International Journal of Pharmaceutics (v.321, #1-2)
Editorial Board (iii).
A century of dissolution research: From Noyes and Whitney to the Biopharmaceutics Classification System by Aristides Dokoumetzidis; Panos Macheras (1-11).
Dissolution research started to develop about 100 years ago as a field of physical chemistry and since then important progress has been made. However, explicit interest in drug related dissolution has grown only since the realisation that dissolution is an important factor of drug bioavailability in the 1950s. This review attempts to account the most important developments in the field, from a historical point of view. It is structured in a chronological order, from the theoretical foundations of dissolution, developed in the first half of the 20th century, and the development of a relationship between dissolution and bioavailability in the 1950s, going to the more recent developments in the framework of the Biopharmaceutics Classification System (BCS). Research on relevant fields of pharmaceutical technology, like sustained release formulations, where drug dissolution plays an important role, is reviewed. The review concludes with the modern trends on drug dissolution research and their regulatory implications.
Keywords: Drug dissolution; Bioavailability; Drug release;
On the misinterpretation of the correlation coefficient in pharmaceutical sciences by J.M. Sonnergaard (12-17).
The correlation coefficient is often used and more often misused as a universal parameter expressing the quality in linear regression analysis. The popularity of this dimensionless quantity is evident as it is easy to communicate and considered to be unproblematic to comprehend. However, illustrative examples will demonstrate that the correlation coefficient is highly ineffective as a stand-alone quantity without reference to the number of observations, the pattern of the data and the slope of the regression line. Much more efficient quality methodologies are available where the correct technique depends on the purpose of the investigation. These relevant and precise methods in quality assurance of linear regression as alternative to the correlation coefficient are presented.
Keywords: Methodology; Mathematical models; Regression; Correlation; Functional relationship;
Kinetic study of the transformation of mefenamic acid polymorphs in various solvents and under high humidity conditions by Fumie Kato; Makoto Otsuka; Yoshihisa Matsuda (18-26).
The transformation kinetics of mefenamic acid form II to form I in three kinds of solvents and under high humidity conditions were extensively investigated. Form II crystals were suspended in water, 50% ethanol and ethanol at 28, 33 and 37 °C, or stored at 50, 60 and 70 °C at 97% RH. Form II transformed to form I under all storage conditions and the rate of transformation depended on the kind of solvent. The transformation followed the three-dimensional nuclei growth mechanism, depending on temperature. The nuclei formation and growth processes were significantly accelerated in ethanol compared with water. The addition of seed crystals of the stable form I shortened the both nuclei formation and growth processes and therefore the transformation was accelerated.
Keywords: Mefenamic acid; Polymorphism; Solid-state transformation; Kinetic analysis;
Crystal modification of dipyridamole using different solvents and crystallization conditions by R. Adhiyaman; Sanat Kumar Basu (27-34).
Dipyridamole crystals having different types of habits, improved dissolution rate were prepared by recrystallization from selected solvents, such as acetonitrile, benzene and methanol (Method I); crystals have also been made by solvent change using methanolic solution of dipyridamole in the presence of 2% solutions of Tween-80, Povidone K30 and polyethylene glycol (PEG) 4000 (Method II). Scanning electron microscopy, X-ray powder diffractometry, IR spectrometry and differential scanning calorimetry were used to investigate the physicochemical characteristics of the crystals. The comparative dissolution behavior of the newly developed crystals and that of the untreated dipyridamole were also studied. It was found that the newly developed crystals were different from each other with respect to physical properties but are chemically identical. The crystals, obtained (Method I) from benzene and acetonitrile, produced needle shaped crystals and that obtained from methanol produced rectangular shaped crystals. But the crystals obtained (Method II) with the methanolic solution of the drug in the presence of Tween-80, Povidone K30 and PEG-4000 produced smooth needle shaped crystals. X-ray diffraction spectra and differential scanning calorimetry study of the newly developed crystals, clearly indicate that dipyridamole exist in different crystal modification. The dissolution rate of newly developed crystals was found to be greater than the pure drug dipyridamole. Stability studies at 40 °C (75% RH) for 1 month for the modified crystals as well as the pure drug did show some changes in the XRD and DSC but not in IR studies.
