International Journal of Pharmaceutics (v.448, #2)

In this work, the influence factors of pulsed frequency, binder spray rate and atomisation pressure of a top-spray fluidised bed granulation process were studied using the Box–Behnken experimental design method. Different mathematical models were developed to predict the mean size of granules, yield, relative width of granule distribution, Hausner ratio and final granule moisture content. The study has supported the theory that the granule size can be controlled through the liquid feed pulsing. However, care has to be taken when the pulsed frequency is chosen for controlling the granule size due to the nonlinear quadratic relation in the regression model. The design space of the ranges of operating parameters has been determined based on constraints of the mean size of granules and granule yield. High degree of prediction obtained from validation experiments has shown the reliability and effectiveness of using the Box–Behnken experimental design method to study a fluidised bed granulation process.
Keywords: Top-spray fluidised bed granulation; Box–Behnken design method; Hausner ratio; Operating parameters; Moisture content;

Polyethylene glycol (PEG) 400/Miglyol 812 non-aqueous sub-micron emulsions were developed due to the fact that they are of interest for the design of drug-loaded biocompatible topical formulations. These types of emulsions were favourably stabilized by poly (2-vinylpyridine)-b-poly (butadiene) (P2VP-b-PBut) copolymer with DPBut  > DP2VP, each of these sequences being well-adapted to the solubility parameters of PEG 400 and Miglyol 812, respectively. This type of block copolymers, which might limit the Ostwald ripening, appeared to be more efficient stabilizers than low molecular weight non-ionic surfactants. The emulsion characteristics, such as particle size, stability and viscosity at different shear rates were determined as a function of the phase ratio, the copolymer concentration and storage time. It was further shown that Acyclovir, as a model drug of low water solubility, could be incorporated into the PEG 400 dispersed phase, with no significant modification of the initial emulsion characteristics.
Keywords: Miglyol 812; PEG 400; Biocompatible sub-micron non-aqueous emulsion; Block copolymer stabilizer; Ostwald ripening; Acyclovir;

One of the promising approaches to predict in vivo disintegration time of orally disintegrating tablets (ODT) is the use of texture analyzer instrument. Once the method is able to provide good in vitro in vivo correlation (IVIVC) in the case of different tablets, it might be able to predict the oral disintegration time of similar products. However, there are many tablet parameters that influence the in vivo and the in vitro disintegration time of ODT products. Therefore, the measured in vitro and in vivo disintegration times can occasionally differ, even if they coincide in most cases of the investigated products and the in vivo disintegration times may also change if the aimed patient group is suffering from a special illness. If the method is no longer able to provide good IVIVC, then the modification of a single instrumental parameter may not be successful and the in vitro method must be re-set in a complex manner in order to provide satisfactory results. In the present experiment, an optimization process was developed based on texture analysis measurements using five different tablets in order to predict their in vivo disintegration times, and the optimized texture analysis method was evaluated using independent tablets.
Keywords: Fast disintegrating tablets; Texture analysis; Optimization;

Proof of concept studies to confirm the delivery of curcumin loaded solid lipid nanoparticles (C-SLNs) to brain by Vandita Kakkar; Anil Kumar Mishra; Krishna Chuttani; Indu Pal Kaur (354-359).
Having achieved a significant bioavailability of curcumin by its incorporation into SLNs (C-SLNs) during pharmacokinetic (32–155 times) and pharmacodynamic (3–4 times) studies, our intent was to proof their targeting to brain. Hence, fluorescent/confocal microscopy, biodistribution and gamma scintigraphy techniques were explored to observe the presence of C-SLNs in the brain.1 h post p.o administration of C-SLNs/free curcumin (C-S) to rats, blood was withdrawn, following which the animals were sacrificed and their harvested brains were frozen at −80 °C. The obtained plasma and brain cryosections were observed for fluorescence under fluorescent/confocal microscope.Biodistribution study was performed using 99mTc-labeled C-SLNs and C-S in Balb/c mice after p.o. and i.v. administration and % radioactivity/g organ was recorded. Subsequent to this gamma scintigraphs of the New Zealand rabbits following similar treatments were performed.Presence of yellow fluorescent particles in plasma and brain indicated effective delivery of C-SLNs across the gut wall and the BBB. BloodAUCoral value for C-SLNs was 8.135 times greater than that for C-S, confirming a prolonged circulation of former. The ratio of blood AUCi.v. C-SLN/C-S in blood is ≤1 while the ratio in brain promisingly indicates 30 times higher preferential distribution of C-SLNs into brain confirming their direct delivery.
Keywords: Curcumin; Solid lipid nanoparticles; Fluorescent/confocal microscopy; Gamma scintigraphy; Biodistribution;

