Abstract In the process design of tablet manufacturing, understanding and control of the lubrication process is important from various viewpoints. A detailed analysis of thermal effusivity data in the lubrication process was conducted in this study. In addition, we evaluated the risk and benefit in the lubrication process by a detailed investigation. It was found that monitoring of thermal effusivity detected mainly the physical change of bulk density, which was changed by dispersal of the lubricant and the coating powder particle by the lubricant. The monitoring of thermal effusivity was almost the monitoring of bulk density, thermal effusivity could have a high correlation with tablet hardness. Moreover, as thermal effusivity sensor could detect not only the change of the conventional bulk density but also the fractional change of thermal conductivity and thermal capacity, two-phase progress of lubrication process could be revealed. However, each contribution of density, thermal conductivity, or heat capacity to thermal effusivity has the risk of fluctuation by formulation. After carefully considering the change factor with the risk to be changed by formulation, thermal effusivity sensor can be a useful tool for monitoring as process analytical technology, estimating tablet hardness and investigating the detailed mechanism of the lubrication process.

Abstract As an oral delivery carrier for poorly water soluble drugs, the nanosuspension was prepared by melt emulsification method combined with high-pressure homogenization. The objective of this study was to clarify the absorption mechanism in rats of fenofibrate nanosuspension using the model of in situ gut perfusion. The release rate of drug from nanosuspension was fast which about 70% of the drug would be released within 5 minutes. The absorption of fenofibrate nanosuspension in the gastrointestinal (GI) tract was studied by the in situ closed loop method in rats. It was found that the absorption process in intestine was first-process with passive diffusion mechanism, and the whole intestine was the major segment for the drug absorption. Additionally, GI absorption in situ studies indicated that the fenofibrate nanosuspension had great success in regard to enhancement of intestinal absorption compared to the fenofibrate suspension of coarse powder. The pharmacokinetic characteristics were studied in rats after oral administration of fenofibrate nanosuspension or suspension at the dosage of 27 mg/kg. The plasma concentration-time curve was fitted to the one-compartment model. The correlation between in vitro dissolution (P), in situ intestinal absorption (F) and in vivo absorption (Fa) in rats was investigated with the results as follows: Fa = 6.2061P-456.38(r = 0.9559), F = 3.6911P-2.2169(r = 0.970), F = 0.5095P + 44.189(r = 0.9609). The highest level A could be obtained from the in vitro--in vivo correlation (IVIVC) between dissolution percentage and intestinal absorption of the fenofibrate nanosuspension in rats. Consequently, the in situ intestinal perfusion model could be used to predict the in vivo pharmacokinetic characteristics in rats.

Abstract

Context:

Although the general pharmacokinetics of cephalexin is quite established up-to-date, however, no population-based study on Cephalexin pharmacokinetics profile in Malay population has been reported yet in the literature.

Objective:

The objective of this study was to investigate the pharmacokinetics and to compare the bioavailability of three cephalexin products, Ospexin® versus MPI Cephalexin® tablet and MPI Cephalexin® capsule, in healthy Malay ethnic male volunteers in Malaysia. Material and method: A single dose, randomized, fasting, three-period, three-treatment, three-sequence crossover, open label bioequivalence study was conducted in 24 healthy Malay adult male volunteers, with 1 week washout period. The drug concentration in the sample was analyzed using high performance liquid chromatography. Result: The mean (SD) pharmacokinetic parameter results of Ospexin® were Cmax, 17.39 (4.15) μg/mL; AUC0-6, 28.90 (5.70) µg/mL * h; AUC0-∞, 30.07 (5.94) µg/mL * h; while, those of MPI Cephalexin® tablet were Cmax, 18.29 (3.01) μg/mL; AUC0-6, 30.02 (4.80) µg/mL * h; AUC00-∞, 31.33 (5.18) µg/mL * h and MPI Cephalexin® capsule were Cmax, 18.25 (3.92) μg/mL; AUC0-6, 30.04 (5.13) µg/mL * h; AUC0-∞, 31.22 (5.29) µg/mL * h.

Conclusion:

The 90% confidence intervals for the logarithmic transformed Cmax, AUC0-6 and AUC0-∞, of Ospexin® versus MPI Cephalexin® tablet and Ospexin® versus MPI Cephalexin® capsule were between 0.80 and 1.25. Both Cmax and AUC met the predetermined criteria for assuming bioequivalence. The pharmacokinetic profile of cephalexin in Malay population does not vary much from other world population.

