Bilayer Tablet Dissolution Kinetics Based on a Degassing Cyclic Flow UV-Vis Spectroscopy with Chemometrics.

Dissolution kinetics of a bilayer direct compress tablet was evaluated by using degassing cyclic flow UV-visible (Vis) spectroscopy with chemometrics. The model bilayer nicotinamide (NA)-pyridoxine hydrochloride (PH) 100.0 mg tablets were prepared via the dual compress method. The fast diffusion layer of the bilayer tablet contained nicotinamide, microcrystal cellulose, beta-lactose, magnesium stearate, and croscarmellose sodium. The slow release layer contained pyridoxine hydrochloride and carnauba wax. The monolayer direct compress tablets were prepared as dual ingredient (API)s formulation tablets. The degassing cyclic flow UV-Vis spectroscopy dissolution test was carried out using the prepared tablets. The dissolution test conditions were as follows: time, 60 min; temperature, 37°C; paddle method, 50 rpm, and UV-Vis spectra measurement 1 time/min. The UV-Vis spectra of the flow solution were measured in the range of 240-380 nm. API concentration was predicted by partial least squares (PLS) regression models based on UV-Vis spectra. The dissolution kinetics of the bilayer and monolayer tablets were evaluated based on the UV-Vis spectra with the predicted API concentration profile. The degassing flow system could prevent air bubbles in the flow cell at 1800 min. Therefore, simultaneous determination of NA and PH concentration based on the PLS regression was suggested to have high accuracy. PLS regression has advantages over the conventional λmax absorbance method of simultaneous determination. We found that the kinetics of the separated bilayer tablet can be evaluated by the same kinetic analysis method used for the single layer model tablet.

Quantification of Pharmaceutical Compounds Based on Powder X-Ray Diffraction with Chemometrics.

We propose an approach for the simultaneous determination of multiple components in pharmaceutical mixed powder based on powder X-ray diffraction (PXRD) method coupled with chemometrics. Caffeine anhydrate, acetaminophen and lactose monohydrate were mixed at various ratios. The samples were analyzed by PXRD method in the ranges of 2θ=5.00-30.0 and 35.0-45.0 degrees. Obtained diffractograms were analyzed by conventional peak intensity method, multi curve resolution (MCR)-alternating least squares (ALS) method and partial least squares (PLS) method. Constructed PLS models can most accurately predict the concentrations among different methods used. Each regression vector of PLS correlates not only to the compound of interest but also to the coexisting compounds. The combination of PXRD and PLS methods is concluded to be powerful approach for analyzing multi components in pharmaceutical formulations.

Integrated continuous flow method with dual feedback-based controls for online analysis and process control.

The concept of an integrated automated continuous flow method with dual feedback controls is presented for diluting a stock solution to provide a solution of a given concentration. The one control is used for the online process monitoring by a feedback-based flow ratiometry, where the product (the diluted liquid) is titrated through the rapid bidirectional scan of the product/reagent flow ratio. The feedback control limits the scanning to the necessary range to increase the analytical throughput. The other control is used for the process control to output the product with a preset concentration. The merging ratio of the stock solution and a solvent (diluent) is changed based on the information from the online analysis. The concept was verified by applying it to producing 0.1 mol dm-3 CH3COOH. When the stock concentration was changed from 0.1 (reference concentration) to 0.3 and then 0.2 mol dm-3, the system searched for the suitable merging ratio and converged the output concentration to the reference value within 7.43 min with a relative error below 1.05%. The mean throughput rate of the process analysis was 11.2 titrations min-1. Successful results were also obtained for the 0.1 mol dm-3 HCl production. The present concept could be the basis for process control with reduced wasteful output and effluent treatment with eco-friendly treated water discharge, resulting in the contribution to SDGs' goals of 6 (Clean water and sanitation), 9 (Industry, innovation and infrastructure), and 14 (Life below water).

Determination of trace perchlorate in river water by ion chromatography with online matrix removal and sample concentration.