Formulation of carbenoxolone for delivery to the skin by Kazumasa Hirata; Fouad Helal; Jonathan Hadgraft; Majella E. Lane (360-365).
Carbenoxolone (CEX), a semi-synthetic derivative of glycyrrhetinic acid, has previously been used as a disodium salt for the management of dyspepsia and peptic ulcer because of its anti-inflammatory properties. Although glycyrrhetinic acid is available in pharmaceutical and personal care products for skin care, the topical use of the free acid form of CEX, has not previously been reported. In this work we investigated the percutaneous penetration of CEX. Solubility and permeability studies were conducted using a range of solvents or skin permeation enhancers (SPEs) commonly used for skin delivery. Binary combinations of dimethyl isosorbide (DMI) and Transcutol™ (TC) with isopropyl myristate (IPM) were effective in promoting skin permeation of CEX although individual solvents were not. Alternative fatty acid esters to IPM were subsequently investigated with the most promising formulation consisting of TC and propylene glycol laurate (PGL). Interestingly, propylene glycol monolaurate (PGML) did not demonstrate comparable efficacy when combined with TC. A ternary formulation consisting of TC, PGL and IPM demonstrated the best permeation enhancement of CEX compared with all other vehicles. The findings confirm (i) the feasibility of promoting CEX penetration across the skin (ii) the synergistic effect of combinations of solvents and SPEs on dermal and transdermal delivery (iii) the necessity for more fundamental studies to explain the differential effects of fatty acid esters on the skin barrier.
Keywords: Carbenoxolone; Solvents; Skin penetration enhancers; Synergy; Formulation;

DSC curves for PP and MT and their binary mixtures with variable composition.Solid–liquid equilibrium (SLE) for binary mixture of Propafenone Hydrocloride (PP) with Metoprolol Tartrate (MT) was investigated using differential scanning calorimetry (DSC) and corresponding activity coefficients were calculated. Simple eutectic behavior for this system was observed. The excess thermodynamic functions: G E and S E for the pre-, post-, and eutectic composition have been obtained using the computed activity coefficients data of the eutectic phase with their excess chemical potentials μ i E (i  = 1, 2). The experimental solid–liquid phase temperatures were compared with predictions obtained from available eutectic equilibrium models. The results indicate non-ideality in this mixture.Also, the compatibility of each component and their eutectic mixture with usual excipients was investigated, and the DSC experiments indicate possible weak interactions with α-lactose monohydrate and compatibility with corn starch. The results obtained were confirmed by FT-IR measurements.
Keywords: Phase equilibrium; Thermochemistry; DSC; Eutectic; Excipient compatibility;

Development of an ex vivo retention model simulating bioadhesion in the oral cavity using human saliva and physiologically relevant irrigation media by Katrine D. Madsen; Camilla Sander; Stefania Baldursdottir; Anne Marie L. Pedersen; Jette Jacobsen (373-381).
In recent years, there has been a particular interest in bioadhesive formulations for oromucosal drug delivery as this may promote prolonged local therapy and enhanced systemic effect. Saliva plays a vital role in oromucosal drug absorption by dissolving the drug and presenting it to the mucosal surface. However, the rheological, chemical, and interfacial properties of this complex biological fluid may strongly affect the adhesion of bioadhesive formulations. There is a need for well characterized in vitro models to assess the bioadhesive properties of oral dosage forms for administration in the oral cavity. Thus we aimed at developing an advanced ex vivo buccal retention model, with focus on choosing a physiologically relevant irrigation media closely resembling human saliva. Spray dried chitosan microparticles containing metformin hydrochloride as an example of a small hydrophilic drug, were employed as bioadhesive formulations. Chewing-stimulated human whole saliva was collected and characterized for use in retention studies in comparison with four artificial irrigation media; phosphate buffer, Saliva Orthana®, porcine gastric mucin base media (PGM3), and xanthan gum based media (XG2). Retention of metformin, applied as spray dried microparticles on porcine buccal mucosa, greatly depended on the characteristics of the irrigation media. When rheology of the irrigation media was examined, changes in retention profiles could be interpreted, as irrigation media containing mucin and xanthan gum possessed a higher viscosity than phosphate buffer, which led to longer retention of the drug due to better hydration of the mucosa and the spray dried microparticles. Metformin retention profiles were comparable when human saliva, Saliva Orthana®, or PGM3 were used as irrigation media. Moreover, PGM3 displayed physico-chemical properties closest to those of human saliva with regard to pH, protein content and surface tension. Saliva Orthana® and PGM3 are therefore considered as suitable irrigation media for further retention studies.
Keywords: Whole saliva; Bioadhesion; Buccal; Retention model; Metformin hydrochloride; Saliva substitute;

