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Levothyroxine sodium pentahydrate (LEVO) tablets have been on the US market since the mid-twentieth century and remain the most highly prescribed product. Unfortunately, levothyroxine sodium tablets have also been one of the most highly recalled products due to potency and dissolution failures on stability. In 2008, the assay limits were tightened, yet the recalls did not decline, which highlights the serious quality concerns remaining to be elucidated. The aim of the present investigation was to test the hypothesis that the solid-state physical instability of LEVO precedes the chemical instability leading to product failure. The failure mode was hypothesized to be the dehydration of the crystal hydrate, when exposed to certain humidity and temperature conditions, followed by the oxidation of the API through vacated channels. It was previously reported by the authors that LEVO degradation occurred in the presence of oxygen at a low relative humidity (RH). Furthermore, powder X-ray diffractometry shows changes in the crystal lattice of LEVO initially and through the dehydration stages. Storage of LEVO at RT and 40 °C at 4-6% RH for 12 days shows a decrease in d-spacing of the (00 l) planes. Based on a structure solution from the powder data of the dehydrated material, the basic packing motif persists to varying degrees even when fully dehydrated along with disordering. Therefore, the crystal structure changes of LEVO depend on RH and temperature and are now explicable at the structural level for the first time. This exemplifies the dire need for "new prior knowledge" in generic product development.

Fusing complex data from two disparate sources has been demonstrated to improve the accuracy in quantifying active ingredients in mixtures of pharmaceutical powders. A four-component simplex-centroid design was used to prepare blended powder mixtures of acetaminophen, caffeine, aspirin and ibuprofen. The blends were analyzed by Fourier transform infra-red spectroscopy (FTIR) and powder X-ray diffraction (PXRD). The FTIR and PXRD data were preprocessed and combined using two different data fusion methods: fusion of preprocessed data (FPD) and fusion of principal component scores (FPCS). A partial least square (PLS) model built on the FPD did not improve the root mean square error of prediction. However, a PLS model built on the FPCS yielded better accuracy prediction than PLS models built on individual FTIR and PXRD data sets. The improvement in prediction accuracy of the FPCS may be attributed to the removal of noise and data reduction associated with using PCA as a preprocessing tool. The present approach demonstrates the usefulness of data fusion for the information management of large data sets from disparate sources.

Understanding the properties and behavior of pharmaceutical materials is critical to the design of a safe and effective dosage form. The desired performance of pharmaceutical products differs from other areas of engineered material products. With pharmaceutical products, there is an increased level of importance on solubility, dissolution and stability; while a secondary level of importance is given to mechanical properties. The use of multi-scale process understanding suggests incorporating data from the different scales (particle, powder, and dosage form) into a single informatics database. The properties of the active pharmaceutical ingredient and the excipients must be interrogated at each scale. At the particle level, the primary concerns are with solubility, dissolution rate, the anisotropic properties of pharmaceutical crystals, polymorphism and the degree of crystallinity. At the level of the powder scale, the primary concerns are powder flow and the ability of the bulk powder to be compacted into a dosage form. Finally, at the dosage form level, critical issues include the effect of excipient crystallinity on dosage form dissolution rate and the tensile strength of compacts made from milled, roller compacted ribbons. Examples of existing and emerging approaches for understanding these properties and behaviors at each scale are illustrated as key elements in developing a multi-scale process understanding of a pharmaceutical process.

