Understanding solid-state transformations during dehydration: new insights using vibrational spectroscopy and multivariate modelling

Many active pharmaceutical ingredients (APIs) have both anhydrate and hydrate forms. Due to the different physicochemical properties of solid forms, the changes in solid-state may result in therapeutic, pharmaceutical, legal and commercial problems. In order to obtain good solid dosage form quality and performance, there is a constant need to understand and control these phase transitions during manufacturing and storage. Thus it is important to detect and also quantify the possible transitions between the different forms. In recent years, vibrational spectroscopy has become an increasingly popular tool to characterise the solid-state forms and their phase transitions. It offers several advantages over other characterisation techniques including an ability to obtain molecular level information, minimal sample preparation, and the possibility of monitoring changes non-destructively in-line. Dehydration is the phase transition of hydrates which is frequently encountered during the dosage form production and storage. The aim of the present thesis was to investigate the dehydration behaviour of diverse pharmaceutical hydrates by near infrared (NIR), Raman and terahertz pulsed spectroscopic (TPS) monitoring together with multivariate data analysis. The goal was to reveal new perspectives for investigation of the dehydration at the molecular level. Solid-state transformations were monitored during dehydration of diverse hydrates on hot-stage. The results obtained from qualitative experiments were used to develop a method and perform the quantification of the solid-state forms during process induced dehydration in a fluidised bed dryer. Both in situ and in-line process monitoring and quantification was performed. This thesis demonstrated the utility of vibrational spectroscopy techniques and multivariate modelling to monitor and investigate dehydration behaviour in situ and during fluidised bed drying. All three spectroscopic methods proved complementary in the study of dehydration. NIR spectroscopy models could quantify the solid-state forms in the binary system, but were unable to quantify all the forms in the quaternary system. Raman spectroscopy models on the other hand could quantify all four solid-state forms that appeared upon isothermal dehydration. The speed of spectroscopic methods makes them applicable for monitoring dehydration and the quantification of multiple forms was performed during phase transition. Thus the solid-state structure information at the molecular level was directly obtained. TPS detected the intermolecular phonon modes and Raman spectroscopy detected mostly the changes in intramolecular vibrations. Both techniques revealed information about the crystal structure changes. NIR spectroscopy, on the other hand was more sensitive to water content and hydrogen bonding environment of water molecules. This study provides a basis for real time process monitoring using vibrational spectroscopy during pharmaceutical manufacturing.

Survival, growth and quality of life in children after orthotopic liver transplantation: A 5 year experience

The aims of this study were to investigate outcome and to evaluate areas of potential ongoing concern after orthotopic liver transplantation (OLT) in children. Actuarial survival in relation to age and degree of undernutrition at the time of OLT was evaluated in 53 children (age 0.58-14.2 years) undergoing OLT for endstage liver disease. Follow-up studies of growth and quality of life were undertaken in those with a minimum follow-up period of 12 months (n = 26). The overall 3 year actuarial survival was 70%. Survival rates did not differ between age groups (actuarial 2 year survival for ages <1, 1-5 and >5 years were 70, 70 and 69% respectively) but did differ according to nutritional status at OLT (actuarial 2 year survival for children with Z scores for weight <-1 was 57%, >-1 was 95%; P = 0.004). Significant catch-up weight gain was observed by 18 months post-transplant, while height improved less rapidly. Quality of life (assessed by Vineland Adaptive Behaviour Scales incorporating socialization, daily living skills, communication and motor skills) was good (mean composite score 91 ± 19). All school-aged children except one were attending normal school. Two children had mild to moderate intellectual handicap related to post-operative intracerebral complications. Satisfactory long-term survival can be achieved after OLT in children regardless of age but the importance of pre-operative nutrition is emphasized. Survivors have an excellent chance of a good quality of life and of satisfactory catch-up weight gain and growth.

