Increased Drug Dissolution Research Articles

Particle design of itraconazole by evaporative recrystallization for dissolution improvement

The aim of this study was to improve dissolution of a poorly water-soluble drug, itraconazole (ITZ), by evaporative recrystallization under vacuum using lyophilizer and rotary evaporator, and compared with that prepared under the ambient conditions. Different organic solvents were used as crystallizing solvent. The amorphous ITZ was obtained by vacuum evaporation using lyophilizer and rotary evaporator. Immediate evaporation of chloroform or methylene chloride out from the drug solution caused the rapid crystallization, leading to amorphous phase formation. Using chloroform as crystallizing solvent caused the complete amorphous ITZ while some ITZ crystals were still found when using methylene chloride. Thus, the dissolution of amorphous ITZ obtained from chloroform showed better dissolution than that from methylene chloride. The crystallization method also influenced the properties of ITZ powders. The ITZ powders prepared from vacuum evaporation using both rotary evaporator and lyophilizer showed a significant increase in drug dissolution. By using lyophilizer, the ITZ powders with faster dissolution were obtained. This is because extremely low temperatures can limit molecular mobility, therefore, the nucleation of the drug is prevented, and crystallization cannot occur, leading to complete amorphous phase formation. After 1-year storage at ambient conditions, both ITZ powders were partially crystallized, leading to a decrease in dissolution. However, ITZ powders obtained from vacuum crystallization using lyophilization showed less change and still provided higher drug dissolution. The instability of the amorphous ITZ was expected and confirmed by these experiments. Therefore, stabilization of the amorphous ITZ is necessary to maintain the drug effectiveness through a long-term storage.

Development and evaluation of glibenclamide floating tablet with optimum release

Glibenclamide is a poorly soluble drug with narrow absorption window. The strategy of this work was to enhance the dissolution rate of Glibenclamide by solid dispersion (SD) technique with optimum formulation being developed as floating tablets. Binary SDs of drug and poloxamer 407 were prepared at different ratios. Ternary dispersion was prepared by the addition of sodium bicarbonate as third component. For floating tablets, a series of floating formulations was prepared using HPMC k4 (F1), HPMC k15 (F2) and combination of both with Carbopol (F3), using ternary solid dispersion as the drug matrix. Effect of matrix type was studied, F4 and F5 were prepared using the same floating matrix as F3 but drug was either binary poloxamer SD or physically mixed with bicarbonate. Unprocessed drug in floating matrix was used as control. All SDs increased drug dissolution rate, with ternary mixture showing the highest dissolution efficiency reflecting synergism between poloxamer and sodium bicarbonate. Solid state characterization showed evidences of decreased drug crystalline structure. F3 showed the best floating behavior. Considering floating behavior together with the release pattern, F3 was the optimum formulation. Overall, employing drug as ternary SD with optimum dissolution can provide flexibility in developing controlled release floating system.

Physicomechanical and physicochemical characterizations of biexponential compaction process of paracetamol in the presence of talcum-lubricated-MCC

Paracetamol exhibits poor compressibility, poor mechanical performance and very difficult to be tableted alone by direct compression method. In the present study compaction process of paracetamol has been characterized in the presence of microcrystalline cellulose (MCC) after talcum lubrication. Compressibility parameters under tapping related to apparent density were obtained by biphasic linear plots. Compacts were prepared over a compression pressure of 24.5 to 343.2MPa, and change in apparent density and tensile strength was recorded. Primary rearrangement and the secondary rearrangement were the two major steps clearly observed during particle rearrangement process, and the primary rearrangement packing rate was found faster compared to secondary packing rate in all powder formulations. First step of packing compacted to a greater extent compared to the second step during the entire tapping process. Under applied pressure, density difference due to compaction by particle rearrangement was observed to be very high compared to compaction by plastic deformation in the formulations. Solid bridge formation and mechanical interlocking were found to be more intensified as the MCC amount increased with the consequent increase of mechanical strength of the formulation. Level A correlation has been established between tensile strength and apparent density change at the same pressure. Increased loading of MCC in the compacted tablet also increased drug dissolution.