Keywords: Dipyridamole; Recrystallization; Physicochemical characterization;
The effects of surfactants on the dissolution profiles of poorly water-soluble acidic drugs by Sung-Hyun Park; Hoo-Kyun Choi (35-41).
The effects of types of surfactants on the solubilization and dissolution of poorly soluble acidic drugs were compared to identify the most suitable surfactant for conducting an acidic drug dissolution test. Cetyltrimethylammonium bromide (CTAB) as a cationic surfactant, sodium lauryl sulfate (SLS) as an anionic surfactant, and polysorbate 80 as a non-ionic surfactant were used in the study. And, mefenamic acid, nimesulide, and ibuprofen were selected as model drugs. The dissolution rates of these acidic drugs were substantially enhanced in medium containing CTAB. Electrostatic interactions between acidic drugs and cationic surfactants were confirmed by measuring UV spectra of each drug. Solubility of drugs in various media and the partition coefficients of drugs into micelles were found to depend on drug characteristics. For acidic drugs, the ability of media containing a cationic surfactant to discriminate rates of dissolution of acidic drugs seemed to be greater than that of media containing other surfactant types.
Keywords: Poorly soluble acidic drug; Dissolution; Surfactant; Cetyltrimethylammonium bromide; Sodium lauryl sulfate; Polysorbate 80;
Inhibition of liver metastasis by all-trans retinoic acid incorporated into O/W emulsions in mice by Narin Chansri; Shigeru Kawakami; Fumiyoshi Yamashita; Mitsuru Hashida (42-49).
All-trans retinoic acid (ATRA) was incorporated into lipid emulsions in an attempt to alter its distribution characteristics and improve its inhibition of liver cancer metastasis. Lipid emulsions composed of egg phosphatidylcholine, cholesterol, and soybean oil were the optimized carriers for ATRA delivery, as shown by the submicron particle size and high incorporation efficiency. The particle size and zeta potential of ATRA incorporated into emulsions were about 133 nm and −11 mV, respectively. In vitro drug release study demonstrated that the release of ATRA from emulsions was sustained in the absence and present of bovine serum albumin, suggesting that ATRA was stable when incorporated in emulsions. After intravenous administration in mice, [3H]cholesteryl hexadecyl ether incorporated into emulsion, which is the inherent distribution of emulsions, accumulated gradually mainly in the liver. The blood concentration and hepatic accumulation of [3H]ATRA incorporated into emulsion was significantly higher than that of serum dissolving [3H]ATRA, which represent the original distribution characteristic of free ATRA. In a murine liver metastasis model by colon adenocarcinoma, the liver metastasis number and liver weight were significantly reduced and the survival time of mice was prolonged following intravenous injection of ATRA incorporated into emulsions.
Keywords: All-trans retinoic acid; Lipid emulsions; Liver metastasis; Biodistribution; Controlled release;
The focused ion beam technique: A useful tool for pharmaceutical characterization by Shadi H. Moghadam; Rassoul Dinarvand; Louis H. Cartilier (50-55).
Focused ion beam (FIB) instrumentation, a hybrid of the scanning electron micrsocope, ion milling and computer-aided design systems, has special uses in the electronic and semiconductor industries as a tool for failure analysis and device development. This paper examines the pharmaceutical applications of the FIB, particularly microscopic analysis of microspheres. With the FIB, microsphere structures were peeled off, layer by layer, and the structure of each layer was simultaneously observed under scanning microscopy. The particles had a wrinkled but non-porous surface. Going deeper, some holes appeared, with size and numbers increasing toward the particle center. This unique method precisely investigated the inner structure of particles, layer by layer. Then, by FIB milling, samples were extracted with an accuracy of localization of 50 nm from specific parts of the microspheres and prepared to a 200 nm uniform thickness film for examination under transmission electron microscopy. The FIB method also has the potential for a wide range of other quantitative and qualitative analysis of dosage forms and materials.