This paper proposes a simple ion chromatographic approach to determine trace amounts of perchlorate in river water samples. Determination of the trace perchlorate by ion chromatography typically faces two challenges: interference by matrix ions such as chloride, nitrate, and sulfate in the samples and insufficient detection sensitivity. In the present study, online pretreatment of the samples with an OnGuard II Ba/Ag/H disposable sample pretreatment cartridge prevented the sulfate peak tailing from overlapping with the perchlorate peak on the chromatogram. In addition, the matrix removal enabled as large as 10 mL of sample to be loaded into a high exchange capacity anion concentrator, significantly improving perchlorate's detection sensitivity. The proposed approach achieved a detection limit (S/N = 3) of 0.046 µg L-1 without using a costly mass spectrometer and successfully determined sub µg L-1 levels of perchlorate in river water.

Inner product of RGB unit vectors for detecting color transition: application to feedback-based flow ratiometric titration.

The inner product (IP) of RGB unit vectors' approach for detecting color transition has further been applied to a feedback-based flow ratiometric titration, including nonaqueous titration. While the flow ratio of titrand/titrant containing an indicator was varying, the video image of the merged solution was taken with a digital microscope downstream. The indicator's color was converted to an RGB unit vector. The change in IP between vectors was used for determining the equivalence point. The concept was successfully applied to the determinations of drug and vinegar samples with reasonable throughput rate (> 18 s/titration) and precision (RSD < 4.4%).

Triangular-wave controlled amplitude-modulated flow analysis for extending dynamic range to saturated signals.

We have applied our amplitude-modulated flow analysis concept to extend the dynamic range to saturated analytical signals. Sample solution, the flow rate FS of which is periodically varied with a triangular control signal Vc, is merged with a reagent solution delivered at a constant flow rate FR. While the total flow rate FT is kept constant, a diluent with FT-(FS + FR) flow rate is aspirated from the third channel. The analytical signal Vd obtained downstream is processed by fast Fourier transform to obtain the amplitudes of the wave components in Vd. When the sample concentration CS is low, Vd shows a triangular profile like Vc; the sum of the amplitudes ΣA is proportional to CS. When CS is high, Vd shows a trapezoidal profile because of the Vd saturation. A linear calibration curve can also be obtained for such saturated signals by plotting CSΣA against CS. The proof of the concept is validated by applying it to spectrophotometric determinations of a dye (Methylene Blue) and colored complexes of Fe2+ - phenanthroline and Fe3+ - Tiron.

Inner Product of RGB Unit Vectors for Simple and Versatile Detection of Color Transition.

We propose a novel concept for detecting color transition by the inner product (IP) of RGB unit vectors. A digital microscope-based detector and a Visual Basic program were developed in-house. The concept is applied to indicator-based flow titration. The IP is 1 or < 1 if the vector's direction is the same or different, respectively. The IP's change can be used as a criterion for the indicator's color transition. The present IP-based approach is simple, economical, and versatile because it is applicable to any color transition without selecting an analytical wavelength.

Predictive evaluation of powder X-ray diffractograms of pharmaceutical formulation powders based on infrared spectroscopy.

BACKGROUND: To ensure quality and stability, monitoring systems are recommended to analyze pharmaceutical manufacturing processes. OBJECTIVE: This study was performed to predict powder X-ray diffraction (PXRD) patterns of formulation powders through attenuated total reflectance (ATR)-infrared (IR) spectroscopy in a nondestructive manner along with chemometrics. RESULTS: Caffeine anhydrate, acetaminophen, and lactose monohydrate were grinded at six weight ratios. The six sample groups were evaluated using ATR-IR spectroscopy and PXRD analysis. Partial least squares models were constructed to predict the PXRD intensities of the samples from the ATR-IR spectra. The prediction accuracy on the prepared PLS regression models was as high as R2 = 0.993. CONCLUSIONS: Linear relationships were obtained between the prediction data set and reference PXRD intensity at each degree. 2D PLS regression coefficient analysis enabled the analysis of the correlation between PXRD patterns and IR spectra.