Formulation and characterization study of itraconazole-loaded microparticles

The aim of the work was to realize itraconazole-loaded formulations in form of microparticles using a fast, simple and solvent free production procedure. The selected excipients were able to enhance wettability of the final product, to increase drug dissolution rate and to maintain drug in solution thanks to the formation of an emulsified system after contact with the gastrointestinal fluids. Itraconazole formulations contained a structuring lipid, a solubilizing agent and a surface active substance and were prepared by a hot melt method (MMS, melting–milling–sieving). The characterization included drug content determination, granulometric distribution, differential scanning calorimetry (DSC) and in vitro drug release test, physical and technological stability after 12 months of ambient condition storage. The formulations were composed of particles with diameter lower than 355 μm. DSC analysis evidenced that itraconazole was almost completely in the amorphous form; the results of the in vitro drug release tests showed that these formulations were able to increase the rate of the drug release compared to that of the free drug. Stability data showed no significant changes in the thermal and release profiles, confirming that the selected excipients protected the drug avoiding its conversion from amorphous state into crystalline form and maintaining unchanged the delivery behavior.

Preparation of naproxen–excipient formulations by CO2 precipitation on a slurry

The work focused on screening the impact of various excipients and/or procedure in a new method that consists in a CO2-induced precipitation of a drug on a slurry. Naproxen (NPX) is a drug whose bioavailability could be improved by formulation with hydrophilic excipients. The investigated excipients were of various type, size and porosity, i.e. mannitol, silicas (SiO2 and SIO2 aminopropyl) and an anion exchange resin Duolite. The precipitation process used compressed CO2 as antisolvent for NPX and acetone as solvent to dissolve NPX and to suspend the excipient particles. Naproxen precipitated as crystals with a size distribution influenced by the NPX:excipient ratio for mannitol-based formulations. For other excipient co-precipitates, the overall size distributions were in the same range and below 330μm except for the 5μm silica. Due to the hydrophilic nature of the excipients, most formulations yielded an increased drug dissolution rate. Compared to physical mixtures, the benefit of the CO2 treatment was demonstrated in case of the excipient mannitol.

Effect of a Fiber-Optic Probe on the Dissolution of Salicylic Acid Tablets in USP Apparatus 2

Fiber-optic probes permanently inserted in the dissolution medium in dissolution vessels can automate the sampling process but can also potentially affect the hydrodynamics in the vessel, possibly resulting in increased drug dissolution rates. In this work, dissolution experiments with non-disintegrating salicylic acid calibrator tablets were conducted in dissolution testing Apparatus 2 in both the presence and absence of a commercially available fiber-optic probe (Opt-Diss). Tests were conducted using tablets dropped in the medium according to USP guidelines, as well as with tablets fixed at nine positions on the vessel bottom (i.e., either centered in the vessel or placed at different off-center locations with respect to the vessel vertical centerline). The results were compared using statistical tools. In many cases, the presence of the probe resulted in slightly faster dissolution rates. The difference between the results obtained in experimental systems with the probe and those obtained with the control system without the probe depended on tablet position. Larger differences were observed when the tablets were on inner circle positions (10° off-center circle), especially when the tablets were located immediately downstream of the probe. A paired t-test as well as the difference factor (f1) and similarity factor (f2) were used to statistically analyze the results. In most cases, the results obtained with the inserted probe were statistically different, according to the paired t-test, from those obtained without it. It can be concluded that fiber-optic sampling probes can often result in small but measurable enhancements in the dissolution rates, which can produce appreciable variations in test results.

Design of superdisintegrant- and effervescent agent-less dispersible fast-release melt pellets

Abstract Fast-release matrix utilizing superdisintegrants and effervescent agents was met with slow matrix disaggregation during dissolution and effervescence loss during storage, thereby delaying drug dissolution. This study employed electrolyte as alternative dispersant of fast-release matrix prepared using solvent-free melt pelletization technique which prevented instantaneous reaction between electrolyte and solvent during agglomeration and allowed such reaction to occur only in dissolution phase. The melt pellets were prepared using lactose and polyethylene glycol (PEG) 3000 as hydrophilic filler/binder, calcium acetate and calcium carbonate as electrolytes, tolbutamide as poorly water-soluble drug in free form and embedded in PEG 3000. These pellets were subjected to drug dissolution and physicochemical tests at molecular scale. The dissolution of tolbutamide in simulated gastric milieu increased following its formulation into pellets due to enhanced drug segregation and amorphization. A further increase in drug dissolution was attainable through pellet formulation with water-soluble calcium acetate instead of effervescent acid-soluble carbonate salt. Calcium acetate dissolved rapidly in aqueous medium to initiate turbulence in core matrix and fast pellet break-up through erosion and disintegration, unlike channeling agent. Small dispersible particles with elevated dissolution surface area were formed and had pellet fast-release characteristics unaffected by prolonged matrix storage.

