Application of terahertz pulsed imaging to analyse film coating characteristics of sustained-release coated pellets.

Terahertz pulsed imaging (TPI) was employed to explore its suitability for detecting differences in the film coating thickness and drug layer uniformity of multilayered, sustained-release coated, standard size pellets (approximately 1mm in diameter). Pellets consisting of a sugar starter core and a metoprolol succinate layer were coated with a Kollicoat(®) SR:Kollicoat(®) IR polymer blend for different times giving three groups of pellets (batches I, II and III), each with a different coating thickness according to weight gain. Ten pellets from each batch were mapped individually to evaluate the coating thickness and drug layer thickness between batches, between pellets within each batch, and across individual pellets (uniformity). From the terahertz waveform the terahertz electric field peak strength (TEFPS) was used to define a circular area (approximately 0.13 mm(2)) in the TPI maps, where no signal distortion was found due to pellet curvature in the measurement set-up used. The average coating thicknesses were 46 µm, 71 µm and 114 µm, for batches I, II and III respectively, whilst no drug layer thickness difference between batches was observed. No statistically significant differences in the average coating thickness and drug layer thickness within batches (between pellets) but high thickness variability across individual pellets was observed. These results were confirmed by scanning electron microscopy (SEM). The coating thickness results correlated with the subsequent drug release behaviour. The fastest drug release was obtained from batch I with the lowest coating thickness and the slowest from batch III with the highest coating thickness. In conclusion, TPI is suitable for detailed, non-destructive evaluation of film coating and drug layer thicknesses in multilayered standard size pellets.

Detection of tulobuterol crystal in transdermal patches using terahertz pulsed spectroscopy and imaging.

Applicability of a Terahertz Pulsed Spectroscopy (TPS) and a Terahertz Pulsed Imaging (TPI) for detection of tulobuterol (TBR) crystals in transdermal patches was investigated. Because TBR has high permeability in dermis, crystalline TBR in patch matrices contributes to controlling the release rate of TBR from a matrix. Therefore, crystalline TBR is one of the important factors for quality control of TBR transdermal tapes. A model tape that includes 5 w/w%, 10 w/w%, 20 w/w% or 30 w/w% of TBR was measured by TPS/TPI. TBR crystals in the matrices were successfully detected by TPI. Identification of TBR in an image of a crystal-like mass was done by comparison between the spectra of tapes and a TBR standard substance. These results indicate that TPS and TPI are applicable to identifying crystalline lumps of an active drug in tapes for quality control.

Analysis of sustained-release tablet film coats using terahertz pulsed imaging.

The coating quality of a batch of lab-scale, sustained-release coated tablets was analysed by terahertz pulsed imaging (TPI). Terahertz radiation (2 to 120 cm(-1)) is particularly interesting for coating analysis as it has the capability to penetrate through most pharmaceutical excipients, and hence allows non-destructive coating analysis. Terahertz pulsed spectroscopy (TPS) was employed for the determination of the terahertz refractive indices (RI) on the respective sustained-release excipients used in this study. The whole surface of ten tablets with 10 mg/cm(2) coating was imaged using the fully-automated TPI imaga2000 system. Multidimensional coating thickness or signal intensity maps were reconstructed for the analysis of coating layer thickness, reproducibility, and uniformity. The results from the TPI measurements were validated with optical microscopy imaging and were found to be in good agreement with this destructive analytical technique. The coating thickness around the central band was generally 33% thinner than that on the tablet surfaces. Bimodal coating thickness distribution was detected in some tablets, with thicker coatings around the edges relative to the centre. Aspects of coating defects along with their site, depth and size were identified with virtual terahertz cross-sections. The inter-day precision of the TPI measurement was found to be within 0.5%.

Understanding the influence of polymorphism on phonon spectra: lattice dynamics calculations and terahertz spectroscopy of carbamazepine.

