Kimie Awa

Self-modeling curve resolution (SMCR) analysis of near-infrared (NIR) imaging data of pharmaceutical tablets

The idea of quality by design (QbD) has been proposed in pharmaceutical field. QbD is a systematic approach to control the product performance based on the scientific understanding of the product quality and its manufacturing process. In the present study, near-infrared (NIR) imaging is utilized as a tool to achieve this concept. A practical use of a chemometrics technique called self-modeling curve resolution (SMCR) is demonstrated with NIR imaging analysis of pharmaceutical tablets containing two ingredients, a soluble active ingredient, pentoxifylline (PTX), and an insoluble excipient, palmitic acid. Concentration profiles obtained by SMCR reveal that the homogenous distribution of chemical ingredients strongly depends on the grinding time and that its process plays a central role in quantitative control, say sustained-release of PTX. In addition, pure component spectra by SMCR indicate a sequential change of specific NIR peak intensities following the increase of the grinding time. The spectra change shows a molecular structure change related to its crystallinity during grinding process. Accordingly, this study clearly demonstrates that NIR imaging combined with SMCR can be a powerful tool to reveal chemical or physical mechanism induced by the manufacturing process of pharmaceutical products and that it may be a solid solution for QbD of pharmaceutical products.

Multiple Perturbation Two-Dimensional Correlation Analysis of Cellulose by Attenuated Total Reflection Infrared Spectroscopy

An extension of the two-dimensional (2D) correlation analysis scheme for multi-dimensional perturbation is described. A simple computational form is provided to construct synchronous correlation and disrelation maps for the analysis of microscopic imaging data based on two independent perturbation variables. Sets of time-dependent attenuated total reflection infrared (ATR-IR) spectra of water and cellulose mixtures were collected during the evaporation of water from finely ground cellulose. The system exhibits complex behaviors in response to two independent perturbations, i.e., evaporation time and grinding time. Multiple perturbation 2D analysis reveals a specific difference in the rate of evaporation of water molecules when accompanied by crystallinity changes of cellulose. It identifies subtle differences in the volatility of water, which is related to the crystalline structure of cellulose.

Multiple-Perturbation Two-Dimensional Near-Infrared Correlation Study of Time-Dependent Water Absorption Behavior of Cellulose Affected by Pressure

Transient water absorption by cellulosic samples manufactured under varying pressure was monitored by near-infrared spectroscopy to explore the absorption behavior affected by the pressure. A substantial level of variation of the spectral features was induced by the water absorption and changes in the pressure. The detail of the spectral changes was analyzed with a multiple-perturbation, two-dimensional (2D) correlation method to determine the underlying mechanism. The 2D correlation spectra indicated that the compression of the cellulose increased the packing density of the samples, preventing the penetration of water. In addition, the compression substantially disintegrated its crystalline structure and eventually resulted in the development of inter- and intrachain hydrogen-bonded structures arising from an interaction between the water and cellulose. Consequently, the cellulose samples essentially underwent an evolutionary change in the polymer structure as well as in the packing density during the compression. This structural change, in turn, led to the seemingly complicated absorption trends, depending on the pressure.

Compression-induced morphological and molecular structural changes of cellulose tablets probed with near infrared imaging

An analytical technique based on band shift analysis to derive key information concerning molecular structural changes from near infrared (NIR) imaging data was demonstrated in the present study. Molecular structural changes induced by compression process of sets of cellulose tablets under varying pressure levels were monitored by NIR imaging. The detailed band position shift analysis of the spectral features has provided insight into the compression mechanism of cellulose tablets. It has been shown that fine features of the deformation of the crystalline structure can be readily captured by band shift analysis of specific peaks. Substantial band position shifts were observed when pressure was applied to cellulose samples, indicating the disintegration of crystalline structures and an increase in the amorphous component. Band shift analysis may be applicable to a wide range of NIR imaging data to derive an in-depth understanding of systems even if the NIR images exhibit unwanted baseline shifts due to morphological changes in the samples.