Novel disintegrating microcrystalline cellulose pellets with improved drug dissolution performance

Abstract Pellets obtained from extrusion/spheronization generally do not disintegrate, especially those prepared from microcrystalline cellulose (MCC). The aim of present study was to develop fast disintegrating MCC pellets in order to improve drug dissolution. Formulations containing a model drug having a low aqueous solubility (i.e., indomethacin) and MCC were prepared with or without the addition of polyethylene glycol 400 (PEG 400; 0–10% w/w), polysorbate 80 (0–10% w/w) and croscarmellose sodium (CCS; 0–10% w/w) using a basket extruder and spheronizer. Ethanolic solution (15% v/v) was used as a granulating liquid. All formulations of pellets showed acceptable yield, aspect ratio and mechanical strength. The MCC pellets did not disintegrate and showed slow drug dissolution while the formulations with PEG 400 and/or polysorbate 80 disintegrated within 90 s and their drug dissolution was increased. The incorporation of CCS allowed the pellets to explode and disintegrate into two smaller pieces within 5 s after contact to an aqueous medium. The increased amount of CCS (from 2 to 10% w/w) insignificantly decreased disintegration time or increased drug dissolution. A slight difference in drug dissolution between freshly prepared pellets and pellets stored for 18 months may be due to the instability of drug in liquisolid environment. The results from this study suggest that the disintegrating or exploding MCC pellets could be prepared by incorporating PEG 400, polysorbate 80 and CCS, and promising for increasing dissolution of poorly water-soluble drugs.

Solubility enhancement of desloratadine by solid dispersion in poloxamers

The present study investigates the possibility of using poloxamers as solubility and dissolution rate enhancing agents of the poorly water soluble drug substance desloratadine that can be used for the preparation of immediate release tablet formulation. Two commercially available poloxamer grades (poloxamer P 188 and poloxamer P 407) were selected, and solid dispersions (SDs) containing different weight ratio of poloxamers and desloratadine were prepared by a low temperature melting method. All SDs were subjected to basic physicochemical characterization by thermal and vibrational spectroscopy methods in order to evaluate the efficiency of poloxamers as solubility enhancers. Immediate release tablets were prepared by direct compression of powdered solid dispersions according to a General Factorial Design, in order to evaluate the statistical significance of two formulation (X(1) - type of poloxamer in SD and X(2) - poloxamer ratio in SD) and one process variable (X(3) - compression force) on the drug dissolution rate. It was found that desloratadine in SDs existed in the amorphous state, and that can be largely responsible for the enhanced intrinsic solubility, which was more pronounced in SDs containing poloxamer 188. Statistical analysis of the factorial design revealed that both investigated formulation variables exert a significant effect on the drug dissolution rate. Increased poloxamer ratio in SDs resulted in increased drug dissolution rate, with poloxamer 188 contributing to a faster dissolution rate than poloxamer 407, in accordance with the results of intrinsic dissolution tests. Moreover, there is a significant interaction between poloxamer ratio in SD and compression force. Higher poloxamer ratio in SDs and higher compression force results in a significant decrease of the drug dissolution rate, which can be attributed to the lower porosity of the tablets and more pronounced bonding between poloxamer particles.

Dissolution rate enhancement of gliclazide by ordered mixing

The poorly water soluble antidiabetic drug gliclazide was selected to study the effect of excipients on dissolution rate enhancement. Ordered mixtures of micronized gliclazide with lactose, mannitol, sorbitol, maltitol and sodium chloride were prepared by manual shaking of glass vials containing the drug and excipient(s). Different water soluble excipients, addition of surfactant and superdisintegrant, drug concentration and carrier particle size influenced the dissolution rate of the drug. Dissolution rate studies of the prepared ordered mixtures revealed an increase in drug dissolution with all water soluble excipients. The order of dissolution rate improvement for gliclazide was mannitol > lactose > maltitol > sorbitol > sodium chloride. Composite granules of the particle size range 355-710 μm were superior in increasing the drug dissolution rate from ordered mixtures. Reducing the carrier particle size decreased the dissolution rate of the drug as well as the increase in drug concentration. Kinetic modeling of drug release data fitted best the Hixson-Crowell model, which indicates that all the ordered mixture formulations followed the cube root law fairly well.