Introduction of Air-Segmentation Approach to Flow Titration by Feedback-based and Subsequent Fixed Triangular Wave-controlled Flow Ratiometry.

An air-segmentation approach has been introduced to a feedback-based and subsequent fixed triangular wave-controlled flow ratiometry to suppress axial dispersion in flow titration. The flow rate of a base solution containing an indicator is linearly varied with a control signal, Vc, supplied by a computer. The solution is merged with an acid solution under a constant total flow rate. Air is introduced to the merged solution in order to segment the solution with air bubbles. Both phases are led to a UV/Vis detector without phase separation. Air signals are removed by signal processing. The effect of the lag time between the merging of solutions upstream and the sensing of the corresponding signal downstream is offset by feedback-based upward and downward Vc scans, and thus the Vc that gives the equivalence composition is determined. Subsequently, fixed triangular wave control is applied to a narrower Vc range with a higher scan rate to enhance the throughput rate (maximally 11.8 titrations/min). Air-segmentation has been found to be effective to reduce axial dispersion and to preserve the titrand/titrant composition upon their just being merged. Consequently, the applicable range is extended especially to lower titrand concentration. The proposed method has been successfully applied to various acid-base titrations, including the nonaqueous titration of the Japanese Pharmacopoeia drug.

Population pharmacokinetics of darbepoetin alpha in peritoneal dialysis and non-dialysis patients with chronic kidney disease after single subcutaneous administration.

OBJECTIVE: To characterize the pharmacokinetics of darbepoetin alpha and covariate relationships in chronic kidney disease (CKD) patients after a single subcutaneous administration. METHODS: A total of 989 serum concentration recordings from 64 patients were analyzed using NONMEM with a model including endogenous erythropoietin production. The basic and final models were evaluated for stability using bootstrapping. RESULTS: The selected basic model had one-compartment with a combination of the additive and constant coefficient of variation error models for residual variability. The significant covariate was weight for apparent clearance (CL/f) and apparent volume of central compartment (V(1)/f). The typical values of CL/f, V(1)/f, and absorption rate constant were 0.158 l/h, 13.7 l, and 0.0376/h, respectively. Evaluation by bootstrapping showed that the final model was stable. CONCLUSION: The present analysis indicated that weight is a significant covariate for CL/f and V(1)/f. However, dosage adjustment according to weight is not necessary for subcutaneous administration of darbepoetin alpha in CKD patients.

Stroke frequency, but not swimming speed, is related to body size in free-ranging seabirds, pinnipeds and cetaceans.

It is obvious, at least qualitatively, that small animals move their locomotory apparatus faster than large animals: small insects move their wings invisibly fast, while large birds flap their wings slowly. However, quantitative observations have been difficult to obtain from free-ranging swimming animals. We surveyed the swimming behaviour of animals ranging from 0.5 kg seabirds to 30 000 kg sperm whales using animal-borne accelerometers. Dominant stroke cycle frequencies of swimming specialist seabirds and marine mammals were proportional to mass(-0.29) (R(2)= 0.99, n = 17 groups), while propulsive swimming speeds of 1-2 m s(-1) were independent of body size. This scaling relationship, obtained from breath-hold divers expected to swim optimally to conserve oxygen, does not agree with recent theoretical predictions for optimal swimming. Seabirds that use their wings for both swimming and flying stroked at a lower frequency than other swimming specialists of the same size, suggesting a morphological trade-off with wing size and stroke frequency representing a compromise. In contrast, foot-propelled diving birds such as shags had similar stroke frequencies as other swimming specialists. These results suggest that muscle characteristics may constrain swimming during cruising travel, with convergence among diving specialists in the proportions and contraction rates of propulsive muscles.

Arterial stiffness is associated with left ventricular diastolic function in patients with cardiovascular risk factors: early detection with the use of cardio-ankle vascular index and ultrasonic strain imaging.