As described in this Supplement and elsewhere, consumption of grapes or grape products has been associated with various health benefits. Resveratrol is a unique component of grapes. Following our report on potential cancer chemopreventive activity, thousands of studies have been performed to characterize the mode of action of this substance. Nonetheless, scores of additional chemicals are known to be constituents of grapes, several of which are capable of mediating biological responses. Accordingly, when considering grapes and health, a holistic view appears to be more meaningful, taking into account all chemical components, metabolism, biological potential, biodistribution, absorption, processing, etc. To fathom such a massive amount of information, we propose the creation of focused ontologies. Grapes seem reasonable as a test bed for exploring this approach, especially because a fair amount of results are available with whole-grape powder. In essence, by utilizing a next generation intelligent system, attempts can be made to leverage the existing complexity. This approach involves bringing together all available information, together with expert judgment, and processing this information through a computational "engine" or engines to provide suggested solutions (or implicit functional relationships). Accomplishment of this task, employing grapes as a prototype, could lead to broader application by incorporating the myriad of features associated with other fruits and vegetables. The ability to correlate heretofore-uncharacterized "signatures" with biologic outcome could fundamentally transform copious amounts of disparate information into a coherent explanation of human disease prevention.

The purpose of this work was to evaluate and compare the functionality of bovine fatty acids-derived (MgSt-B) and vegetable fatty acids-derived (MgSt-V) magnesium stearate powders when used for the lubrication of granules prepared by high-shear (HSG) and fluid bed (FBG) wet granulation methods. The work included evaluation of tablet compression and ejection forces during tabletting and dissolution testing of the compressed tablets. Granules prepared by both granulation methods required significantly lower ejection force (p

This study aimed to track the inclusion of women in clinical trials for new drugs approved by the Food and Drug Administration (FDA) between 2000 and 2002 and to evaluate the extent of analyses by sex.Data were extracted from FDA reviewers' reports, summaries of clinical trials in New Drug Applications (NDAs), and product labeling and organized into a Microsoft Access database. The information collected includes subject enrollment by sex per clinical phase and sex differences in pharmacokinetics, safety, and efficacy as determined by either sponsors or reviewers.There were 67 New Molecular Entities (NMEs) approved by the FDA between 2000 and 2002. A total of 397,825 subjects were enrolled in 2,323 clinical trials. If 9 sex-specific NMEs are excluded, 297,697 subjects were enrolled in 1,974 clinical trials. Forty-seven percent of participants were male, 49% were female, and 4% of subjects were not specified. Of the 58 sex-nonspecific products in the study, 71% (41 of 58) of sex analyses were performed either by the sponsor or FDA reviewers. Twenty-five NMEs were found to have sex differences in pharmacokinetics, efficacy or adverse events. However, no recommendation was made to adjust dosage based on sex differences.The percentages of women and men participating in clinical trials varied by year, phase, and product type. However, the overall participation by women and men was comparable, suggesting an improvement in including more women in clinical trials when compared with the previous FDA study evaluating women's participation from 1995 through 1999. As with the previous study, however, a significant underrepresentation of women in early phase trials and in certain areas, such as cardiovascular products, was observed and continues to be an issue of concern. Lack of appropriate analyses by sex should also be noted as an issue of concern.

Magnesium stearate is a functional excipient used to ensure efficient ejection of tablets. This study compares the functionality of a vegetable and bovine grade of magnesium stearate. Tablets were prepared by direct compression and dry granulation of a model formulation. Physical and chemical tests were performed on bulk powders, granule intermediates, and finished tablets to provide a comprehensive comparison of the two grades of magnesium stearates. Raw material characterization of the two grades showed no difference in particle size, surface area, true density, and total moisture content. However, significant differences in fatty acid composition, surface tension, and zeta potential were detected. Tablet ejection force for the physical mixture formulations was variable, showing similar ejection force for the two grades of magnesium stearate at some concentrations and different ejection forces at other concentrations. The dry granulated formulation containing vegetable-based magnesium stearate showed a lower ejection force than the formulation containing bovine-based magnesium stearate. There was no difference between the dissolution profiles of the tablets containing the two grades of magnesium stearate prepared by both methods. The results indicated that magnesium stearate interchangeability with respect to lubricant efficiency depends upon the level in which it is used and the manufacturing method.