Abstract

Context:

Approaching of pharmaceutical and cosmetic industries in some aspects inevitably influence formulation of topical pharmaceuticals, urging researchers to introduce novel excipients with proven benefits over traditional ones. In that context, alkyl polyglucosides (APG) emerge as prominent natural-origin emulsifiers with numerous favorable features (biodegradability, dermatological acceptability, desirable sensory properties).

Objective:

To evaluate APG-stabilized bases (alone and upon addition of isopropyl alcohol) and their impact on skin performance. A simultaneous in vitro/in vivo skin absorption study was conducted to evaluate whether the tape stripping technique could be recommended as an in vivo tool for skin penetration assessment during formulation optimization process. Materials and methods: After a comprehensive physicochemical characterization, biopharmaceutical properties of APG-bases versus reference ones were assessed through a combined in vitro (release/permeation) and in vivo approach. Results and discussion: Physicochemical characterization revealed substantial difference in structural ordering due to the formation of various mesomorphic phases. The enhancer-loaded APG base resulted in significantly higher drug levels at all depths into the stratum corneum, indicating that the selected enhancer along with specific colloidal structure has increased the extent of drug delivery.

Conclusion:

Results recommend the investigated emulsifier for stabilization of topical drug delivery systems, not only for their ability to sustain the addition of isopropyl alcohol which proved to be a valuable enhancer, but also satisfactory skin absorption and tolerability when compared to samples stabilized by conventional emulsifier. Tape stripping proved to be a useful and yet inexpensive tool for in vivo trials, able to discriminate subtle differences in dermal availability.

Abstract

Context:

Gambogic acid (GA) can inhibit the growth of various cancer cells. However, the low bioavailability caused by insolubility, limits its clinical application. L-arginine is always used with GA to form a complex to obtain the higher solubility. Moreover, guanidyl group from arginine, which can facilitate the cellular uptake, was identified.

Objective:

In this study, L-arginine and chitosan (CS) were used for the first time to prepare N-octyl-N-arginine CS (OACS), a novel amphiphilic carrier for GA with solubility- and absorption-enhancing functions; the characterization of the GA loaded OACS micelles (GA-OACS) and its absorption-enhancing effect were also investigated. Materials and methods: GA-OACS were prepared by the dialysis method. The formed micelles were characterized and evaluated by atomic force microscope (AFM), dynamic light scattering, differential scanning calorimeter (DSC), solubility test, in vitro release and in situ intestinal perfusion.

Results:

The GA-OACS micelles were successfully prepared attaining a 35.3% drug loading and 82.2% entrapment efficiency. GA-OACS had a homogeneous particle size of 160.3 nm; +21.8 mv zeta potential with smooth continuous surface was observed by using AFM. DSC diagram suggested that GA was encapsulated in the micelles. Meanwhile, GA encapsulated in micelles exhibited a desirable slow release in vitro experiment. The solubility of GA in OACS micelles was increased up to 3.16 ± 0.13 mg/mL, 2320 times than that of free GA. The single pass perfusion showed that the absorption of GA-OACS micelles was enhanced 3.6-fold, 2.1-fold and 2.2-fold for jejunum, ileum and colon, respectively. Discussion and conclusion: OACS provided excellent ability of drug loading, increasing solubility and enhanced absorption for GA, which indicated that OACS micelles as an oral drug delivery carrier may have potential research and application values.

Abstract Spray drying is a technique used to produce solid particles from liquid solutions, emulsions or suspensions. Buchi Labortechnik developed the latest generation of spray dryers, Nano Spray Dryer B-90. This study aims to obtain, directly, submicron drug particles from an organic solution, employing this equipment and using dexamethasone as a model drug. In addition, we evaluated the influence of both the type of solvent and surfactant on the properties of the powders using a 3(2) full factorial analysis. The particles were obtained with high yields (above 60%), low water content (below 2%) and high drug content (above 80%). The surface tension and the viscosity were strongly influenced by the type of solvent. The highest powder yields were obtained for the highest surface tension and the lowest viscosity of the drug solutions. The use of ionic surfactants led to higher process yields. The laser diffraction technique revealed that the particles deagglomerate into small ones with submicrometric size, (around 1 µm) that was also observed by scanning electron microscopy. Interaction between the raw materials in the spray-dried powders was verified by calorimetric analysis. Thus, it was possible to obtain dexamethasone submicrometric particles by vibrational atomization from organic solution.

Abstract

Objective:

The aim of this work was to study the granule growth kinetics during in situ fluid bed melt granulation process using real-time particle size measurement techniques. In addition, the usefulness of these techniques during scale-up of melt granulation was evaluated. Materials and methods: Focused beam reflectance measurement (FBRM) and spatial filtering technique (SFT) probes were used within the process chamber of fluid bed granulator for real-time in-line granule size analysis.