Development of a compact near infrared imaging device with high-speed and portability for pharmaceutical process monitoring

Daitaro Ishikawa, Kodai Murayama, Takuma Genkawa, Kimie Awa, Makoto Komiyama and Yukihiro Ozaki School of Science and Technology, Kwansei Gakuin University, 2–1 Gakuen, Sanda, Hyogo, 669-1337 Japan. E-mail: ozaki@kwansei.ac.jp Yokogawa Electric Corporation, 2-9-32 Nakacho, Musashino, Tokyo, 180-8750, Japan Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana, Osaka, 554-0022, Japan

Near-infrared imaging analysis of cellulose tablets by a band position shift.

Advances in near-infrared (NIR) imaging technology have brought a new technique to chemical imaging analysis. A unique feature of NIR imaging is that it can take full advantage of spatial and molecular structural information about chemical moieties. A series of NIR spectra are measured for every pixel that divides an object into many spatial parts. For example, each pixel point of such an image consists of a full NIR spectrum, and each micro-image is a collection of spectral intensity measured at a fixed wavenumber. Consequently, not only spectral variable but also spatial information becomes available. Namely, it has the outstanding advantage that it can harness both spectral and spatial information characterizing moieties. In the collection of NIR imaging data, the more pixels, the more detailed is the spatial information that can be included in the measured data. Such high dimensional data including two spatial and one spectral (wavenumber) dimensions often bring some difficulties in the interpretation because of the high dimensional data structure. In practice, representative information of the data condensed by statistical or mathematical means such as principal component analysis (PCA) are often used for easy interpretation of NIR imaging data. Using PCA, the data matrix can be decomposed into a product of score and loading matrices. Abstract information of spectral intensity variation referred to as scores in PCA can be conceptually seen as a reflection of concentration of components. For example, scores provide information closely related to the distribution of components in the analysis of NIR image data. Seemingly most of the research on NIR chemical imaging analysis has principally been based on the observation of spectral intensity change with the aid of PCA. It is important to point out that PCA does not reveal the ‘‘true’’ underlying physical sources of data but provides only their linear combination fulfilling the orthogonal constraints. Thus, scores and loadings can take both positive and negative values, such that they usually do not have any direct connection to physical meaning, even though these solutions are based on a solid mathematical foundation. In this paper, an alternative analytic technique is presented for the handling of NIR imaging data. The main purpose of this study is to demonstrate the analytic technique based on the observations of a band position shift. Physical transitions of components usually result in the systematic alteration of vibrational spectroscopic features. Vibrational frequency for a diatomic molecule can be described as a function of reduced mass and bonding force constant, which is a measure of the strength or rigidity of a chemical bond in its normal equilibrium position. For example, the degree of molecularlevel interactions such as hydrogen bonding often influences the band position of a vibrational spectrum. The increase in the degree for hydrogen bonding can be observed as a band position shift in the lower wavenumber direction. Thus, a substantial change in molecular structure in turn can be readily detected as a form of band position shift such as a red or blue shift, and it can be a useful way to derive key information closely related to molecular structure of objects. Compared to projection-based analysis such as PCA, a direct observation of specific molecular structure based on band shift provides another kind of information that can not be described by the variation of concentration of the analytes. It can be a useful asset to estimate characteristic features of objects at the molecular level. A practical example is presented here to demonstrate how this analytic techniques works in the analysis of NIR imaging data. NIR spectra were collected for several kinds of cellulose tablets prepared using different grinding times. The physical properties of excipients such as cellulose are important to control the pharmaceutical properties of tablets, as the solubility of chemical components is strongly related to their distribution and molecular structure within tablets. The observation of a band position shift clearly reveals a structural change of cellulose crystalline structure, which is substantially induced by grinding. Thus, the solubility of the tablets, which is associated with crystalline structure, can be controlled in turn by the simple grinding process. The result demonstrates that the detection of specific structure on the surface (or within) tablets becomes possible.