Keywords: Focused ion beam; Microspheres; Ion milling; Microscopy; Image analysis;
Enhanced anti-tumor activity and alleviated hepatotoxicity of clotrimazole-loaded suppository using poloxamer–propylene glycol gel by Chul Soon Yong; Jing Ji Xuan; Seung-Hwan Paek; Yu-Kyoung Oh; Jong-Soo Woo; Mann Hyung Lee; Jung-Ae Kim; Han-Gon Choi (56-61).
To develop a novel clotrimazole-loaded poloxamer-based suppository with enhanced anti-tumor activity and alleviated hepatotoxicity, the melting point of various formulations composed of P 188 and propylene glycol were investigated. The dissolution and anti-tumor activity of clotrimazole delivered by the poloxamer-based suppository was performed. Furthermore, the hepatotoxicity of clotrimazole was carried out after its rectal administration compared to oral administration in mice. The poloxamer mixtures composed of P 188 and propylene glycol were homogeneous phases. P 188 greatly affected the melting point of poloxamer mixtures. In particular, the poloxamer mixture [P 188/propylene glycol (70%/30%)] with the melting point of about 32 °C was a solid form at room temperature and instantly melted at physiological temperature. The ratio of P 188/propylene glycol greatly affected the dissolution rates of clotrimazole from poloxamer-based suppository. Dissolution mechanism analysis showed the dissolution rate of clotrimazole from poloxamer-based suppositories was independent of the time. The clotrimazole-loaded suppository with P 188 and propylene glycol could not irritate or damage the rectal tissues of rats and gave the improved anti-tumor activity in a dose-dependent manner at mouse. Furthermore, its rectal administration decreased the hepatotoxicity compared to oral administration. Thus, the poloxamer-based solid suppository system with clotrimazole/P 188/propylene glycol was an effective rectal dosage form for the treatment of tumors with alleviated adverse effects.
Keywords: Clotrimazole; Poloxamer 188; Suppository; Melting point; Anti-tumor activity; Hepatotoxicity;
Extruded and spheronized beads containing Carbopol® 974P to deliver nonelectrolytes and salts of weakly basic drugs by Ganesh S. Bommareddy; Safak Paker-Leggs; Kalyan K. Saripella; Steven H. Neau (62-71).
The purpose of the study was to explore the utilization of Carbopol® 974P, NF, resin in a bead dosage form manufactured by extrusion and spheronization. It was possible to prepare beads in this study by using calcium chloride to overcome the tack problem associated with wetted Carbopol® 974P. The actives included both salts of weakly basic drugs (chlorpheniramine maleate and diphenhydramine hydrochloride) and nonelectrolytes (caffeine and dyphylline) which have a broad range of solubilities. Nonelectrolytes were released faster than the salts of weakly basic drugs. This is contrary to the behavior typically seen with a matrix system where the more soluble drug is released faster than a poorly soluble one. In the results of the present study, the solubility does not determine the drug release rate. Ionic interactions between the protonated amines of the salts and the carboxylates of the Carbopol resin are suggested to be the reason for the slower release of the salts of weakly basic drugs. Data from tack measurements confirm that this ionic interaction affects the behavior of the wetted Carbopol. In addition to the drug release profiles, bead average diameter, roundness, friability, and density were also determined.
Keywords: Carbopol; Carbomer; Extrusion–spheronization; Pellets; Beads;
Influence of granulation and compaction on the particle size of ibuprofen—Development of a size analysis method by V.N.P. Le; P. Leterme; A. Gayot; M.P. Flament (72-77).