Traditional monitoring of pharmaceutical manufacturing combines physical sampling and analytical methodologies (e.g. HPLC). Process analytical technology (PAT) can be implemented to collect real-time measurements, although successful monitoring requires that sampling be representative. The maximum spot size for a spectroscopic tool (e.g. near-infrared; Raman) should be equivalent to a single dosage size. A smaller spot size may provide a PAT tool that is sensitive to monitoring process changes, but if too small, produces non-reproducible data. The current study uses chemical imaging to determine appropriate spot size. A chemical image is an array of pixels which maps the chemical composition of the sample. "Macropixel Analysis" is introduced as a measure of image heterogeneity based on clusters of pixels (macropixels) within near-infrared chemical images. Analyses were conducted using non-overlapping tiles of macropixels (Discrete-Level Tiling) and all possible macropixels of the image (Continuous-Level Moving Block). Both methods minimize the variance between macropixel intensities by varying the size of the macropixels. Spot size is then chosen as the minimum macropixel size for which the range of macropixel intensities falls within an acceptable criterion. Both imaging-based algorithms provide useful quantitative information about the heterogeneity of pharmaceutical products.

Design and development of a dynamic interfacial pressure detector (DIPD) is reported. The DIPD measures the differential pressure as a function of time across the liquid-liquid interface of organic liquid drops (i.e., n-hexane) that repeatedly grow in water at the end of a capillary tip. Using a calibration technique based on the Young-Laplace equation, the differential pressure signal is converted, in real-time, to a relative interfacial pressure. This allows the DIPD to monitor the interfacial tension of surface active species at liquid-liquid interfaces in flow-based analytical techniques, such as flow injection analysis (FIA), sequential injection analysis (SIA) and high performance liquid chromatography (HPLC). The DIPD is similar in principle to the dynamic surface tension detector (DSTD), which monitors the surface tension at the air-liquid interface. In this report, the interfacial pressure at the hexane-water interface was monitored as analytes in the hexane phase diffused to and arranged at the hexane-water interface. The DIPD was combined with FIA to analytically measure the interfacial properties of cholesterol and Brij((R))30 at the hexane-water interface. Results show that both cholesterol and Brij((R))30 exhibit a dynamic interfacial pressure signal during hexane drop growth. A calibration curve demonstrates that the relative interfacial pressure of cholesterol in hexane increases as the cholesterol concentration increases from 100 to 10,000mugml(-1). An example of the utility of the DIPD as a selective detector for a chromatographic separation of interface-active species is also presented in the analysis of cholesterol in egg yolk by normal-phase HPLC-DIPD.

Dissolution testing is a quantitative analytical technique used to measure the release rate of ingredients from tablets and capsules. This instrumental analysis lab experiment teaches students how to compress tablets from a mixture of powders and challenges students to build their own apparatus to measure dissolution rates of their tablets. Each group of students was able to complete the experiment successfully and elucidate two predicted trends in dissolution rates from a set of five tablets. Students learned the fundamentals of UV spectroscopy, data handling, calibration, and sampling, while gaining insight and experience regarding an important test used in the pharmaceutical and dietary supplement industries.

Levothyroxine sodium is an important medication used primarily for treating patients with hypothyroidism. Levothyroxine sodium tablets have been recalled many times since their 1955 introduction to the US market. These recalls resulted from the failure of lots to meet their content uniformity and potency specifications. The purpose of this study is to test the hypothesis that the chemical stability of levothyroxine sodium pentahydrate is compromised upon exposing the dehydrated substance to molecular oxygen. The impact of temperature, oxygen and humidity storage conditions on the stability of solid-state levothyroxine sodium was examined. After exposure to these storage conditions for selected periods of time, high performance liquid chromatography (HPLC) was used to quantify the formation of impurities. The results showed that levothyroxine sodium samples degraded significantly over a 32-day test period when subjected to dry conditions in the presence of molecular oxygen. However, dehydrated samples remained stable when oxygen was removed from the storage chamber. Furthermore, hydrated samples were stable in the presence of oxygen and in the absence of oxygen. These results reveal conditions that will degrade levothyroxine sodium pentahydrate and elucidate measures that can be taken to stabilize the drug substance.