Compression effect on sustained-release and water absorption properties of cellulose tablets studied by heterospectral two-dimensional (2D) correlation analysis

Chemical and physical effects of the compression process on cellulose excipients are explored by near infrared (NIR) spectroscopy, X-ray diffraction (XRD), dissolution test and water absorption test. A set of pharmaceutical tablets including pentoxifylline (PTX) and cellulose are prepared under varying levels of compression. The compressive deformation of the tablets is probed by NIR spectroscopy and XRD. The interaction of tablet with water molecules is also analyzed with the dissolution and water absorption tests. The essential relationship between the two different classes of data, e.g. XRD and dissolution (or absorption) test, is effectively elucidated by heterospectral two-dimensional (2D) correlation analysis. It revealed that the compression produces a disordered amorphous component of cellulose. Such development of the mobile amorphous phase results in a more tightly packed matrix with less porosity. Thus, in turn, it prevents penetration of water molecules into the tablet and direct contact with PTX, which eventually brings the delay in the dissolution. Consequently, by carrying out the hetero-correlation analysis of the two datasets, it effectively provided a more detailed picture of the compression process.

The Effect of Microcrystalline Cellulose Crystallinity on the Hydrophilic Property of Tablets and the Hydrolysis of Acetylsalicylic Acid as Active Pharmaceutical Ingredient Inside Tablets

The crystal structures of active pharmaceutical ingredients and excipients should be strictly controlled because they influence pharmaceutical properties of products which cause the change in the quality or the bioavailability of the products. In this study, we investigated the effects of microcrystalline cellulose (MCC) crystallinity on the hydrophilic properties of tablets and the hydrolysis of active pharmaceutical ingredient, acetylsalicylic acid (ASA), inside tablets by using tablets containing 20% MCC as an excipient. Different levels of grinding were applied to MCC prior to tablet formulation, to intentionally cause structural variation in the MCC. The water penetration and moisture absorbability of the tablets increased with decreasing the crystallinity of MCC through higher level of grinding. More importantly, the hydrolysis of ASA inside tablets was also accelerated. These results indicate that the crystallinity of MCC has crucial effects on the pharmaceutical properties of tablets even when the tablets contain a relatively small amount of MCC. Therefore, controlling the crystal structure of excipients is important for controlling product qualities.

An Effect of Cellulose Crystallinity on the Moisture Absorbability of a Pharmaceutical Tablet Studied by Near-Infrared Spectroscopy

In this study, we investigated molecular-level variation of tablets caused by grinding and its effect on their actual moisture absorbability. Model tablets contained acetaminophen as an active pharmaceutical ingredient and microcrystalline cellulose (MCC) as an excipient. Different levels of grinding were applied during the tablet formulation to intentionally cause the structural variation of the MCC. The moisture absorbability of tablets showed obvious variation depending on the grinding time, and the corresponding change in near-infrared spectra was readily captured. The detailed analysis of the variation of the band frequencies (i.e., wavenumber) revealed that the grinding process substantially disintegrates the crystalline and generates a glassy amorphous structure of MCC, which is a requirement to absorb water molecules. Consequently, it is very likely that the change of the moisture absorbability of the tablets is closely related to the development of the amorphous structure. These results indicate that the pharmaceutical product performances can be influenced by the physical properties of the excipient, which in turn can be controlled by the grinding process.

Monitoring of recrystallisation of microcrystalline cellulose inside pharmaceutical tablets during storage using near infrared diffuse reflectance spectroscopy

Changes in the crystallinity of microcrystalline cellulose (MCC) inside pharmaceutical tablets during storage were monitored by near infrared (NIR) diffuse reflectance spectroscopy to investigate transient variation at the molecular level. The MCC used in the tablets was ground before tablet formulation to intentionally cause a decrease in crystallinity. The variation in crystalline structure of MCC was evaluated from the intensity of NIR spectra peaks ascribed to OH groups in the crystalline region. The MCC exhibited clear signs of recrystallisation during 63 days of storage. In addition, the recrystallisation became even more pronounced when the MCC was stored under high-humidity conditions. Results also showed that the inclusion of anhydrous silicic acid induces a clear delay in recrystallisation by restricting the penetration of water molecules into the tablets. The findings derived from NIR spectra were substantiated by differential thermal analysis. The results from this study suggest that crystallinity of MCC inside tablets can be controlled by other excipients during storage, which has useful applications for controlling pharmaceutical product performance during storage.