The aim of this work was to study the impact of the process on drug particle size. We chose ibuprofen, practically insoluble in water, as granulometry greatly influences its dissolution rate. We developed an original method using a laser granulometer to assess the size of ibuprofen within a blend before and after granulation and then compression. Wet granulation was performed with a Lodige and a Diosna granulator. The granules were then compressed. The evolution of ibuprofen particle size after these operations was checked. Two grades of ibuprofen differing in size were studied: ibuprofen 25 and ibuprofen 50.After the wet granulation of ibuprofen 50 with a Lodige or a Diosna granulator, a decrease in size was observed. This could be caused by shocks occurring in the granulator. On the other hand, after compression of the granules, ibuprofen particle size increased and was greater than that measured before granulation. Compression could induce some fragmentation of ibuprofen associated with the plastic deformation and then, under pressure, a closeness of the fragments or deformed particles which could bind or associate with one another because the melting point of ibuprofen is not very high.In the case of ibuprofen 25, the same phenomena were observed after compression. But, after granulation, particle size was not modified. There was little breaking of ibuprofen particles in the granulator because they are much smaller than those of ibuprofen 50.This work shows the impact of the process on drug particle size when producing tablets. The method developed made it possible to differentiate and measure the size of ibuprofen particles in a blend.
Keywords: Size analysis; Ibuprofen; Granulation; Compression; Process impact;
The influence of PVP incorporation on moisture-induced surface crystallization of amorphous spray-dried lactose particles by Denny Mahlin; Jonas Berggren; Ulrik Gelius; Sven Engström; Göran Alderborn (78-85).
We have recently shown that atomic force microscopy (AFM) may be an appropriate method for characterisation of the re-crystallization of amorphous particles. In this study, spray-dried composite particles consisting of lactose and polyvinyl pyrrolidon (PVP) were characterised by AFM and electron spectroscopy for chemical analysis (ESCA), and their response on increasing the relative humidity (RH) was investigated. The PVP content in the particles used was 0, 5 or 25 wt.% of either PVP K17 or PVP K90. All composite particles were found to be enriched with PVP at the surface. The incorporation of PVP in the particles influenced the way the particles responded to an increase in RH. The specific RH interval in which the surface of the particles smoothened and the RH where crystallization could be detected, increased with an increase in the amount and molecular weight of the PVP in the particles. The crystallization kinetics of single particles was analysed with AFM and by utilising the JMAK equation. The rate constant for this transformation increased in an exponential manner with increasing RH. Furthermore, above the RH needed for the crystallization to occur, the exponential increase in the crystallization rate was larger for particles with higher polymer content which indicates that the stabilising effect decreases as the water content in the particles becomes higher. In this study we report a method for determination of crystallization kinetics on single composite particles, which is valuable when evaluating the effect of stabilisers in amorphous powders.
Keywords: Lactose; Atomic force microscopy; Crystallization; Rate constant; Spray-dried particles; Electron spectroscopy for chemical analysis;
Colon-specific drug delivery: Influence of solution reticulation properties upon pectin beads performance by O. Chambin; G. Dupuis; D. Champion; A. Voilley; Y. Pourcelot (86-93).
In this study, pectinate gel beads were produced by ionotropic gelation method with different solutions of cross-linking agents and ketoprofen was entrapped as model drug. The influence of these formulation parameters was investigated upon bead properties and upon their performance to target the colon. Zinc pectinate beads obtained with 10% of counter-ions solution at pH 1.6 exhibited the strongest gel network due to “egg-box” dimmer formation helped by hydrogen bonding. Furthermore the gel network formed at low pH was arranged in a compact three-fold conformation. Thus, this matrix structure in enteric capsules induced the lowest drug release in the upper gastro-intestinal tract (pH 1.2 following by pH 7.4). However ketoprofen release occurred specifically in the colon thanks to the presence of pectinolytic enzymes and the release rate can be modulated by the counter-ion concentration during the reticulation process. Therefore this approach using pectinate beads is very promising as efficient carrier for specific delivery of drug into the colon, after oral administration.
Keywords: Colon targeting; Pectinate beads; Low-methoxy pectin; Ionotropic gelation; Cross-linking agents; Cross-linking conditions; Drug release; Ketoprofen;
Spectrophotometric evaluation of stability constants of 1:1 weak complexes from continuous variation data by Ana Sayago; Agustin G. Asuero (94-100).
