroscopy was used as a viable technique to determine the secondary or local glass-transition temperature, Tg,ß, a major indicator of the physical stability of neat amorphous pharmaceutical systems.

Combined Effect of the Preparation Method and Compression on the Physical Stability and Dissolution Behavior of Melt-Quenched Amorphous Celecoxib.

In an earlier investigation, amorphous celecoxib was shown to be sensitive to compression-induced destabilization. This was established by evaluating the physical stability of uncompressed/compressed phases in the supercooled state (Be̅rzins . Mol. Pharmaceutics, 2019, 16(8), 3678-3686). In this study, we investigated the ramifications of compression-induced destabilization in the glassy state as well as the impact of compression on the dissolution behavior. Slow and fast melt-quenched celecoxib disks were compressed with a range of compression pressures (125-500 MPa) and dwell times (0-60 s). These were then monitored for crystallization using low-frequency Raman spectroscopy when kept under dry (∼20 °C; <5% RH) and humid (∼20 °C; 97% RH) storage conditions. Faster crystallization was observed from the samples, which were compressed using more severe compression parameters. Furthermore, crystallization was also affected by the cooling rate used to form the amorphous phases; slow melt-quenched samples exhibited higher sensitivity to compression-induced destabilization. The behavior of the melt-quench disks, subjected to different compression conditions, was continuously monitored during dissolution using low-frequency Raman and UV/vis for the solid-state form and dissolution properties, respectively. Surprisingly the compressed samples exhibited higher apparent dissolution (i.e., higher area under the dissolution curve and initial celecoxib concentration in solution) than the uncompressed samples; however, this is attributed to biaxial fracturing throughout the compressed compacts yielding a greater effective surface area. Differences between the slow and fast melt quenched samples showed some trends similar to those observed for their storage stability.

Monitoring the Isothermal Dehydration of Crystalline Hydrates Using Low-Frequency Raman Spectroscopy.

Detection of the solid-state forms of pharmaceutical compounds is important from the drug performance point of view. Low-frequency Raman (LFR) spectroscopy has been demonstrated to be very sensitive in detecting the different solid-state forms of pharmaceutically relevant compounds. The potential of LFR spectroscopy to probe the in situ isothermal dehydration was studied using piroxicam monohydrate (PXM) and theophylline monohydrate (TPMH) as the model drugs. The dehydration of PXM and TPMH at four different temperatures (95, 100, 105, and 110 °C and 50, 60, 70, and 80 °C, respectively) was monitored in both the low- (20-300 cm-1) and mid-frequency (335-1800 cm-1) regions of the Raman spectra. Principal component analysis and multivariate curve resolution were applied for the analysis of the Raman data. Spectral differences observed in both regions highlighted the formation of specific anhydrous forms of piroxicam and theophylline from their respective monohydrates. The formation of the anhydrous forms was detected on different timescales (approx. 2 min) between the low and mid-frequency Raman regions. This finding highlights the differing nature of the vibrations being detected between these two spectral regions. Computational simulations performed were also in agreement with the experimental results, and allowed elucidating the origin of different spectral features.

Surface Stabilization and Dissolution Rate Improvement of Amorphous Compacts with Thin Polymer Coatings: Can We Have It All?

The distinction between surface and bulk crystallization of amorphous pharmaceuticals, as well as the importance of surface crystallization for pharmaceutical performance, is becoming increasingly evident. An emerging strategy in stabilizing the amorphous drug form is to utilize thin coatings at the surface. While the physical stability of systems coated with pharmaceutical polymers has recently been studied, the effect on dissolution performance as a function of storage time, as a further necessary step toward the success of these formulations, has not been previously studied. Furthermore, the effect of coating thickness has not been elucidated. This study investigated the effect of these polymer-coating parameters on the interplay between amorphous surface crystallization and drug dissolution for the first time. The study utilized simple tablet-like coated dosage forms, comprising a continuous amorphous drug core and thin polymer coating (hundreds of nanometers to a micrometer thick). Monitoring included analysis of both the solid-state of the model drug (with SEM, XRD, and ATR FTIR spectroscopy) and dissolution performance (and associated morphology and solid-state changes) after different storage times. Stabilization of the amorphous form (dependent on the coating thickness) and maintenance of early-stage intrinsic dissolution rates characteristic for the unaged amorphous drug were achieved. However, dissolution in the latter stages was likely inhibited by the presence of a polymer at the surface. Overall, this study introduced a versatile coated system for studying the dissolution of thin-coated amorphous dosage forms suitable for different drugs and coating agents. It demonstrated the importance of multiple factors that need to be taken into consideration when aiming to achieve both physical stability and improved release during the shelf life of amorphous formulations.