Grapes are hypothesized to be a "food medicine." Freeze-dried grape powder (FDGP) is being used to test clinical activity for a variety of applications and a reproducible and reliable delivery system was required. The FDGP was characterized using traditional physico-chemical methods to generate the data needed to identify its primary liability, i.e. moisture sorption. Above a threshold level of moisture content (~25% w/w, at RT), the material becomes both difficult to handle and exhibits significant degradation of several potentially clinically important chemical components (catechin, epicatechin, resveratrol). A moisture sorption isotherm was then used to tie the threshold to the exposure relative humidity above which this occurs. Kinetic uptake studies were used to estimate the maximum safe exposure time at a given humidity (a square root time dependence of moisture uptake was observed). Armed with this knowledge, a FDGP compact coated with a compression coat [100% bees wax or combinations of carnauba wax (70%) with HPC (30%) or Avicel(®) PH 102 (30%) or lactose monohydrate (30%)] was developed that will insure the shelf life of the material without the need for special handling for approximately more than 3 months.

In pharmaceutical processing, the lubricant magnesium stearate (MgS) can affect compaction efficiency based on blend time and amount of MgS used. Insufficient lubrication produces intra-tablet variations in density. Consistent tablet density profiles and uniform compaction force, as managed by proper lubrication, are important for predictable performance. The current work demonstrates the utility of near-infrared (NIR) chemical imaging in measuring density variations within compacts, and relates these variations to tabletting forces as controlled by frictional properties and quantity of MgS. Lactose monohydrate was blended with 0%, 0.25%, or 1.0% MgS for 30 s or 30 min. Compacts were prepared of each blend, with compaction forces monitored by load cells. Frictional properties were measured by automated shear cell. NIR chemical images were collected for each tablet, and the density at each image pixel was calculated. Density distribution within compacts was well perceived within the NIR images. Uniformity of intra-tablet density was strongly dependent upon friction between powder and die walls: tablets with no MgS or 0.25% MgS were less uniform than tablets with 1.0% MgS. In addition, absorbance variations along tablet edges, reflective of corresponding density variation, agreed with force transmission within the tablet and final tablet ejection force. Chemical imaging techniques can be used to non-destructively assess density profiles of tablets, and confirm prediction of friction alleviation and improvement in force distribution during tabletting. The density profiles were both qualitative, showing differences in density profiles between tablets of different blends, and quantitative, providing actual density and tabletting force information within a single tablet. This work demonstrates that near-infrared chemical imaging can be an effective tool in monitoring not only the physical quality of pharmaceutical tablets, but the corresponding die forces controlling tabletting and final ejection.

An optical diagnostic method, grating light reflection spectroscopy (GLRS), has been demonstrated for the in situ monitoring of properties of heterogeneous matrices in industrial processes. The technique is based on measurements near the critical points of intensity and phase in waves reflected from a transmission diffraction grating in contact with a diagnostic sample. The features contained in the reflection spectrum near these thresholds allow for the simultaneous determination of the real and imaginary parts of the dielectric function of the sample. Using these data, the milling progress of highly concentrated fluid suspensions is observed as the material is milled from approximately 40 μm to 160 nm in diameter. A theoretical model that closely resembles experimentally determined spectra was constructed and applied in combination with principal components analysis (PCA) to demonstrate that GLRS can be used to closely monitor changes in the mean particle size of the nanomilled drug product.

The ultrasonic diffraction grating is formed by machining triangular grooves, 300 microns apart, on a stainless steel surface. The grating surface is in contact with the liquid or slurry. The ultrasonic beam, traveling in the solid, strikes the back of the grating and produces a transmitted m = 1 beam in the liquid. The angle of this beam in the liquid increases with decreasing frequency and the critical frequency F CR occurs when the angle is 90°. At frequencies below F CR , this m = 1 wave does not exist and its energy is shared with other types of waves. The signal of the reflected m = 0 wave is observed and an increase is observed at F CR . This information yields the velocity of sound in the liquid and particle size.