A bilogarithmic hyperbolic cosine method for the spectrophotometric evaluation of stability constants of 1:1 weak complexes from continuous variation data has been devised and applied to literature data. A weighting scheme, however, is necessary in order to take into account the transformation for linearization. The method may be considered a useful alternative to methods in which one variable is involved on both sides of the basic equation (i.e. Heller and Schwarzenbach, Likussar and Adsul and Ramanathan). Classical least squares lead in those instances to biased and approximate stability constants and limiting absorbance values. The advantages of the proposed method are: the method gives a clear indication of the existence of only one complex in solution, it is flexible enough to allow for weighting of measurements and the computation procedure yield the best value of log β 11 and its limit of error. The agreement between the values obtained by applying the weighted hyperbolic cosine method and the non-linear regression (NLR) method is good, being in both cases the mean quadratic error at a minimum.
Keywords: Stability constants; Weak complexes; Continuous variation; Spectrophotometry;
Solubility and stability of anhydrate/hydrate in solvent mixtures by Haiyan Qu; Marjatta Louhi-Kultanen; Juha Kallas (101-107).
In this paper, the thermodynamics of the anhydrate/dihydrate carbamazepine (CBZA/CBZH) in ethanol–water mixtures was studied by measuring the solubility of anhydrate and dihydrate carbamazepine at 0–60 °C. Both stable form solubility and metastable form solubility were measured, the latter with the assistance of Raman immersion probe. The thermodynamic properties of the anhydrate/dihydrate system, such as the relative stability, and enthalpy and entropy of dissolution, were estimated by plotting the measured solubility data according to the van’t Hoff equation. The anhydrate/dihydrate carbamazepine showed an enantiotropic relationship in the studied mixtures and temperature ranges. It was shown that at a certain temperature, there was an equilibrium water activity value at which the anhydrate and dihydrate carbamazepine were in equilibrium. This equilibrium water activity value depends significantly on the temperature. The lower the temperature, the smaller is the water activity value needed to attain equilibrium between anhydrate and dihydrate. The obtained results are useful in determining crystallization parameters to achieve a desired anhydrate or hydrate phase. The approach can be applied to other anhydrate and hydrate systems.
Keywords: Hydrate; Solubility; Metastable solubility; Carbamazepine; Phase transition; Water activity;
Formation of hollow core granules by fluid bed in situ melt granulation: Modelling and experiments by Mansoor A. Ansari; Frantisek Stepanek (108-116).
Granules with a characteristic core–shell internal structure have been formed by in situ melt fluid-bed granulation, using d-mannitol primary solid particles and poly-ethylene glycol (PEG-6000) binder. The effect of binder particle size and binder/solids ratio on granule size distribution was systematically investigated. The mean granule size was found to be directly proportional to the binder particle size. The binder amount did not measurably affect the granule size, only the fraction of un-granulated fines. The microstructure of the granules was analysed by X-ray micro-tomography; the average shell thickness in the granules was found to depend on the binder/solids ratio, and the core volume was found to be directly proportional to the binder particle size. However, for binder particle size below a certain value the core–shell structure disappeared. A mathematical model based on a layering growth mechanism has been proposed and found to be consistent with experimental data. The proposed growth mechanism was confirmed by creating granules with bi-modal size distribution using a mixture of differently sized binder seeds.
Keywords: Fluid-bed granulation; X-ray micro-tomography; Granule structure; Particle size; Melt binder; Nucleation; Regime separation;
Investigation of microemulsion system for transdermal delivery of meloxicam by Yue Yuan; San-ming Li; Feng-kui Mo; Da-fang Zhong (117-123).
A new oil-in-water microemulsion containing 0.375% meloxicam was developed in order to improve the skin permeability of meloxicam. Among various surfactants and cosurfactants investigated in the microemulsion system, polyoxyethylene sorbitan trioleate (Tween 85) showed excellent solubility and ethanol expressed skin permeation enhancing effect for meloxicam. The microemulsion existence ranges were defined through the construction of the pseudo-ternary phase diagram. The effect of the content of isopropyl myristate (IPM) and the effect of the mass ratio of the surfactant/cosurfactant (Km) on skin permeation of meloxicam were evaluated with excised rat skins. The optimum formulation with the highest skin permeation rate (5.40 μg/cm2/h) consisted of 0.375% meloxicam, 5% IPM, 50% Tween 85/ethanol (1:1) and water.