Enhancement of Solubility and Permeability of Candesartan Cilexetil by Using Different Pharmaceutical Interventions

The poor solubility and wettability of Candesartan cilexetil (CAN) leads to poor dissolution and hence, low bioavailability after oral administration. The aim of the present study was to improve the solubility and dissolution rate and hence the permeability of CAN by preparing solid dispersions/inclusion complexes. Solid dispersions were prepared using PEG 6000 [hydrophilic polymer] and Gelucire 50/13 [amphiphilic surfactant] by melt agglomeration (MA) and solvent evaporation (SE) methods in different drug-to-carrier ratios, while inclusion complexes were made with hydroxypropyl-β-cyclodextrin (HP-β-CD) [complexing agent] by grinding and spray drying method. Saturation solubility method was used to evaluate the effect of various carriers on aqueous solubility of CAN. Based on the saturation solubility data, two drug-carrier combinations, PEG 6000 (MA 1:5) and HP-β-CD (1:1 M grinding) were selected as optimized formulations. FTIR, DSC, and XRD studies indicated no interaction of the drug with the carriers and provided valuable insight on the possible reasons for enhanced solubility. Dissolution studies showed an increase in drug dissolution of about 22 fold over the pure drug for PEG 6000 (MA 1:5) and 12 fold for HP-β-CD (1:1 M grinding). Ex-vivo permeability studies revealed that the formulation having the greatest dissolution also had the best absorption through the chick ileum. Capsules containing solid dispersion/ complex exhibited better dissolution profile than the marketed product. Thus, the solid dispersion/inclusion complexation technique can be successfully used for enhancement of solubility and permeability of CAN.

Physicochemical Properties of the Amorphous Drug, Cast Films, and Spray Dried Powders to Predict Formulation Probability of Success for Solid Dispersions: Etravirine

Solid dispersion technology represents an enabling approach to formulate poorly water-soluble drugs. While providing for a potentially increased oral bioavailability secondary to an increased drug dissolution rate, amorphous dispersions can be limited by their physical stability. The ability to assess formulation risk in this regard early in development programs can not only help in guiding development strategies but can also point to critical design elements in the configuration of the dosage form. Based on experience with a recently approved solid dispersion-based product, Intelence® (etravirine), a three part strategy is suggested to predict early formulate-ability of these systems. The components include an assessment of the amorphous form, a study of binary drug/carrier cast films and the evaluation of a powder of the drug and polymer processed in a manner relevant to the intended final dosage form. A variety of thermoanalytical, spectroscopic, and spectrophotometric approaches were applied to study the prepared materials. The data suggest a correlation between the glass forming ability and stability of the amorphous drug and the nature of the final formulation. Cast films can provide early information on miscibility and stabilization and assessment of processed powders can help define requirements and identify issues with potential final formulations.

Fast-dissolving microparticles fail to show improved oral bioavailability

Oral dosage forms are the preferred means of delivering drugs for systemic absorption. However, development problems occur for drugs with poor water solubility and/or gastrointestinal permeability. It is generally believed that the in-vivo bioavailability of poorly water-soluble drugs from Class II of the Biopharmaceutics Classification System can be improved by increasing the dissolution rate. We have attempted to increase the in-vivo oral bioavailability of a model Class II drug (griseofulvin) by preparing rapidly-dissolving particles. The solvent-diffusion method was used to prepare particles with hydrophilic surfactants (Brij 76/Tween 80 surfactant blend) and in-vivo studies were conducted in rats. The griseofulvin particles produced were bipyramidal in habit with a particle size of 2.18 +/- 0.12 microm; they contained crystalline drug and a relatively large proportion (12% w/w) of hydrophilic surfactant. The latter and the small particle size ensured rapid particle dispersion and dissolution in-vitro. Thus, within 30 min of the in-vitro dissolution test, the bipyramidal particles had released approximately 70% of drug compared with approximately 10% from the starting material (particle size 12.61 +/- 1.11 microm). However, the rapid and increased drug dissolution in-vitro was not translated to rapid and enhanced absorption in-vivo, and the oral bioavailability of the model drug was found to be the same from the control and from the bipyramidal particles. The poor in-vivo performance of the bipyramidal particles showed that although the dissolution rate of a Class II drug is thought to be a good indicator of its in-vivo bioavailability, this is not always the case.

