International Journal of Pharmaceutics (v.292, #1-2)
TITLE PAGE (EDI BOARD) (iii).
Design and process aspects of laboratory scale SCF particle formation systems by Chandra Vemavarapu; Matthew J. Mollan; Mayur Lodaya; Thomas E. Needham (1-16).
Consistent production of solid drug materials of desired particle and crystallographic morphologies under cGMP conditions is a frequent challenge to pharmaceutical researchers. Supercritical fluid (SCF) technology gained significant attention in pharmaceutical research by not only showing a promise in this regard but also accommodating the principles of green chemistry. Given that this technology attained commercialization in coffee decaffeination and in the extraction of hops and other essential oils, a majority of the off-the-shelf SCF instrumentation is designed for extraction purposes. Only a selective few vendors appear to be in the early stages of manufacturing equipment designed for particle formation. The scarcity of information on the design and process engineering of laboratory scale equipment is recognized as a significant shortcoming to the technological progress. The purpose of this article is therefore to provide the information and resources necessary for startup research involving particle formation using supercritical fluids. The various stages of particle formation by supercritical fluid processing can be broadly classified into delivery, reaction, pre-expansion, expansion and collection. The importance of each of these processes in tailoring the particle morphology is discussed in this article along with presenting various alternatives to perform these operations.
Keywords: Supercritical fluid equipment; SCF; Particle formation; Design; Vendors;
Hydrodynamics-induced variability in the USP apparatus II dissolution test by Jennifer L. Baxter; Joseph Kukura; Fernando J. Muzzio (17-28).
The USP tablet dissolution test is an analytical tool used for the verification of drug release processes and formulation selection within the pharmaceutical industry. Given the strong impact of this test, it is surprising that operating conditions and testing devices have been selected empirically. In fact, the flow phenomena in the USP test have received little attention in the past. An examination of the hydrodynamics in the USP apparatus II shows that the device is highly vulnerable to mixing problems that can affect testing performance and consistency. Experimental and computational techniques reveal that the flow field within the device is not uniform, and dissolution results can vary dramatically with the position of the tablet within the vessel. Specifically, computations predict sharp variations in the shear along the bottom of the vessel where the tablet is most likely to settle. Experiments in which the tablet location was carefully controlled reveal that the variation of shear within the testing device can affect the measured dissolution rate.
Keywords: Dissolution testing; Hydrodynamics; USP apparatus II; Shear; Computational fluid dynamics;
Determination of the in vitro disintegration profile of rapidly disintegrating tablets and correlation with oral disintegration by G. Abdelbary; C. Eouani; P. Prinderre; J. Joachim; Jp. Reynier; Ph. Piccerelle (29-41).
The assessment of the in vitro disintegration profile of rapidly disintegrating tablets (RDT) is very important in the evaluation and the development of new formulations of this type. So far neither the US Pharmacopoeia nor the European Pharmacopoeia has defined a specific disintegration test for RDT; currently, it is only possible to refer to the tests on dispersible or effervescent tablets for the evaluation of RDT's disintegration capacity. In the present study, we have evaluated the disintegration profile of RDT manufactured by main commercialised technologies, using the texture analyser (TA). In order to simulate as much as possible the oral disintegration of these dosage forms, a new operating structure was developed. This structure mimics the situation in the patient's mouth and provides a gradual elimination of the detached particles during the disintegration process. The obtained time–distance profiles or disintegration profiles enabled the calculation of certain quantitative values as the disintegration onset (t 1) and the total disintegration time (t 2). These values were used in the characterisation of the effect of test variables as the disintegration medium and temperature on the disintegration time of RDT. Moreover, the oral disintegration time of the same products was evaluated by 14 healthy volunteers. Results obtained when artificial saliva at 37 °C was employed as disintegration medium were used to correlate the in vitro (t 2) and oral disintegration times. Excellent correlation was found and in addition, we were able to achieve a qualitative measure of the mouthfeel by comparing the thickness of the tablets and the penetration distance obtained from the disintegration profile. This method also permitted the discrimination between different RDT, where differences in the disintegration mechanism were reflected on the disintegration profile achieved for each tablet.