A comment on the consistency of truncated nonlinear integral equation based theories of freezing

We report the results of two studies of aspects of the consistency of truncated nonlinear integral equation based theories of freezing: (i) We show that the self-consistent solutions to these nonlinear equations are unfortunately sensitive to the level of truncation. For the hard sphere system, if the Wertheim–Thiele representation of the pair direct correlation function is used, the inclusion of part but not all of the triplet direct correlation function contribution, as has been common, worsens the predictions considerably. We also show that the convergence of the solutions found, with respect to number of reciprocal lattice vectors kept in the Fourier expansion of the crystal singlet density, is slow. These conclusions imply great sensitivity to the quality of the pair direct correlation function employed in the theory. (ii) We show the direct correlation function based and the pair correlation function based theories of freezing can be cast into a form which requires solution of isomorphous nonlinear integral equations. However, in the pair correlation function theory the usual neglect of the influence of inhomogeneity of the density distribution on the pair correlation function is shown to be inconsistent to the lowest order in the change of density on freezing, and to lead to erroneous predictions. The Journal of Chemical Physics is copyrighted by The American Institute of Physics.

The crystal structure of the amino-terminal pentapeptide of suzukacillin. Occurrence of a four-fold peptide helix

The monohydrate of the protected amino-terminal pentapeptide of suzukacillin, t-butoxycarbonyl--aminoisobutyryl-L-prolyl-L-valyl--aminoisobutyryl-L-valine methyl ester, C29H51N5O8, crystallizes in the orthorhombic space group P212121 with a= 10.192, b= 10.440, c= 32.959 Å, and Z= 4. The structure has been solved by direct methods and refined to an R value of 0.101 for 1 827 observed reflections. The molecule exists as a four-fold helix with a pitch of 5.58 Å. The helix is stabilised by N–H O hydrogen bonds, two of the 51 type (corresponding to the -helix) and the third of the 41 type (310 helix). The carbonyl oxygen of the amino-protecting group accepts two hydrogen bonds, one each from the amide NH groups of the third (41) and fourth (51) residues. The remaining 51 hydrogen bond is between the two terminal residues. The lone water molecule in the structure is hydrogen bonded to carbonyl oxygens of the prolyl residue in one molecule and the non-terminal valyl residue in a symmetry-related molecule.

A comment on the consistency of truncated nonlinear integral equation based theories of freezing

We report the results of two studies of aspects of the consistency of truncated nonlinear integral equation based theories of freezing: (i) We show that the self-consistent solutions to these nonlinear equations are unfortunately sensitive to the level of truncation. For the hard sphere system, if the Wertheim–Thiele representation of the pair direct correlation function is used, the inclusion of part but not all of the triplet direct correlation function contribution, as has been common, worsens the predictions considerably. We also show that the convergence of the solutions found, with respect to number of reciprocal lattice vectors kept in the Fourier expansion of the crystal singlet density, is slow. These conclusions imply great sensitivity to the quality of the pair direct correlation function employed in the theory. (ii) We show the direct correlation function based and the pair correlation function based theories of freezing can be cast into a form which requires solution of isomorphous nonlinear integral equations. However, in the pair correlation function theory the usual neglect of the influence of inhomogeneity of the density distribution on the pair correlation function is shown to be inconsistent to the lowest order in the change of density on freezing, and to lead to erroneous predictions. The Journal of Chemical Physics is copyrighted by The American Institute of Physics.

Geometry Of Proline And Hydroxyproline .1. An Analysis Of X-Ray Crystal-Structure Data

We have carried out an analysis of crystal structure data on prolyl and hydroxyprolyl moieties in small molecules. The flexibility of the pyrrolidine ring due to the pyramidal character of nitrogen has been defined in terms of two projection angles δ1 and δ2. The distribution of these parameters in the crystal structures is found to be consistent with results of the energy calculations carried out on prolyl moieties in our laboratory.

Handling of Two Tropical Australian Sharks to Improve Quality and to Identify the Cause of Tough Texture

Sharks caught in tropical Australian waters occasionally exhibit tough texture. Two species of Carcharinid shark, originally known as the sorrah shark (Carcharinus sorrah) and the black spot shark (Carcharinus tilstoni), compose the majority of the catch. Experiments were conducted to identify the cause of tough texture and to improve the overall quality of the catch. The possibility that a cold shock reaction may occur was investigated by observing the contraction of fillets under a range of temperature conditions before freezing. The effect of on-board handling practices were evaluated using frozen shark fillets, which had been stored prior to freezing in refrigerated seawater at different rigor stages, temperatures and times as trunks. Fillets were analyzed for nucleotides, lactate, thaw pH, sarcomere length and raw and cooked shear force values. The existence of thaw rigor was also investigated. There was little difference in the texture between the individual strips of a fillet exposed to different temperatures but there were significant differences between individual sharks. A cold shock reaction could not be demonstrated in these species. The main influences on texture were of biological origin. The species, sex and size were found to have significant links with texture of fillets. The quality of the fillets deteriorated quicker during the warmer season and were at their worst if the trunks were kept on deck till post-rigor or held in 15 degree C refrigerated seawater before freezing

Changes in sensory quality of sterile cantaloupe dice stored in controlled atmospheres.