Bio-Dis and the Paddle Dissolution Apparatuses Applied to the Release Characterization of Ketoprofen from Hypromellose Matrices

The purposes of this work were: (1) to comparatively evaluate the effects of hypromellose viscosity grade and content on ketoprofen release from matrix tablets, using Bio-Dis and the paddle apparatuses, (2) to investigate the influence of the pH of the dissolution medium on drug release. Furthermore, since direct compression had not shown to be appropriate to obtain the matrices under study, it was also an objective (3) to evaluate the impact of granulation on drug release process. Six formulations of ketoprofen matrix tablets were obtained by compression, with or without previous granulation, varying the content and viscosity grade of hypromellose. Dissolution tests were carried out at a fixed pH, in each experiment, with the paddle method (pH 4.5, 6.0, 6.8, or 7.2), while a pH gradient was used in Bio-Dis (pH 1.2 to 7.2). The higher the hypromellose viscosity grade and content were, the lower the amount of ketoprofen released was in both apparatuses, the content effect being more expressive. Drug dissolution enhanced with the increase of the pH of the medium due to its pH-dependent solubility. Granulation caused an increase in drug dissolution and modified the mechanism of the release process.

Advantages of celecoxib nanosuspension formulation and transformation into tablets

Drugs with low aqueous solubility and high permeability (BCS class II) present a high proportion of all drugs. This study examines the critical issues regarding engineering of a nanosuspension tailored to increase drug dissolution rate and its transformation into dry powder suitable for tabletting. Nanosuspensions of celecoxib, a selective COX-2 inhibitor with low water solubility, were produced by the emulsion-diffusion method using three different stabilizers (Tween ® 80, PVP K-30 and SDS) and characterized by particle size analysis, dissolution testing, scanning electron microscopy imaging, differential scanning calorimetry and X-ray powder diffraction. Spray-dried nanosuspension was blended with microcrystalline cellulose, and compressed to tablets, and their tensile strength, porosity and elastic recovery of tablets were investigated. The selection of solvent and stabilizers is critical, firstly to achieve controlled crystallization and size, and secondly to increase the wettability of the hydrophobic drug. The crystalline nano-sized celecoxib alone or in tablets showed a dramatic increase of dissolution rate and extent compared to micronized. SEM images showed that the nanoparticle morphology was influenced by the choice of stabilizers. Celecoxib nanosuspension stabilized with PVP K-30 and SDS showed advantages over Tween ® 80 due to sticking of the dried product and unexpected changes observed on DSC curves. Markedly lower compaction forces are needed for nano-sized compared to micro-sized celecoxib to produce tablets of equal tensile strength.

Physicochemical characterization and dissolution properties of binary systems of pyrimethamine and 2- hydroxypropyl-&#946-cyclodextrin

Pyrimethamine (PYR), a drug effective against protozoan parasites, such as Toxoplasma gondii and Plasmodium falciparum, is poorly water soluble and exhibits marked variation in oral bioavailability. This study was aimed at investigating the possibility and extent of enhancement of the dissolution properties of PYR via complexation with 2-hydroxypropyl-
-cyclodextrin (HP-
-CD) as well as characterization of the complex formation of the drug with the cyclodextrin. The interaction between PYR and HP-
-CD in solution was studied by phase solubility analysis while binary systems of the compounds at 1:1 molar ratios were prepared by using the physical mixture, kneading, co-evaporation and freeze-drying methods. The binary systems were characterized using differential scanning calorimetry (DSC), powder x-ray diffractometry (PXRD) and Fourier transform infrared (FT-IR) spectroscopy. Phase solubility studies revealed an AL-type diagram indicating a 1:1 stoichiometric inclusion complex and a stability constant value of 914 M-1. Solubility and dissolution rates of PYR and the binary systems were determined and found to be markedly enhanced by cyclodextrin complexation. The extent of enhancement of dissolution properties was dependent on the preparation method of the complex, and the product prepared by the freeze-drying method was shown to have the most superior dissolution efficiency than the other binary systems. The PXRD patterns and DSC curves especially for the co-evaporated and freeze-dried systems indicated strong drug amorphization and/or inclusion of PYR in the CD cavities. The results of this study suggest that the complexation of PYR with HP-
-CD could reduce variability in the drug absorption and improve therapeutic efficacy of the drug through increased drug dissolution efficiency.