Low-Frequency Raman Scattering Spectroscopy as an Accessible Approach to Understand Drug Solubilization in Milk-Based Formulations during Digestion.

Techniques enabling in situ monitoring of drug solubilization and changes in the solid-state of the drug during the digestion of milk and milk-based formulations are valuable for predicting the effectiveness of such formulations in improving the oral bioavailability of poorly water-soluble drugs. We have recently reported the use of low-frequency Raman scattering spectroscopy (region of analysis <200 cm-1) as an analytical approach to probe solubilization of drugs during digestion in milk using ferroquine (SSR97193) as the model compound. This study investigates the wider utilization of this technique to probe the solubilization behavior of other poorly water-soluble drugs (halofantrine, lumefantrine, and clofazimine) in not only milk but also infant formula in the absence or presence of bile salts during in vitro digestion. Multivariate analysis was used to interpret changes to the spectra related to the drug as a function of digestion time, through tracking changes in the principal component (PC) values characteristic to the drug signals. Characteristic low-frequency Raman bands for all of the drugs were evident after dispersing the solid drugs in suspension form in milk and infant formula. The drugs were generally solubilized during the digestion of the formulations as observed previously for ferroquine and correlated with behavior determined using small-angle X-ray scattering (SAXS). A greater extent of drug solubilization was also generally observed in the infant formula compared to milk. However, in the case of the drug clofazimine, the correlation between low-frequency Raman scattering and SAXS was not clear, which may arise due to background interference from clofazimine being an intense red dye, which highlights a potential limitation of this new approach. Overall, the in situ monitoring of drug solubilization in milk and milk-based formulations during digestion can be achieved using low-frequency Raman scattering spectroscopy, and the information obtained from studying this spectral region can provide better insights into drug solubilization compared to the mid-frequency Raman region.

Tissue-specific study across the stem reveals the chemistry and transcriptome dynamics of birch bark.

Tree bark is a highly specialized array of tissues that plays important roles in plant protection and development. Bark tissues develop from two lateral meristems; the phellogen (cork cambium) produces the outermost stem-environment barrier called the periderm, while the vascular cambium contributes with phloem tissues. Although bark is diverse in terms of tissues, functions and species, it remains understudied at higher resolution. We dissected the stem of silver birch (Betula pendula) into eight major tissue types, and characterized these by a combined transcriptomics and metabolomics approach. We further analyzed the varying bark types within the Betulaceae family. The two meristems had a distinct contribution to the stem transcriptomic landscape. Furthermore, inter- and intraspecies analyses illustrated the unique molecular profile of the phellem. We identified multiple tissue-specific metabolic pathways, such as the mevalonate/betulin biosynthesis pathway, that displayed differential evolution within the Betulaceae. A detailed analysis of suberin and betulin biosynthesis pathways identified a set of underlying regulators and highlighted the important role of local, small-scale gene duplication events in the evolution of metabolic pathways. This work reveals the transcriptome and metabolic diversity among bark tissues and provides insights to its development and evolution, as well as its biotechnological applications.

Low-Frequency Raman Spectroscopic Study on Compression-Induced Destabilization in Melt-Quenched Amorphous Celecoxib.

A series of melt-quenched disks of amorphous celecoxib were obtained using two different cooling rates (>100 °C/min and ∼25-30 °C/min) and subjected to different compression pressures (125, 250, and 500 MPa) and dwell times (0, 30, and 60 s). The kinetics of crystallization for these differently prepared melt-quenched disks were probed using a number of methods. Low-frequency Raman spectroscopy was used to monitor isothermal crystallization kinetics, whereas dynamic differential scanning calorimetry served as a complimentary technique to identify changes in form. Although both compression parameters destabilized the amorphous celecoxib, the dwell time was found to have a more critical overall effect. Additionally, the sample history was affirmed to be a factor for limiting the magnitude of compression-induced destabilization.

Understanding Dissolution and Crystallization with Imaging: A Surface Point of View.