Diced cantaloupe flesh that was microbiologically sterile was prepared in order to study the physiological deterioration of fruit when stored under a range of controlled atmospheres at 4.5°C. Sterile fruit pieces were prepared by boiling whole melons for 3 min, then dicing aseptically. Storage atmospheres were in continuous flow and contained from 0 to 26% CO2 and 3.5 to 17% O2. Sensory assessments were carried out by a highly trained panel at 14-day intervals. Products that were acceptable for up to 28 days were obtained when the following 3 treatments were used: 6% CO2 and 6% O2; 9.5% CO2 and 3.5% O2; and 15% CO2 and 6% O2. Overall, treatment with 0, 19.5 or 26% CO2 (irrespective of O2 concn.) caused significant deterioration in sensory properties.

Non-invasive assessment of pineapple and mango fruit quality using near infra-red spectroscopy

The potential of near infra-red (NIR) spectroscopy for non-invasive measurement of fruit quality of pineapple (Ananas comosus var. Smooth Cayenne) and mango (Magnifera indica var. Kensington) fruit was assessed. A remote reflectance fibre optic probe, placed in contact with the fruit skin surface in a light-proof box, was used to deliver monochromatic light to the fruit, and to collect NIR reflectance spectra (760–2500 nm). The probe illuminated and collected reflected radiation from an area of about 16 cm2. The NIR spectral attributes were correlated with pineapple juice Brix and with mango flesh dry matter (DM) measured from fruit flesh directly underlying the scanned area. The highest correlations for both fruit were found using the second derivative of the spectra (d2 log 1/R) and an additive calibration equation. Multiple linear regression (MLR) on pineapple fruit spectra (n = 85) gave a calibration equation using d2 log 1/R at wavelengths of 866, 760, 1232 and 832 nm with a multiple coefficient of determination (R2) of 0.75, and a standard error of calibration (SEC) of 1.21 °Brix. Modified partial least squares (MPLS) regression analysis yielded a calibration equation with R2 = 0.91, SEC = 0.69, and a standard error of cross validation (SECV) of 1.09 oBrix. For mango, MLR gave a calibration equation using d2 log 1/R at 904, 872, 1660 and 1516 nm with R2 = 0.90, and SEC = 0.85% DM and a bias of 0.39. Using MPLS analysis, a calibration equation with R2 = 0.98, SEC = 0.54 and SECV = 1.19 was obtained. We conclude that NIR technology offers the potential to assess fruit sweetness in intact whole pineapple and DM in mango fruit, respectively, to within 1° Brix and 1% DM, and could be used for the grading of fruit in fruit packing sheds.

Effect of an Ethylene Absorbent on Quality of Tomato Slices

Ethylene production is stimulated during the slicing of fresh cut tomato slices. Experiments were conducted to investigate whether the inclusion of ethylene absorbents in packaging affects the quality of tomato slices cv. Revolution during storage at 5OC. ‘Pink’ maturity stage tomatoes were cut into 7mm thick slices and vertically stacked in closed glass containers for 12 days with or without Purafil® to remove ethylene. The ethylene removal treatment resulted in reduced ethylene, less CO2 accumulation, and firmer slices.

Synthesis and Reactions of Binuclear Diolefin Rhodium(I) Compounds bridged by Nitrogen Heterocycles, Crystal Structure of Dichloro-Di-1,5-Cyclooctadiene(Mu-Pyrazine)-Dirhodium(I) [[Rh(1,5-C8h12)Cl]2(Mu-C4h4n2)]

Binuclear complexes of rhodium(I) of the type [(dien)(X)Rh(μ-N-N)Rh(X)(dien)] (dien = 1,5-cyclooctadiene or norbornadiene; N-N = pyrazine, 4,4′-bipyridine or Phenazine and X = Cl or Br) with bridging heterocycles have been isolated and their reactions with carbon monoxide, 2,2′-bipyridine and 1,10-phenanthroline investigated. The crystal structure of [(COD)(Cl)Rh(μ-pyrazine)Rh(Cl)(COD)] has been determined.