Keywords: Rapidly disintegrating tablets; In vitro disintegration profile; Texture analyser; Oral disintegration;
PLA-PEG particles as nasal protein carriers: the influence of the particle size by A. Vila; A. Sánchez; C. Évora; I. Soriano; O. McCallion; M.J. Alonso (43-52).
Previous studies have shown that PLA-PEG nanoparticles (NP) are able to enhance the transport of the encapsulated model protein, tetanus toxoid (TT), across the rat nasal mucosa. The aim of this work was to study if the size of PLA-PEG particles affects the nasal transport of the encapsulated protein and, also, the potential contribution of blank nanoparticles to the transport of the free protein. To achieve this purpose, 125I-TT was encapsulated into PLA-PEG particles of different sizes (200 nm, 1.5, 5 and 10 μm) prepared by the water-in-oil-in-water solvent evaporation technique. Firstly, in order to investigate the carrier role of the particles, two series of either conscious or anaesthetized rats were nasally treated with 125I-TT-loaded NP, free 125I-TT, and a physical mixture of blank NP and free 125I-TT. Secondly, the influence of the particle size on the nasal transport of TT encapsulated into PLA-PEG particles was evaluated in conscious rats. The amount of radioactivity recovered in the blood compartment, lymph nodes and other relevant tissues was monitored for up to 24 h. Finally, the nasal bioavailability of 125I-TT-loaded PLA-PEG NP was calculated. The results indicated that the use of anaesthesia enhances the transport of 125I-TT and that the physical presence of PLA-PEG NP does not affect the transport of the toxoid. In contrast, when TT was encapsulated into the particles its transport across the nasal mucosa of conscious rats was significantly enhanced. Furthermore, the efficacy of this transport was related to the particle size, reaching the most important transport for the smallest particle size. The intensity of this transport was also illustrated by the high nasal bioavailability of TT encapsulated into nanoparticles (200 nm) (F = 70–80%). These results led us to conclude that PLA-PEG NP can be accepted as nasal protein carriers for nasal administration.
Keywords: PLA-PEG; Microparticles (MP); Nanoparticles (NP); Nasal administration; Protein delivery; Vaccine delivery;
Rheological characterization of Microcrystalline Cellulose/Sodiumcarboxymethyl cellulose hydrogels using a controlled stress rheometer: part I by Varma S. Rudraraju; Christy M. Wyandt (53-61).
Rheological properties of two different commercial grades of Microcrystalline Cellulose/Sodiumcarboxymethyl Cellulose (MCC/NaCMC) hydrogels were investigated. A controlled stress rheometer fitted with parallel plate geometry was used. Application of the Cross Model relating the viscosity and shear rate data indicated the gels are extremely shear thinning. The two grades of Avicel (RC-591 and CL-611) made of varying MCC and NaCMC concentrations, exhibited distinguishable changes in yield stress and shear thinning behavior attributable to the individual composition. The hydrogels reached structural equilibrium in 1 week after manufacture. Lot to lot variability of Formula A hydrogels had minimal influence on the rheological properties of the resulting hydrogels. The yield stress and/or initial viscosity values observed were proportional to the concentration or phase volume of the MCC/NaCMC in water.
Keywords: Microcrystalline Cellulose; Oscillatory testing; Rheology; Shear thinning; Sodiumcarboxymethyl Cellulose; Structure build up and yield stress;
Rheology of Microcrystalline Cellulose and Sodiumcarboxymethyl Cellulose hydrogels using a controlled stress rheometer: part II by Varma S. Rudraraju; Christy M. Wyandt (63-73).