Rigid molecule atomistic lattice dynamics calculations have been performed to predict the phonon spectra of the four polymorphs of carbamazepine, and these calculations predict that there should be differences in the spectra of all four forms. Terahertz spectra have been measured for forms I and III, and there are clearly different features between polymorphs' spectra, that are accentuated at low temperature. While carbamazepine adopts the same hydrogen bonded dimers in all of its known polymorphs, the calculations show that differences in packing arrangements of the dimers lead to changes in the frequency ranges for each type of hydrogen bond vibration, giving a physical explanation to the observed differences between the spectra. Although the agreement between calculated and observed spectra does not allow a definitive characterization of the spectra, it is possible to make tentative assignments of many of the observed features in the terahertz region for the simpler form III; we can only make some tentative assignments of specific modes in the more complex spectrum of form I. While harmonic rigid molecule lattice dynamics shows promise for understanding the differences in spectra between polymorphs of organic molecules, discrepancies between observed and calculated spectra suggest areas of improvement in the computational methods for more accurate modeling of the dynamics in molecular organic crystals.

The use of Fourier-transform infrared spectroscopy for the quantitative determination of glucose concentration in whole blood.

Fourier-transform infrared transmission spectroscopy has been used for the determination of glucose concentration in whole blood samples from 28 patients. A 4-vector partial least-squares calibration model, using the spectral range 950-1200 cm(-1), yielded a standard-error-of-prediction of 0.59 mM for an independent test set. For blood samples from a single patient, we found that the glucose concentration was proportional to the difference between the values of the second derivative spectrum at 1082 cm(-1) and 1093 cm(-1). This indicates that spectroscopy at these two specific wavenumbers alone could be used to determine the glucose concentration in blood plasma samples from a single patient, with a prediction error of 0.95 mM.

Using Terahertz pulse spectroscopy to study the crystalline structure of a drug: a case study of the polymorphs of ranitidine hydrochloride.

We describe the application of Terahertz pulse spectroscopy to polymorph identification. The particular compounds investigated were the different crystalline Forms 1 and 2 of ranitidine hydrochloride, both in the pure form and also obtained as a marketed pharmaceutical product. Identification was clear. The technique has advantages that excitation is not via a powerful laser source, as used in Raman spectroscopy, so phase changes or photochemical reactions in polymorphs do not occur. Terahertz absorption spectral interpretation and instrumentation are similar to basic Fourier transform infrared (FTIR) spectroscopy and therefore easy to understand. The sample preparation techniques used are the same as those used in FTIR and Raman spectroscopies. The data obtained is complementary to Raman Spectroscopy. As the selection rules are different between the two techniques, we are able to obtain new data set directly related to crystalline structure adding to that obtained by Raman spectroscopy. Terahertz pulse spectroscopy provides information on low-frequency intermolecular vibrational modes; these are difficult to assess in Raman spectroscopy due to the proximity of the laser exciting line. It is concluded that the method has a wide range of applications in pharmaceutical science including formulation, high throughput screening, and inspection in storage.

Terahertz pulse spectroscopy of biological materials: L-glutamic Acid.

We report the terahertzpulse spectra of L-glutamic acid. Thereare a number of well-resolved transitionsin the 1.75-2.5 THz (58-83 cm(-1))region. These are compared with publishedtheoretical data on intra andintermolecular transitions. We could notfind any correlation with the theoreticalvalues. However, it was noted that thetheoretical model did not include anycrystalline or hydrogen-bonding effects.

Determination of Glucose Concentration in Whole Blood using Fourier-Transform Infrared Spectroscopy.

Fourier-transform infrared(FTIR) transmission spectroscopy has beenused for the determination of glucoseconcentrations in whole blood samples fromtwenty-eight patients. A four-vectorpartial least squares calibration model,using the spectral range 950-1200 cm(-1),yielded a standard error of prediction of0.59 mM for an independent test set. Forblood samples from a single patient, wefound that the glucose concentration wasproportional to the difference between thevalues of the second derivative spectrum at1082 cm(-1) and 1093 cm(-1), suggestingthat these two specific wavelengths can beused for determining glucose concentrationsin blood.

Counterintuitive alignment of H2(+) in intense femtosecond laser fields.

The multiphoton ionization of H2 has been studied using laser pulses of 266 nm wavelength, 250 fs duration, and 5x10(13) W/cm(2) peak intensity. Dissociation of H2(+) via one-photon absorption proceeds through two channels with markedly different proton angular distributions. The lower-energy channel (2.6 eV kinetic energy release) is produced in the bond softening mechanism, which generates parallel alignment. The higher-energy channel (3.5 eV) originates from population trapping in a light-induced bound state, where bond hardening generates orthogonal, counterintuitive alignment.