Results:

The results demonstrated that the use of in-line particle size probes in fluid bed granulator during the process offers an insightful view of granule growth and allows in-process monitoring of granule chord length changes. The effect of selected critical parameters (binder content, inlet air temperature and product endpoint temperature) on the granule growth was clearly presented by in-line measurements in a laboratory scale. A comparison of granule size measurements from both FBRM and SFT probes showed similar particle growth trends, which were in close correlation to the product temperature. Comparable trends in end granule particle size were observed when comparing different in-line, at-line and off-line particle size measurements.

Conclusion:

The in-line FBRM and SFT probes were successfully employed in in situ fluid bed melt granulation process to study the influence of critical formulation/process parameters on the granule growth kinetics. The scale-up experiment confirmed the potential of these in-line granule size measurement techniques as a viable tool for process monitoring during the transfer of granulation to the larger scale or another manufacturing site/equipment.

Abstract

Context:

Although several methods have been investigated to measure the film thickness of tablets and its correlation with the dissolution behavior, much fewer such investigations exist for pharmaceutical pellets.

Objective:

To study the possibility of measuring the film thickness and predicting the dissolution behavior of pellets produced in different fluid bed equipments with Raman spectroscopy. Materials and methods: Pyridoxine hydrochloride-layered pellets were produced and coated in two different Strea-1 equipments. Raman spectra were collected and analysed to set up a calibration model based on the film thickness data calculated from Camsizer analysis results. Dissolution tests were done according to Ph. Eur. standards.

Results:

Raman spectroscopy proved to be a good tool in the measurement of film thickness. Polymer weight gain showed a linear correlation with film thickness but was a poor predictor of dissolution results below a threshold value.

Conclusion:

The Raman spectroscopic measurement of a small sample can provide accurate data of the film thickness. The investigation suggests that a threshold value might exist for the film thickness above which it can be used to judge future dissolution results.

Abstract In this study, tetrandrine-loaded cationic solid lipid nanoparticles (TET-CNP) and solid lipid nanoparticles (TET-NP) were prepared by the emulsion evaporation-solidification at low temperature method. The particle size, zeta potential, and entrapment efficiency of TET-CNP and TET-NP were characterized. The results showed that the TET-CNP and TET-NP had average diameters of (15.29 ± 1.34) nm and (18.77 ± 1.23) nm with zeta potentials of (5.11 ± 1.03) mV and (-8.71 ± -1.23) mV and entrapment efficiencies of (94.1 ± 2.37)% and (95.6 ± 2.43)%, respectively. In vitro release studies indicated that the TET-CNP and TET-NP retained the drug entity better than tetrandrine ophthalmic solutions (TET-SOL). In the pharmacokinetics studies, the AUC values of TET-CNP and TET-NP were 1.96-fold and 2.00-fold higher than that of TET-SOL ( p < 0.05); the Cmax values of TET-CNP and TET-NP were 2.45-fold and 2.53-fold higher than that of the TET-SOL (p < 0.05), respectively. Cytotoxicity study showed that TET-CNP and TET-NP had no significant toxicity at low concentrations. Flow cytometry studies and confocal microscopy analysis demonstrated that calcein labeled NP (CA-NP) uptake by SRA 01/04 cells was much higher than those of calcein labeled CNP (CA-CNP) and calcein solution (CA-SOL).

Abstract

Objective:

The objective of this study was to determine the impact that the micro-environment, as measured by PyroButton data loggers, experienced by tablets during the pan coating unit operation had on the layer adhesion of bilayer tablets in open storage conditions. Materials and methods: A full factorial design of experiments (DOE) with three center points was conducted to study the impact of final tablet hardness, film coating spray rate and film coating exhaust temperature on the delamination tendencies of bilayer tablets. PyroButton data loggers were placed (fixed) at various locations in a pan coater and were also allowed to freely move with the tablet bed to measure the micro-environmental temperature and humidity conditions of the tablet bed.

Results:

The variance in the measured micro-environment via PyroButton data loggers accounted for 75% of the variance in the delamination tendencies of bilayer tablets on storage (R(2 )= 0.75). A survival analysis suggested that tablet hardness and coating spray rate significantly impacted the delamination tendencies of the bilayer tablets under open storage conditions. The coating exhaust temperature did not show good correlation with the tablets' propensity to crack indicating that it was not representative of the coating micro-environment. Models created using data obtained from the PyroButton data loggers outperformed models created using primary DOE factors in the prediction of bilayer tablet strength, especially upon equipment or scale transfers.

Conclusion:

The coating micro-environment experienced by tablets during the pan coating unit operation significantly impacts the strength of the bilayer interface of tablets on storage.