Rheological properties of two different commercial grades of Microcrystalline Cellulose/Sodiumcarboxymethyl Cellulose (MCC/NaCMC) hydrogels were investigated. Viscoelastic characterization of the hydrogels using a controlled stress rheometer revealed that structure formation in the gels could be detected at a concentration as low as 1.0% w/w MCC/NaCMC in purified water. The elastic modulus (G′) and the linear viscoelastic region (LVR) increased with increase in hydrogel concentration. The frequency sweep study of the hydrogels exhibited a flat G′, indicating a stable structure at 1.5% w/w and 2.0% w/w concentrations. The oscillation time sweep study indicated that the rate of structure build up was dependent on the concentration of hydrogel. Structure buildup at various temperatures indicated that structure formation was rapid at higher temperature (40 °C), and the gel point was reached fairly quickly. Phase volume of the hydrogel significantly influenced structural recovery at different temperatures.
Keywords: Microcrystalline Cellulose; Sodiumcarboxymethyl Cellulose; Yield stress; Oscillatory testing; Rheology; Shear thinning; Structure build up;
Analysis of macromolecular changes and drug release from hydrophilic matrix systems by Shahla Jamzad; Lara Tutunji; Reza Fassihi (75-85).
The influence of water-soluble and insoluble excipients on dynamics of hydration, front movement, erosion, and drug release from hydrophilic matrix tablets containing water-soluble drug was studied. Tablets were manufactured by direct compression, and their un-constrained swelling behavior and gel strength were assessed with a texture analyzer. Dissolution was performed using USP 26 apparatus II modified by insertion of a mesh to prevent sticking of tablets to the bottom of the vessel and to allow free three-dimensional matrix swelling. Significant release differences between tablet batches were observed and this was consistent with changes in swelling rate, gel thickness, and swelling front movement within the tablets. Matrices containing approximately 30% drug load and water-soluble lactose, demonstrated more pronounced swelling front movement and hence drug release relative to the matrix tablets containing dicalcium phosphate dihydrate. The observed differences in release were verified by calculating the similarity and difference factors. The interdependence of front movement and mass erosion in relation to excipient types on progression of swelling front movement and alteration of water penetration, erosion, and drug release are explained. It is concluded that unlike in conventional dosage forms inclusion of excipients in hydrophilic controlled-release tablets containing water-soluble drugs should be carefully analyzed as their various physico-chemical properties may have significant implications on swelling dynamics, front movement, drug release kinetics, and consequently in vivo performance.
Keywords: Non-ionizable soluble and insoluble excipients; Release kinetics; Swelling dynamics; HPMC; Monolithic matrix systems; Front movement determination;
Solubility of drugs in aqueous solutions by E. Ruckenstein; I. Shulgin (87-94).
This paper is devoted to the verification of the quality of experimental data regarding the solubility of sparingly soluble solids, such as drugs, environmentally important substances, etc. in mixed solvents. A thermodynamic consistency test based on the Gibbs–Duhem equation for ternary mixtures is suggested. This test has the form of an equation, which connects the solubilities of the solid, and the activity coefficients of the constituents of the solute-free mixed solvent in two mixed solvents of close compositions.The experimental data regarding the solubility of sparingly soluble substances can be verified with the suggested test if accurate data for the activity coefficients of the constituents of the solute-free mixed solvent are available.The test was applied to a number of systems representing the solubilities of sparingly soluble substances in mixed solvents. First, the test was scrutinized for four nonaqueous systems for which accurate solubility data were available. Second, the suggested test was applied to a number of systems representing experimental data regarding the solubility of sparingly soluble substances in aqueous mixed solvents.
Keywords: Drug solubility; Mixed solvent; Thermodynamic consistency test;
Dispersion of microemulsion drops in HEMA hydrogel: a potential ophthalmic drug delivery vehicle by Derya Gulsen; Anuj Chauhan (95-117).