Keywords: Meloxicam; Microemulsion; Transdermal; IPM; Phase diagram; Skin permeability;
Lipoplexes with biotinylated transferrin accessories: Novel, targeted, serum-tolerant gene carriers by Moganavelli Singh; Arthur Hawtrey; Mario Ariatti (124-137).
Novel transfecting assemblies comprising biotinylated cationic liposomes, DNA and tribiotinylated transferrin-streptavidin (streptavidin(bio3-transferrin)) accessories have been prepared, characterized and evaluated for toxicity and DNA delivery capability in human cervical carcinoma cells (HeLa). Two new lipophilic cholesteryl-based biotin derivatives, biotinylcholesterylformylhydrazide (MSB1) and aminohexanoylbiotinylcholesterylformylhydrazide (MSB2) provided docking points for streptavidin(bio3-transferrin) on cationic liposomes which were formulated with N,N-dimethylaminopropylaminylsuccinylcholesterylformylhydrazide (MS09) and dioleoylphosphatidylethanolamine (DOPE) in a 2:48:50 molar ratio. Ethidium dye displacement assays and gel retardation studies suggest that in ternary complexes, the DNA is electrostatically bound to the cationic liposomes while transferrins remain liposome-bound through streptavidin–biotin interactions. Assemblies fully protected plasmid DNA from serum nuclease digestion over a range of liposome:pGL3 DNA ratios (3–8:1, w/w) and exhibited low growth inhibition of HeLa cells (circa 5%) at the optimal transfection composition for streptavidin(bio3-transferrin):liposome:pGL3 DNA of 10:6:1 (w/w/w). Transfection levels, which were twice those of untargeted lipoplexes containing MSB1 or MSB2, were not significantly diminished in the presence of 10% foetal bovine serum. Excess transferrin (200 μg per well) reduced transfection levels to those of untargeted complexes, supporting the notion that at least 50% of ternary complexes gained entry into the cervical carcinoma cells by receptor mediation. Conversely, transfection levels with untargeted lipoplexes were only slightly reduced in the presence of transferrin at the same concentration.
Keywords: Biotin; Transferrin; Cationic liposome; Transfection; Streptavidin;
HPMC effect on catalyzed hydrolysis of α-naphthyl acetate in cationic micellar systems by Pornpen Werawatganone; Walaisiri Muangsiri; Amaraporn Roopdee (138-142).
Micelle formation is an important property of surfactants. Micellar solutions of cetyltrimethylamonium bromide (CTAB) have been found to accelerate the hydrolysis of α-naphthyl acetate (α-NA) by o-iodosobenzoic acid (IBA), a strong nucleophile. Critical micelle concentration (CMC) of CTAB was determined in the absence and presence of various concentrations and grades of hydroxypropylmethyl cellulose (HPMC) using surface tension measurement. Reaction under pseudo-first-order condition was utilized for rate constant determination. The aggregation of CTAB in the polymer solution started at higher concentration than in the absence of the polymer. The observed rate constants for the degradation of α-NA in the presence of various concentrations of CTAB with and without HPMC were calculated. The presence of HPMC retarded the reaction rate. However, there was no obvious difference in the observed rate constant among the different grades of HPMC (Methocel E50®, Methocel E4M®, Methocel E10M®) while the higher the polymer concentration the lower the rate constant.
Keywords: Micelle; Kinetics; Polymer; Hydroxypropylmethylcellulose; Cetyltrimethylammonium bromide; Hydrolysis;
Uptake characteristics of NGR-coupled stealth PEI/pDNA nanoparticles loaded with PLGA-PEG-PLGA tri-block copolymer for targeted delivery to human monocyte-derived dendritic cells by Stanley Moffatt; Richard J. Cristiano (143-154).