BACKGROUND: It is well known that left ventricular (LV) diastolic function declines in the elderly, especially in patients with cardiovascular risk factors. However, few data are available on the early detection of relationship between arterial stiffness and LV diastolic dysfunction. METHODS AND RESULTS: The common carotid artery intima-media thickness (IMT) and cardio-ankle vascular index (CAVI) were measured to determine the presence of subclinical atherosclerosis in 30 patients (13 men and 17 women; mean age 59 +/- 5.7 years) with 1 or more cardiovascular risk factors. LV systolic and diastolic function also were determined by measuring transmitral flow velocity, mitral annular motion velocity, and myocardial strain and strain rate profiles using pulsed Doppler, tissue velocity, and ultrasonic strain imaging. The CAVI correlated with the peak early diastolic velocity of transmitral flow velocity (r = -0.50, P < .01), the ratio of peak early to late diastolic transmitral flow velocity (r = -0.37, P < .05), the deceleration time from peak to baseline of the early diastolic transmitral flow velocity (r = 0.57, P < .01), the peak early diastolic mitral annular motion velocity (r = -0.41, P < .05), and the peak early diastolic strain rates at the endocardial sites of the LV posterior and inferior walls (r = 0.61, P < .001; r = 0.56, P < .001, respectively). There were no relationships between CAVI and LV ejection fraction, peak systolic mitral annular motion velocity, or peak systolic strain rates of the LV walls. Multiple regression analysis revealed that the early diastolic strain rates at the endocardial sites of the LV walls are strongly correlated with CAVI. There were no relationships between the IMT and the LV systolic and diastolic parameters. CONCLUSION: These results suggest that cardiovascular risk factors interact to affect arterial stiffness and LV relaxation, and therefore support the importance of screening using CAVI and ultrasonic strain imaging and early intervention in this patient population.

Effect of cinacalcet hydrochloride, a new calcimimetic agent, on the pharmacokinetics of dextromethorphan: in vitro and clinical studies.

Cinacalcet hydrochloride (cinacalcet) is a positive allosteric modulator of the calcium-sensing receptor indicated for the treatment of secondary hyperparathyroidism in dialysis patients. In vitro study has demonstrated that cinacalcet is a potent inhibitor of cytochrome P450 (CYP) 2D6 with a K(i) value of 0.087 micromol/L, which is comparable to the well-known potent CYP2D6 inhibitor, quinidine (0.064 micromol/L). A clinical study was conducted to assess the inhibitory effect of cinacalcet on CYP2D6 substrates in healthy volunteers. Each subject received 50 mg of cinacalcet or a matched placebo orally once daily for 8 days with 30 mg of dextromethorphan coadministered on day 8. The mean AUC(0-infinity) and C(max) of dextromethorphan increased 11- and 7-fold, respectively, in extensive metabolizers when coadministered with cinacalcet versus placebo. Therefore, during concomitant treatment with cinacalcet, it may be necessary to consider making dose adjustments for drugs with a narrow therapeutic index that are mainly metabolized by CYP2D6.

Dry Mechanochemical Synthesis of Caffeine/Oxalic Acid Cocrystals and Their Evaluation by Powder X-Ray Diffraction and Chemometrics.

We report the effects of dry mechanochemical synthesis conditions on the crystallization of caffeine (CA) and oxalic acid (OX) 2:1 cocrystal. CA anhydrate and OX dihydrate were grinded at various temperatures, rotation speeds, and grinding time. The cocrystal was also synthesized by an organic solvent evaporation method, as a reference. The produced samples were measured by a powder X-ray diffraction (PXRD) analysis. The PXRD spectra suggest that the grinded cocrystal has a lower crystallinity than the evaporated one. The diffractograms for the cocrystals synthesized by 2 kinds of methods were further evaluated by multivariate curve resolution-alternating least squares method. Sources of the mathematical models constructed were assigned to the cocrystal and unreacted mixture of CA and OX dihydrate. The present approach is concluded to be useful for the improvement of pharmaceutical property because cocrystallization is closely relating to the solubility characteristics, bioavailability, stability, and so on of drugs.