Approximately 90% of all ophthalmic drug formulations are now applied as eye-drops. While eye-drops are convenient and well accepted by patients, about 95% of the drug contained in the drops is lost due to absorption through the conjunctiva or through the tear drainage. A major fraction of the drug eventually enters the blood stream and may cause side effects. The drug loss and the side effects can be minimized by using disposable soft contact lenses for ophthalmic drug delivery. The essential idea is to encapsulate the ophthalmic drug formulations in nanoparticles, and disperse these drug-laden particles in the lens material. Upon insertion into the eye, the lens will slowly release the drug into the pre lens (the film between the air and the lens) and the post-lens (the film between the cornea and the lens) tear films, and thus provide drug delivery for extended periods of time. This paper focuses on dispersing stabilized microemulsion drops in poly-2-hydroxyethyl methacrylate (p-HEMA) hydrogels. The results of this study show that the p-HEMA gels loaded with a microemulsion that is stabilized with a silica shell are transparent and that these gels release drugs for a period of over 8 days. Contact lenses made of microemulsion-laden gels are expected to deliver drugs at therapeutic levels for a few days. The delivery rates can be tailored by controlling the particle and the drug loading. It may be possible to use this system for both therapeutic drug delivery to eyes and the provision of lubricants to alleviate eye problems prevalent in extended lens wear.
Keywords: Microemulsions; Ophthalmic drug delivery; Contact lenses; Hydrogel; HEMA;
Effect of lactic acid and iontophoresis on drug permeation across rabbit ear skin by P. Sebastiani; S. Nicoli; P. Santi (119-126).
The aim of this paper was to explore the efficacy of lactic acid as permeation enhancer for drug molecules across the skin. Three model permeants were chosen: acetaminophen (non-ionized), buspirone hydrochloride (cationic drug) and ibuprofen lysine (anionic drug). We also explored the association of lactic acid and iontophoresis as a means of enhancing drug delivery. Permeation experiments were performed in vitro, using rabbit ear skin as barrier. The results obtained indicate that lactic acid has some effects on model drug permeation across the skin. The effect was more evident with the anionic drug ibuprofen. Cathodal intophoresis increased ibuprofen transport, but when lactic acid was associated with cathodal iontophoresis, a concentration-dependent reduction of ibuprofen iontophoretic flux was observed, probably for the competition by the co-ion. The application of electric current (anodal iontophoresis) to a solution of acetaminophen produced an increase in its transport, due to the presence of an electroosmotic contribution; however, the effect of the association of anodal iontophoresis and lactic acid produced no further enhancement.
Keywords: Transdermal; Permeation enhancer; Iontophoresis; Permeability; Skin;
Stability assessment of pharmaceuticals by isothermal calorimetry: two component systems by Cyrus V. Skaria; Simon Gaisford; Michael A.A. O’Neill; Graham Buckton; Anthony E. Beezer (127-135).
Isothermal calorimetry offers the potential to determine rapidly the stability of formulated pharmaceuticals because it is indifferent to physical form and sensitive enough to detect extremely small powers; ca. 50 nW at 25 °C. However, its use in this area is not widespread, principally because the power–time data obtained often comprise contributions from more than one process and are thus difficult to analyse quantitatively. In this work, we demonstrate how power–time data recorded for systems in which two components are degrading in parallel (in this case, binary mixtures of selected parabens) can be analysed using a kinetic-based model; the methodology allows the determination of the first-order rate constant and reaction enthalpy for each process, so long as one rate constant is at least twice the magnitude of the other. It was found that the reactions did not need to run to completion in order for the analysis to be successful; a minimum of 15 min of data were required for samples with one degrading component and a minimum of 4 h of data were required for samples with two degrading components. It was observed that the rate constants for paraben degradation in binary systems were significantly lower than expected. This was ascribed to the fact that the parabens degrade to a common product and is an important factor that should be accounted for when the two or more parabens are formulated together.
Keywords: Isothermal calorimetry; Microcalorimetry; Degradation kinetics; Stability assessment; Methyl paraben; Ethyl paraben; Propyl paraben;
The use of colloidal microgels as a (trans)dermal drug delivery system by V. Castro Lopez; J. Hadgraft; M.J. Snowden (137-147).