We have investigated the in vitro uptake, toxicity, phenotypic consequences and transfection efficiency of a stealth NGR/PEG/PDBA-coupled-SHA-PEI/pDNA targeting polyplex loaded with PLGA-PEG-PLGA tri-block copolymer in human monocyte-derived dendritic cells (DCs). Modification with PEG effectively shielded and reduced non-specific phagocytosis by immature DCs to approximately 20%. Coupling the NGR cell-specific peptide to the PEGylated polyplex (NGR/PEG/PDBA-SHA-PEI/pDNA) however resulted in specific and enhanced phagocytosis in DCs without any observable toxicity at the optimum concentration of 0.25% of the copolymer. DNase treatment had no effect on DNA integrity in the encapsulated polyplex. Confocal microscopy confirmed intracellular localization of the targeting NGR/PEG/PDBA-SHA-PEI/pDNA microparticles, resulting in more enhanced uptake of the radiolabeled plasmid DNA and approximately 5- and 10-fold increase over the control tri-block Pluronic F68 copolymer and the non-targeting polyplex, respectively. More importantly, phagocytosis of the targeting microparticles neither altered the functionality of immature DCs nor the phenotypic expression of DC-specific cell surface molecules, CD80, CD86, CD40 and CD54 (ICAM-1), suggesting that uptake of the targeting microparticles by themselves did not induce DC maturation. Taken together, these results suggest that PLGA-PEG-PLGA encapsulation of this stealth targeting polyplex has no negative effects on key properties of immature DCs and should pave the way for targeting DCs for vaccination purposes.
Keywords: Polyethyleneimine (PEI); PLGA-PEG-PLGA; Polyethylene glycol (PEG); Phenyl(di)boronic acid (PDBA); Salicyl hydroxamic acid (SHA); NGR peptide; Dendritic cells; Targeted delivery;
Solubility parameter of drugs for predicting the solubility profile type within a wide polarity range in solvent mixtures by M.A. Peña; A. Reíllo; B. Escalera; P. Bustamante (155-161).
The solubility enhancement produced by two binary mixtures with a common cosolvent (ethanol–water and ethyl acetate–ethanol) was studied against the solubility parameter of the mixtures (δ 1) to characterize different types of solubility profiles. Benzocaine, salicylic acid and acetanilide show a single peak in the least polar mixture (ethanol–ethyl acetate) at δ 1 = 22.59, 21.70 and 20.91 MPa1/2, respectively. Phenacetin displays two solubility maxima, at δ 1 = 25.71 (ethanol–water) and at δ 1 = 23.30 (ethyl acetate–ethanol). Acetanilide shows an inflexion point in ethanol–water instead of a peak, and the sign of the slope does not vary when changing the cosolvent. The solubility profiles were compared to those obtained in dioxane–water, having a solubility parameter range similar to that covered with the common cosolvent system. All the drugs reach a maximum at about 90% dioxane (δ 1 = 23 MPa1/2). A modification of the extended Hildebrand method is applicable for curves with a single maximum whereas a model including the Hildebrand solubility parameter δ 1 and the acidic partial solubility parameter δ 1a is required to calculate more complex solubility profiles (with inflexion point or two maxima). A single equation was able to fit the solubility curves of all drugs in the common cosolvent system. The polarity of the drug is related to the shape of the solubility profile against the solubility parameter δ 1 of the solvent mixtures. The drugs with solubility parameters below 24 MPa1/2 display a single peak in ethanol–ethyl acetate. The drugs with δ 2 values above 25 MPa1/2 show two maxima, one in each solvent mixture (ethanol–water and ethanol–ethyl acetate). The position of the maximum in ethanol–ethyl acetate shifts to larger polarity values (higher δ 1 values) as the solubility parameter of the drug δ 2 increases.
Keywords: Solubility; Solvent mixtures; Cosolvent action; Solubility parameter; Acetanilide; Phenacetin; Salicylic acid; Benzocaine;
Drug/lactose co-micronization by jet milling to improve aerosolization properties of a powder for inhalation by K. Giry; J.M. Péan; L. Giraud; S. Marsas; H. Rolland; P. Wüthrich (162-166).