Impact of automatic region-of-interest coding on perceived quality in mobile video

At present, the most reliable method to obtain end-user perceived quality is through subjective tests. In this paper, the impact of automatic region-of-interest (ROI) coding on perceived quality of mobile video is investigated. The evidence, which is based on perceptual comparison analysis, shows that the coding strategy improves perceptual quality. This is particularly true in low bit rate situations. The ROI detection method used in this paper is based on two approaches: - (1) automatic ROI by analyzing the visual contents automatically, and; - (2) eye-tracking based ROI by aggregating eye-tracking data across many users, used to both evaluate the accuracy of automatic ROI detection and the subjective quality of automatic ROI encoded video. The perceptual comparison analysis is based on subjective assessments with 54 participants, across different content types, screen resolutions, and target bit rates while comparing the two ROI detection methods. The results from the user study demonstrate that ROI-based video encoding has higher perceived quality compared to normal video encoded at a similar bit rate, particularly in the lower bit rate range.

Assessment of quality defects in macadamia kernels using NIR spectroscopy

Spectral data were collected of intact and ground kernels using 3 instruments (using Si-PbS, Si, and InGaAs detectors), operating over different areas of the spectrum (between 400 and 2500 nm) and employing transmittance, interactance, and reflectance sample presentation strategies. Kernels were assessed on the basis of oil and water content, and with respect to the defect categories of insect damage, rancidity, discoloration, mould growth, germination, and decomposition. Predictive model performance statistics for oil content models were acceptable on all instruments (R2 > 0.98; RMSECV < 2.5%, which is similar to reference analysis error), although that for the instrument employing reflectance optics was inferior to models developed for the instruments employing transmission optics. The spectral positions for calibration coefficients were consistent with absorbance due to the third overtones of CH2 stretching. Calibration models for moisture content in ground samples were acceptable on all instruments (R2 > 0.97; RMSECV < 0.2%), whereas calibration models for intact kernels were relatively poor. Calibration coefficients were more highly weighted around 1360, 740 and 840 nm, consistent with absorbance due to overtones of O-H stretching and combination. Intact kernels with brown centres or rancidity could be discriminated from each other and from sound kernels using principal component analysis. Part kernels affected by insect damage, discoloration, mould growth, germination, and decomposition could be discriminated from sound kernels. However, discrimination among these defect categories was not distinct and could not be validated on an independent set. It is concluded that there is good potential for a low cost Si photodiode array instrument to be employed to identify some quality defects of intact macadamia kernels and to quantify oil and moisture content of kernels in the process laboratory and for oil content in-line. Further work is required to examine the robustness of predictive models across different populations, including growing districts, cultivars and times of harvest.

Effect of nitrogen on the skin colour and other quality attributes of ripe ‘Kensington Pride’ mango (Mangifera indica L.) fruit

Near-ripe ‘Kensington Pride’ mango (Mangifera indica L.) fruit with green skin colour generally return lower wholesale and retail prices. Pre-harvest management, especially nitrogen (N) nutrition, appears to be a major causal factor. To obtain an understanding of the extent of the problem in the Burdekin district (dry tropics; the major production area in Australia), green mature ‘Kensington Pride’ mango fruit were harvested from ten orchards and ripened at 20 ± 0.5 O C. Of these orchards, 70% produced fruit with more than 25% of the skin surface area green when ripe. The following year, the effect of N application on skin colour and other quality attributes was investigated on three orchards, one with a high green (HG) skin problem and two with a low green (LG) skin problem. N was applied at pre-flowering and at panicle emergence at the rate of 0,75,150,300 g per tree (soil applied) or 50 g per tree as foliar N for the HG orchard, and 0,150,300,450 g per tree (soil applied) or 50 g per tree (foliar) for the LG orchards. In all orchards the proportion of green colour on the ripe fruit was significantly (P<0.05) higher with soil applications of 150 g N or more per tree. Foliar sprays resulted in a higher proportion of green colour than the highest soil treatment in the HG orchard, but not in the LG orchards. Anthracnose disease severity was significantly (P<0.05) higher with 300 g of N per tree or foliar treatment in the HG orchard, compared with no additional N. Thus, N can reduce mango fruit quality by increasing green colour and anthracnose disease in ripe fruit.