A co-polymer of poly(N-isopropylacrylamide) (85%) co-butyl acrylate (10%) co-methacrylic acid (5%) (NIPAM/BA/MAA) (85/10/5) microgel was synthesised and investigated as a potential pH and temperature sensitive transdermal delivery device. Three compounds having different octanol/water partition coefficients and solubilities were incorporated into the microgel, namely: salicylamide (SA), methyl paraben (MP) and propyl paraben (PP). Physico-chemical characterisation of these microgel–drug complexes showed that microgels incorporating MP and SA have smaller volumes after changing environmental pH or temperature when compared with the co-polymer NIPAM/BA/MAA (85/10/5) alone. This reduction in volume could be attributed to the incorporation of the compounds into the microgel particles, having a shielding effect on the charged groups present within the network. Diffusion studies, across human skin, were performed at 305 K in the range of pH 3–7 for saturated solutions of SA, MP and PP, and for microgel particles incorporating the three compounds. The transport rate for these microgels incorporating MP was reduced by 2/3-fold compared to the saturated solution, by one order of magnitude for PP, meanwhile the transport rate for these microgels incorporating SA is the same order of magnitude as that for the corresponding saturated solutions. Transdermal release studies of the saturated colloidal dispersions indicated that pH control of the drug release was marginal. The incorporation of compounds into the pH/temperature sensitive co-polymer NIPAM/BA/MAA (85/10/5) and the subsequent release depends on the octanol/water partition coefficient and solubility of the respective compound.
Keywords: Microgel particles; pH/temperature sensitive; Transdermal drug delivery; Octanol/water partition coefficient; Solubility;
Enhanced paclitaxel bioavailability after oral coadministration of paclitaxel prodrug with naringin to rats by Jun-Shik Choi; Sang-Chul Shin (149-156).
The aim of this study was to investigate the effect of naringin on the bioavailability and pharmacokinetics of paclitaxel after oral administration of paclitaxel or its prodrug coadministered with naringin to rats. Paclitaxel (40 mg/kg) and prodrug (280, 40 mg/kg paclitaxel equivalent) were coadministered orally to rats with naringin (1, 3, 10 and 20 mg/kg).The plasma concentrations of paclitaxel coadministered with naringin increased significantly (p < 0.01 at paclitaxel, p < 0.05 at prodrug) compared to the control. The areas under the plasma concentration–time curve (AUC) and the peak concentrations (C max) of paclitaxel with naringin significantly higher (p < 0.01) than the control. The half-life (t 1/2) was significantly (p < 0.05) longer than the control. The absolute bioavailability (AB, %) of paclitaxel with naringin was significantly higher (3.5–6.8%, p < 0.01) than the control (2.2%). Absorption rate constant (K a) of paclitaxel with naringin increased, but not significantly. The AUC of paclitaxel after coadministration of prodrug with naringin to rats was significantly (p < 0.05) higher than the prodrug control. The relative bioavailability (RB, %) of paclitaxel after coadministration of prodrug with naringin was 1.35–1.69-fold higher than prodrug control. The absolute bioavailability (AB, %) of paclitaxel after coadministration of prodrug with naringin increased significantly (p < 0.05) from 6.6 to 9.0% and 11.2%. The bioavailability of paclitaxel coadministered as a prodrug with or without naringin was remarkably higher than the control. Paclitaxel prodrug, a water-soluble compound concerning with its physicochemical properties, passes through the gastrointestinal mucosa more easily than paclitaxel without obstruction of P-gp and cytochrome P-450 in the gastrointestinal mucosa. Oral paclitaxel preparations which is more convenient than the IV dosage forms could be developed with a prodrug form with naringin.
Keywords: Paclitaxel; Prodrug; Naringin; Pharmacokinetic; Bioavailability; Coadministration;
Stable ciliary activity in human nasal epithelial cells grown in a perfusion system by S. Dimova; V. Vlaeminck; M.E. Brewster; M. Noppe; M. Jorissen; P. Augustijns (157-168).