The aim of this work was to formulate a powder for inhalation with fusafungine, a drug substance initially highly cohesive. The classical approach based on micronization by jet milling to prepare respirable drug particles and then blending with a carrier was first applied. A fractional factorial experimental design was implemented to screen six formulation parameters. The effect of drug/lactose co-micronization on aerosolization was then evaluated. In vitro deposition studies were performed with the twin stage glass impinger and the inhaler Spinhaler®. Micronization did not induce DSC-detectable amorphization and gave a highly cohesive, poor flowable powder with a theoretical aerodynamic diameter of 5 μm. The powder was then blended with coarse lactose and optionally fine lactose. Unfortunately, the respirable fraction could not be optimized and remained below 10%. On the other hand, a co-micronized powder drug/fine lactose 50:50 gave a respirable fraction of 16%. Following blending with a carrier, the respirable fraction and the emitted dose fraction reached 23% and 69%, respectively. The use of a fine lactose grade for co-micronization was essential. In conclusion, this study demonstrated that co-micronization with a fine lactose is an efficient and simple strategy to formulate a powder for inhalation with enhanced aerosolization properties, especially for highly cohesive drug substance.
Keywords: Dry powder inhaler; Co-micronization; Jet milling; Lactose; Respirable fraction; Agglomerate;
Skin penetration enhancement of mefenamic acid by ethanol and 1,8-cineole can be explained by the ‘pull’ effect by Charles M. Heard; Denise Kung; Chris P. Thomas (167-170).
The simultaneous skin permeation of drug and penetration enhancer have been studied in vitro. Simple formulations of mefenamic acid in PEG400 incorporating various proportions of ethanol or 1,8-cineole were prepared and applied to porcine ear skin in diffusion cells under infinite conditions. Receptor phases were assayed for mefenamic acid by HPLC and ethanol or 1,8-cineole by GC. Concentration-dependent permeation profiles were obtained for both ethanol or 1,8-cineole, in addition to concentration-dependent enhancement of mefenamic acid. When the steady state flux of mefenamic acid was plotted against ethanol or 1,8-cineole, linear relationships were observed with r 2 values of 0.988 and 0.999, respectively. The close connection between rates of excipient and solute permeation is generally referred to as the ‘pull’ (or ‘drag’) effect, where in this case permeation of the enhancer facilitated permeation of the solute. This appears to be sufficient to account for the enhancing activity of ethanol and 1,8-cineole, notwithstanding initial modulations that may occur within the stratum corneum.
Keywords: Mefenamic acid; Skin; Transdermal; Penetration enhancer; Ethanol; 1,8-Cineole; Co-permeation;
Physicochemical characterization and evaluation of a microemulsion system for antimicrobial activity of glycerol monolaurate by Xiaowei Fu; Fengqin Feng; Bin Huang (171-175).
The purpose of this study was to improve the depression, enhance the bioavailability, hence strengthen the antimicrobial ability of poorly water-soluble glycerol monolaurate (GML) by loading it in microemulsion system. Microemulsions were prepared with GML as oil, tweens as surfactant, and medium-and-short chain alcohols at different ratio as cosurfactants. The effect of the ratio of surfactant to cosurfactant on the stability of microemulsion was tested. And the effect of the composition and ratio of cosurfactant and the effect of potassium sorbate dissolved in water at different concentration on the area of O/W microemulsion region in pseudo-ternary phase diagrams were also investigated. The results showed that the microemulsion is most stable when the ratio of surfactant to cosurfactant was 3:2, the suitable cosurfactant is pentanol to dodecane at 2:1, the area of O/W microemulsion region in pseudo-ternary phase diagram increased with increasing content of potassium sorbate. The conclusion of this study was that GML loaded in microemulsion had much higher anti-microbial activity than GML alone.
Keywords: Glycerol monolaurate; Microemulsion; Pseudo-ternary phase diagram; Anti-microbial activity;