Internal Standard-Amplitude Modulated Multiplexed Flow Analysis.

A new concept of flow analysis, internal standard-amplitude modulated multiplexed flow analysis, is proposed. A proof of concept was verified by applying it to the determination of ferrous ion (Fe2+) by 1,10-phenanthroline (o-Phen) spectrophotometry. The flow rates of sample solutions containing Methylene Blue (MB) as an internal standard substance were sinusoidally varied at different frequencies. The solutions were merged with a color reagent (o-Phen) solution, while the total flow rate was held constant. Downstream, analytical signals were monitored at the maximum absorption wavelengths of Fe2+-o-Phen complex and of MB (510 and 644 nm, respectively). The signals were respectively analyzed by fast Fourier transform. The concentrations of the analytes in respective samples were simultaneously determined from the amplitudes of the corresponding wave components. The precision, linearity of the calibration curve, limit of detection and robustness against deliberate fluctuation in flow rate were greatly improved by introducing the internal standard method. Good recoveries of around 100% were obtained for Fe2+ spiked into real water samples.

Determination of lipophilicity by reversed-phase high-performance liquid chromatography. Influence of 1-octanol in the mobile phase.

Lipophilicity was evaluated using a novel RP-HPLC stationary phase (Discovery-RP-Amide-C16) with and without 1-octanol added to the mobile phase. A set of 46 drugs and flavonoids characterized by a broad structural diversity and a wide log Poct range (-0.69 to 5.70) was selected for this study. This set consists of neutral solutes and solutes with acidic or ampholytic functionalities which were maintained neutral at pH 2.5 or 4. In our conditions, the addition of 1-octanol in the mobile phase proved a key factor to derive a lipophilicity index log k(w) highly correlated with log Poct for all investigated solutes. 1-Octanol improved the correlation between log Poct and log k(w) mainly by influencing the retention behavior of the solutes with log Poct values below +3. This study brings additional evidence that under proper experimental conditions of stationary and mobile phases, RP-HPLC is a very useful method to obtain log Poct values.

High-throughput photometric titrimetry based on a feedback-based and subsequent fixed triangular wave-controlled flow ratiometry.

The principle of flow ratiometry for high-throughput titration, which we recently proposed for potentiometric titration, was extended to photometric titration. The flow rate (FB) of a base solution containing an acid-base indicator was linearly varied in response to a control voltage (Vc) generated from a computer. With the total (acid + base) flow rate (FT) being kept constant, the base solution was merged with an acid solution, which was aspirated to the confluence point at a flow rate of FT - FB. Downstream, the relative transmittance of the mixed solution was measured at the maximum absorption wavelength of the base form of the indicator. Initially, a feedback-based control was applied, where the scan direction of Vc was reversed from upward to downward, and vice versa, whenever the transition of the indicator at the equivalence point (EP) was sensed. Next, the scan range of V. was further limited to the range just around EP by using fixed triangular waves. These processes avoided scanning in a range of no interest. Thus, an unprecedentedly high throughput rate (maximally 34 titrations per minute, corresponding to 1.76 s per titration) was realized with reasonable precision (RSD < 0.5%).

Predictive evaluation of pharmaceutical properties of direct compression tablets containing theophylline anhydrate during storage at high humidity by near-infrared spectroscopy.