Explore the usefulness of a perfusion system in order to establish human nasal epithelial cell cultures suitable for long-term in vitro ciliary beat frequency (CBF) and cilio-toxicity studies.The cells were obtained by protease digestion of nasal biopsy material. The cells were plated at a density of 0.8–1 × 106/cm2 on Vitrogen-coated polyethylene terephthalate membranes, and cultured under submerged conditions in a CO2 incubator or in a perfusion system (initiated on days 8–9 after plating). The CBF was determined at 24.1 ± 0.8 °C by a computerized microscope photometry system. The morphology of the cultured cells was characterized by transmission electron microscopy (TEM).Under CO2 incubator culture conditions, stable ciliary activity was expressed and maintained from day 2 to day 24. Under perfusion system culture conditions, the CBF (mean ± S.D., n = 4) amounted to 8.4 ± 0.9 and 8.8 ± 0.4 Hz on days 7 and 14, respectively. These values were lower as compared to the corresponding CBF obtained in the CO2 incubator cultures (9.5 ± 0.6 and 9.9 ± 1.0 Hz, respectively). Reference cilio-stimulatory (glycocholate) and cilio-inhibitory (chlorocresol) compounds were used to assess CBF reactivity. In the CO2 incubator and 7- and 14-days perfusion system cultures, glycocholate (0.5%) showed a reversible cilio-stimulatory effect of 23, 26 and 21%, respectively, while chlorocresol (0.005%) exerted a reversible cilio-inhibitory effect of 36, 40 and 36%, respectively. TEM revealed polarized cuboidal to columnar epithelial morphology, with well-differentiated ciliated cells under CO2 and perfusion system conditions (up to day 23).Culturing human nasal epithelial cells on Vitrogen-coated polyethylene terephthalate membranes in submerged conditions in a CO2 incubator and in a perfusion system offers the possibility for long-term preservation (up to 22–24 days) of stable and reactive CBF in vitro.
Keywords: Human nasal epithelial cells; Ciliary beat frequency; Perfusion system;
Bioadhesive oesophageal bandages: protection against acid and pepsin injury by Man Tang; Peter Dettmar; Hannah Batchelor (169-177).
The rate of acid and pepsin diffusion through solutions of sodium alginate was measured using in vitro techniques. Previous work has demonstrated that solutions of alginate may adhere to the oesophagus for up to 60 min; this work measured their ability to protect the oesophageal epithelial surface from damage caused by refluxed acid and pepsin. Franz diffusion cells were used to measure the rate of acid and pepsin diffusion through an alginate layer. The effect of the type of alginate, alginate concentration and depth of alginate applied were investigated. The rate of both acid and pepsin diffusion was significantly reduced (ANOVA analysis; P < 0.05) in the presence of an alginate solution compared to the control. A 2% (w/v) alginate solution with a high guluronic acid component, in a layer of 0.44 mm depth, demonstrated the greatest reduction in acid diffusion with a permeation coefficient 14% than that of a control value. All three alginates demonstrated significant reductions in acid diffusion with both increasing depth and increasing concentration, as expected. Pepsin diffusion was also significantly reduced as the depth and concentration of applied alginate increased. This study demonstrates that an adhesive layer of alginate present within the oesophagus will limit the contact of refluxed acid and pepsin with the epithelial surface.
Keywords: Alginate; Oesophagus; Gastro-oesophageal reflux disease; Acid diffusion; Pepsin diffusion;
Drug interaction and location in liposomes: correlation with polar surface areas by G.M.M. El Maghraby; A.C. Williams; B.W. Barry (179-185).