Characterization of antibody–polyol interactions by static light scattering: Implications for physical stability of protein formulations by Shermeen A. Abbas; Vikas K. Sharma; Thomas W. Patapoff; Devendra S. Kalonia (382-389).
In this study, the nature of interactions between monoclonal antibodies and polyols was studied using static light scattering. Solutions of mAb-U and mAb-P (4–12 mg/mL) were analyzed using static light scattering in buffer, 10% w/v trehalose and ethylene glycol solutions at pH 5.0, 7.0 and 9.0. Mechanical stress studies were conducted by shaking the mAb-U solutions (5 mg/mL, pH 5.0, 7.0 and 9.0) and mAb-P solutions (5 mg/mL, pH 7.0) at 200 rpm for 5 days at 25 °C. Addition of trehalose and ethylene glycol resulted in a decrease in the attractive interactions between mAb-U molecules at pH 7.0 and 9.0, and at pH 9.0 between mAb-P molecules. At a higher ionic strength (300 mM, pH 5.0) trehalose and ethylene glycol decreased attractive interactions for both mAbs. Mechanical stress studies showed higher aggregation of mAb-U in trehalose solutions than ethylene glycol and buffer solutions at pH 7.0 and 9.0. A converse trend was seen for mAb-P at pH 7.0. This study showed that polyols, conformational stabilizers or destabilizers, decrease attractive interactions between protein molecules. The decrease is a result of masking of the hydrophobic sites on a protein as polyols can have favorable hydrophobic interactions with the surface exposed hydrophobic groups.
Keywords: Second osmotic virial coefficient; Static light scattering; Protein solubility; Polyols; Interfacial adsorption;

Preformulation study of methazolamide for topical ophthalmic delivery: Physicochemical properties and degradation kinetics in aqueous solutions by Sunmin Jiang; Fengzhen Wang; Shuning Zhu; Xiumei Zhang; Zhigang Guo; Rui Li; Qunwei Xu (390-393).
Methazolamide (MTZ) is an anti-glaucoma drug. The present paper aims to characterize the physicochemical properties and degradation kinetics of MTZ to provide a basis for topical ophthalmic delivery. With the increase in pH (pH 5.5–8.0) of aqueous solution, the solubility of the compound increased while the partition coefficient (Ko/w) which was estimated in the system n-octanol/aqueous solution decreased. The degradation of MTZ in aqueous solution followed pseudo-first-order kinetic. The degradation rate k pH is the rate in the absence of buffer catalysis. Plotting the natural logarithm of k pH versus the corresponding pH value gave a V-shaped pH-rate profile with a maximum stability at pH 5.0. The degradation rate constants as a function of the temperature obeyed the Arrhenius equation (R 2  = 0.9995 at pH 7.0 and R 2  = 0.9955 at pH 9.0, respectively). A decrease in ionic strength and buffer concentration displayed a stabilizing effect on MTZ. Buffer species also influenced the MTZ hydrolysis. Phosphate buffer system was more catalytic than tris and borate buffer systems. In brief, it is important to consider the physicochemical properties and the stability of MTZ during formulation.
Keywords: Methazolamide; Solubility; Partition coefficient; Degradation; Stability;