BACKGROUND: Theophylline anhydrate (TA) in tablet formulation is transformed into monohydrate (TH) at high humidity and the phase transformation affected dissolution behavior. OBJECTIVE: Near-infrared spectroscopic (NIR) method is applied to predict the change of pharmaceutical properties of TA tablets during storage at high humidity. METHODS: The tablet formulation containing TA, lactose, crystalline cellulose and magnesium stearate was compressed at 4.8 kN. Pharmaceutical properties of TA tables were measured by NIR, X-ray diffraction analysis, dissolution test and tablet hardness. RESULTS: TA tablet was almost 100% transformed into TH after 24 hours at RH 96%. The pharmaceutical properties of TA tablets, such as tablet hardness, 20 min dissolution amount (D20) and increase of tablet weight (TW), changed with the degree of hydration. Calibration models for TW, tablet hardness and D20 to predict the pharmaceutical properties at high-humidity conditions were developed on the basis of the NIR spectra by partial least squares regression analysis. The relationships between predicted and actual measured values for TW, tablet hardness and D20 had straight lines, respectively. CONCLUSIONS: From the results of NIR-chemometrics, it was confirmed that these predicted models had high accuracy to monitor the tablet properties during storage at high humidity.

Diagnosis of cardiac amyloidosis based on the myocardial velocity profile in the hypertrophied left ventricular wall.

The myocardial velocity profile (MVP), derived from color-coded tissue Doppler imaging (TDI), can identify transmural heterogeneity based on the physiology and pathology of the myocardium. This study sought to clarify whether the MVP can differentiate cardiac amyloidosis from other causes of left ventricular hypertrophy. We recorded the MVP and determined its myocardial velocity gradient (MVG) in the ventricular septum and left ventricular posterior wall using color-coded TDI in 10 patients with cardiac amyloidosis, in 25 patients with hypertensive hypertrophied left ventricular wall, in 25 patients with asymmetric septal hypertrophy of hypertrophic cardiomyopathy, and in 20 clinically normal controls. End-diastolic ventricular septal thickness was similar among the cardiac amyloidosis, hypertension, and hypertrophic cardiomyopathy groups. Percent systolic thickening of the ventricular septum and left ventricular posterior wall calculated from M-mode left ventricular echocardiograms was lower in the cardiac amyloidosis group than in the hypertension, hypertrophic cardiomyopathy, or control group. Peak MVGs during systole and early diastole were lowest in the cardiac amyloidosis group, followed, in order, by the control, hypertension, and hypertrophic cardiomyopathy groups. The systolic and early diastolic MVPs in the ventricular septum and left ventricular posterior wall showed a characteristic serrated pattern in all patients with cardiac amyloidosis, but not in any other patient groups. In conclusion, MVPs in the ventricular septum and left ventricular posterior wall show a distinctive serrated pattern that may be related to amyloid deposition in the myocardium. Myocardial tissue characterization using color-coded TDI provides diagnostic information in patients with cardiac amyloidosis.

Population pharmacokinetics of the novel anticancer agent KRN7000.

PURPOSE: KRN7000 is a novel anticancer agent, acting through stimulation of the immune system. The first clinical trial with this agent, which included pharmacokinetic studies, has recently been completed. The aim of the study presented here was to develop a population pharmacokinetic model for KRN7000. METHODS: Plasma concentration-time data were gathered from 24 patients enrolled in a phase I trial in which KRN7000 was administered as a weekly slow injection at doses ranging from 50 to 4800 microg/m(2). These data were used to build a pharmacokinetic model using the nonlinear mixed-effect modeling (NONMEM) program. The model was validated by performance of 200 bootstraps. RESULTS: A three-compartment model with interindividual variability on the central and two peripheral volumes of distribution (V1, V2 and V3) and on clearance (CL) adequately described the data. The final estimates were: V1 2.34 l, V2 2.61 l, V3 2.13 l, and CL 0.130 l/h. Of 24 covariates tested, including both demographic and pathophysiological factors, none showed a significant relationship with the pharmacokinetic parameters obtained. The bootstrap analysis provided parameter estimates within approximately 15% of the original estimates, indicating stability of the model. CONCLUSION: The pharmacokinetic behavior of KRN7000 in the clinical trial could be described by a three-compartment model. Hence, KRN7000 demonstrates linear pharmacokinetics over the investigated dose range. The pharmacokinetics of KRN7000 are not influenced by patient demographic or pathophysiological characteristics.