An important step in liposome characterization is to determine the location of a drug within the liposome. This work thus investigated the interaction of dipalmitoylphosphatidylcholine liposomes with drugs of varied water solubility, polar surface area (PSA) and partition coefficient using high sensitivity differential scanning calorimetry. Lipophilic estradiol (ES) interacted strongest with the acyl chains of the lipid membrane, followed by the somewhat polar 5-fluorouracil (5-FU). Strongly hydrophilic mannitol (MAN) showed no evidence of interaction but water soluble polymers inulin (IN) and an antisense oligonucleotide (OLG), which have very high PSAs, interacted with the lipid head groups. Accordingly, the drugs could be classified as: hydrophilic ones situated in the aqueous core and which may interact with the head groups; those located at the water–bilayer interface with some degree of penetration into the lipid bilayer; those lipophilic drugs constrained within the bilayer.
Keywords: Liposomes; High sensitivity differential scanning calorimetry; Polar surface areas; Drug–liposome interaction.;
Cutaneous bioassay of salicylic acid as a keratolytic by S.J. Bashir; F. Dreher; A.L. Chew; H. Zhai; C. Levin; R. Stern; H.I. Maibach (187-194).
Keratolytic efficacy of topical preparations containing salicylic acid was studied in humans utilizing adhesive tape stripping and quantifying SC removal by protein analysis. In combination with tape stripping, squamometry was used to evaluate the influence of salicylic acid on skin surface scaliness and desquamation. Furthermore, skin barrier perturbation and skin irritancy was recorded and related to the dermatopharmacological effect of the preparations. In contrast to squamometry, tape stripping combined with protein analysis was sensitive in detecting keratolytic effect of salicylic acid within hours of application. Importantly, whereas the pH of the preparations only minimally influenced efficacy, local dermatotoxicity was significantly increased at acidic pH. This indicates that the quest to increase the amount of free, non-dissociated SA is, in fact, counterproductive as the more acidic preparations resulted in skin irritation and barrier disruption.
Keywords: Hydroxy acid; Adhesive tape stripping; Skin physiology; Stratum corneum quantification; Protein assay; Dermatotoxicity;
Microbiological assay of ketoconazole in shampoo by Inara Staub; Elfrides E.S. Schapoval; Ana M. Bergold (195-199).
Ketoconazole, an anti-fungal agent, is often incorporated in several pharmaceutical forms and in shampoo formulation it is known to be effective against fungal infection on the scalp. This paper describes a method to quantify ketoconazole in shampoo by comparing the cylinder plate assay and the HPLC method. The test organism used for the agar diffusion assay was Candida albicans ATCC 10231. Three different concentrations of ketoconazole were used for the diffusion assay. A mean zone diameter was obtained for each concentration. A standard curve was obtained by plotting the three values derived from the zone diameters. A prospective validation of the method showed that the method was linear (r = 0.9982), precise (R.S.D. = 2.57%) and accurate. The results obtained by the two methods were statistically evaluated by analysis of variance (ANOVA) and the results obtained indicate that there is no significant difference between these two methods.
Keywords: Ketoconazole shampoo; Microbiological assay; Cylinder-plate method; Candida albicans;
A comparison of two methods to determine the solubility of compounds in aerosol propellants by Abhishek Gupta; Paul B. Myrdal (201-209).
A new on-line reverse phase HPLC method for determining the solubility of compounds in propellant based metered dose inhaler (MDI) formulations was compared with a conventional method. The new method employs a direct injection from a MDI vial into the needle injector port of a manual injector. To evaluate the two methods, beclomethasone dipropionate (BDP), 5,5-diphenyl hydantoin and 3,3′-diindolylmethane, were used as model compounds in propellant HFA-134a. Comparison was performed by analyzing known and unknown concentrations of BDP in various combinations of HFA-134a and ethanol. In addition, the solubility of 5,5-diphenyl hydantoin and 3,3′-diindolylmethane were determined in HFA-134a using both the new and the conventional methods. The two methods were found to be in good agreement with each other, with the new direct injection technique offering enhanced precision and accuracy along with considerable reduction in analysis time.
Keywords: Solubility; Aerosols; Propellant; Metered dose inhalers; Direct injection method; HFA-134a; HPLC; Comparison;
Particle size distribution and evolution in tablet structure during and after compaction by Frauke Fichtner; Åke Rasmuson; Göran Alderborn (211-225).