The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 °C/23% RH and 30 °C/75% RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known α- and γ-forms, the less reported metastable ε- and η-forms were also observed, with the ε-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms.

Multimodal Nonlinear Optical Imaging for Sensitive Detection of Multiple Pharmaceutical Solid-State Forms and Surface Transformations.

Two nonlinear imaging modalities, coherent anti-Stokes Raman scattering (CARS) and sum-frequency generation (SFG), were successfully combined for sensitive multimodal imaging of multiple solid-state forms and their changes on drug tablet surfaces. Two imaging approaches were used and compared: (i) hyperspectral CARS combined with principal component analysis (PCA) and SFG imaging and (ii) simultaneous narrowband CARS and SFG imaging. Three different solid-state forms of indomethacin-the crystalline gamma and alpha forms, as well as the amorphous form-were clearly distinguished using both approaches. Simultaneous narrowband CARS and SFG imaging was faster, but hyperspectral CARS and SFG imaging has the potential to be applied to a wider variety of more complex samples. These methodologies were further used to follow crystallization of indomethacin on tablet surfaces under two storage conditions: 30 °C/23% RH and 30 °C/75% RH. Imaging with (sub)micron resolution showed that the approach allowed detection of very early stage surface crystallization. The surfaces progressively crystallized to predominantly (but not exclusively) the gamma form at lower humidity and the alpha form at higher humidity. Overall, this study suggests that multimodal nonlinear imaging is a highly sensitive, solid-state (and chemically) specific, rapid, and versatile imaging technique for understanding and hence controlling (surface) solid-state forms and their complex changes in pharmaceuticals.

Probing Pharmaceutical Mixtures during Milling: The Potency of Low-Frequency Raman Spectroscopy in Identifying Disorder.

This study uses a multimodal analytical approach to evaluate the rates of (co)amorphization of milled drug and excipient and the effectiveness of different analytical methods in detecting these changes. Indomethacin and tryptophan were the model substances, and the analytical methods included low-frequency Raman spectroscopy (785 nm excitation and capable of measuring both low- (10 to 250 cm-1) and midfrequency (450 to 1800 cm-1) regimes, and a 830 nm system (5 to 250 cm-1)), conventional (200-3000 cm-1) Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray powder diffraction (XRPD). The kinetics of amorphization were found to be faster for the mixture, and indeed, for indomethacin, only partial amorphization occurred (after 360 min of milling). Each technique was capable of identifying the transformations, but some, such as low-frequency Raman spectroscopy and XRPD, provided less ambiguous signatures than the midvibrational frequency techniques (conventional Raman and FTIR). The low-frequency Raman spectra showed intense phonon mode bands for the crystalline and cocrystalline samples that could be used as a sensitive probe of order. Multivariate analysis has been used to further interpret the spectral changes. Overall, this study demonstrates the potential of low-frequency Raman spectroscopy, which has several practical advantages over XRPD, for probing (dis-)order during pharmaceutical processing, showcasing its potential for future development, and implementation as an in-line process monitoring method.

Physical Stability of Freeze-Dried Isomalt Diastereomer Mixtures.

PURPOSE: Isomalt is a sugar alcohol used as an excipient in commercially available solid oral dosage forms. The potential of isomalt as a novel freeze-drying excipient was studied in order to increase knowledge of the behavior of isomalt when it is freeze-dried. METHODS: Isomalt was freeze-dried in four different diastereomer compositions and its physical stability was investigated with differential scanning calorimetry, Fourier-transform infrared and Raman spectroscopy, X-ray powder diffraction, Karl-Fischer titration and thermogravimetric analysis in order to verify the solid state form of isomalt after freeze-drying and observe any changes occurring during storage in three different relative humidity conditions. RESULTS: Isomalt was successfully transformed into the amorphous form with freeze-drying and three diastereomer combinations remained stable as amorphous during storage; one of the diastereomer compositions showed signs of physical instability when stored in the highest relative humidity condition. The four different crystalline diastereomer mixtures showed specific identifiable solid state properties. CONCLUSIONS: Isomalt was shown to be a suitable excipient for freeze-drying. Preferably a mixture of the diastereomers should be used, as the mixture containing only one of the isomers showed physical instability. A mixture containing a 1:1 ratio of the two diastereomers showed the best physical stability in the amorphous form.