The objective of this study was to investigate the effect of the distribution in size of free-flowing particles for the evolution in tablet structure and tablet strength. For sucrose and sodium chloride, three powders of different size distributions were prepared by mixing predetermined quantities of particle size fractions. For paracetamol, three batches with varying particle size distributions were prepared by crystallisation. The powders were formed into tablets. Tablet porosity and tensile strength were determined directly after compaction and after short-term storage at two different relative humidities. Tablets were also formed after admixture of a lubricant (magnesium stearate) and the tablet tensile strength was determined. For the test materials used in this study, the spread in particle size had no influence on the evolution in tablet porosity and tensile strength during compression. However, the spread in particle size had a significant and complex influence on the short-term post-compaction increase in tablet tensile strength. The effect of the spread was related to the instability mechanism and the presence of lubricant. It is concluded that the distribution in size of free-flowing particles is not critical for the tablet porosity but may give significant effects on tablet tensile strength due to a post-compaction reaction.
Keywords: Particle size distribution; Tablet tensile strength; Tablet porosity; Storage; Relative humidity; Lubricant;
The use of microviscometry to study polymer dissolution from solid dispersion drug delivery systems by Solmaz Esnaashari; Yousef Javadzadeh; Hannah K. Batchelor; Barbara R. Conway (227-230).
Solid dispersions can be used to improve dissolution of poorly soluble drugs and PVP is a common polymeric carrier in such systems. The mechanisms controlling release of drug from solid dispersions are not fully understood and proposed theories are dependent on an understanding of the dissolution behaviour of both components of the dispersion. This study uses microviscometry to measure small changes in the viscosity of the dissolution medium as the polymer dissolves from ibuprofen–PVP solid dispersions. The microviscometer determines the dynamic and kinematic viscosity of liquids based on the rolling/falling ball principle. Using a standard USP dissolution apparatus, the dissolution of the polymer from the solid dispersion was easily measured alongside drug release. Drug release was found to closely follow polymer dissolution at the molecular weights and ratios used. The combination of sensitivity and ease of use make microviscometry a valuable technique for the elucidation of mechanisms governing drug release from polymeric delivery systems.
Keywords: Solid dispersion; Microviscometry; Polymer dissolution; Ibuprofen; Polyvinylpyrrolidone;
Induction of apoptosis of human lung carcinoma cells by hybrid liposomes containing polyoxyethylenedodecyl ether by Yasunori Iwamoto; Yoko Matsumoto; Ryuichi Ueoka (231-239).
Hybrid liposomes can be prepared by simply ultrasonicating a mixture of vesicular and micellar molecules in aqueous solution. A clear solution of hybrid liposomes composed of 90 mol% dimyristoylphosphatidylcholine (DMPC) and 10 mol% polyoxyethylene(23)dodecyl ether (C12(EO)23) having a hydrodynamic diameter of 100–120 nm was obtained. Highly inhibitory effects of hybrid liposomes of 90 mol% DMPC/10 mol% C12(EO)23 on the growth of human lung carcinoma (RERF-LC-OK and A549) cells without any drugs were obtained. Induction of apoptosis by hybrid liposomes in RERF-LC-OK and A549 cells was verified on the basis of fluorescence microscopy, agarose gel electrophoresis of DNA and flow cytometry. We elucidated the pathway of apoptosis induced by hybrid liposomes as follows: (a) accumulation of hybrid liposomes in tumor cell membrane was revealed using microphysiometer. (b) Reduction of mitochodrial membrane potential and activation of caspase-9, -3 and -8 were obtained, indicating that apoptotic signal by hybrid liposomes should pass through mitochondria and these caspases. It is worthy to note that such a novel mechanism of apoptosis induced by hybrid liposomes without any drugs was performed for the first time in human lung carcinoma cells.
Keywords: Hybrid liposomes; Lung carcinoma; Apoptosis; Caspase; Antitumor effect;