Biodisponibilité et vecteurs particulaires pour la voie orale

The oral route remains the preferred route of administration to ensure patient satisfaction and compliance. However, new chemical entities may exhibit low bioavailability after oral administration because of poor stability within the gastrointestinal tract, poor solubility in gastrointestinal fluids, low mucosal permeability, and/or extensive first-pass metabolism. Consequently, these new drug substances cannot be further developed using conventional oral formulations. This issue is addressed by an innovative approach based on the entrapment of drug molecules in drug/carrier assembling systems. The carrier materials are lipids, naturally occurring polymers or synthetic polymers, which are considered as nontoxic and biocompatible materials. Drug entrapment is intended to protect drug substances against degradation by gastrointestinal fluids. Fine drug/carrier particle size ensures increased drug dissolution rates. Carriers and particle supramolecular organization can be designed to enhance drug absorption through the intestinal epithelium and lymphatic transport. Promising preclinical results have been obtained with model drugs like paclitaxel, insulin, calcitonin, or cyclosporin. Attention has focused on mucoadhesive carriers like chitosan that favor an intimate and extended contact between drugs and intestinal cells, thus enhancing absorption. Addition of ligands such as lectins improves intestinal drug absorption through specific binding of the carrier to intestinal cell carbohydrates. In conclusion, drug/carrier particulate systems are an attractive and exciting drug delivery strategy for highly potent drug substances unsuitable for oral use. Further evidence will determine whether this approach has marked therapeutic benefits over conventional drug formulations and is compatible with large-scale industrial production and stringent registration requirements. Producing highly effective particulate systems requiring low-complexity manufacturing processes is therefore an ongoing challenge.

Drug loading into β-cyclodextrin granules using a supercritical fluid process for improved drug dissolution

To improve dissolution properties of drugs, a supercritical fluid (SCF) technique was used to load these drugs into a solid carrier. In this study, granules based on β-cyclodextrin (βCD) were applied as a carrier for poor water-soluble drug and loaded with a model drug (ibuprofen) using two different procedures: controlled particle deposition (CPD), SCF process and solution immersion (SI) as a conventional method for comparison. Using the CPD technique, 17.42 ± 2.06 wt.% ( n = 3) ibuprofen was loaded into βCD-granules, in contrast to only 3.8 ± 0.15 wt.% ( n = 3) in the SI-product. The drug loading was confirmed as well by reduction of the BET surface area for the CPD-product (1.134 ± 0.07 m 2/g) compared to the unloaded-granules (1.533 ± 0.031 m 2/g). Such a reduction was not seen in the SI-product (1.407 ± 0.048 m 2/g). The appearance of an endothermic melting peak at 77 °C and X-ray patterns representing ibuprofen in drug-loaded granules can be attributed to the amount of ibuprofen loaded in its crystalline form. A significant increase in drug dissolution was achieved by either drug-loading procedures compared to the unprocessed ibuprofen. In this study, the CPD technique, a supercritical fluid process avoiding the use of toxic or organic solvents was successfully applied to load drug into solid carriers, thereby improving the water-solubility of the drug.

Effect of hydrophilic swellable polymers on dissolution enhancement of carbamazepine solid dispersions studied using response surface methodology

The objective of this work was to study dissolution enhancement efficiency and solid dispersion formation ability of hydrophilic swellable polymers such as sodium carboxymethyl cellulose (Na-CMC), sodium starch glycolate (SSG), pregelatinized starch (PGS), and hydroxypropylmethyl cellulose (HPMC) with carbamazepine using 3(2) full factorial design for each of the polymers. Solid dispersions of carbamazepine were prepared using solvent evaporation method with around 70% solvent recovery. The independent variables were the amount of polymer and organic solvent. The dependent variables assessed were percentage drug dissolved at various time points and dispersion efficiency (ie, in terms of particle size of solid dispersion). Solid dispersions were evaluated for percentage drug dissolved, wettability, differential scanning calorimetry, scanning electron microscopy, and angle of repose. Multiple linear regression of results obtained led to equations, which generated contour plots to relate the dependent variables. Similarity factor and mean dissolution time were used to compare dissolution patterns obtained in distilled water and simulated gastric fluid United States Pharmacopeia (USP) XXVI of pH 1.2. Maximum drug dissolution was obtained with polymer order Na-CMC>SSG>PGS>HPMC. Particle size of drug was reduced ~10-15, 3-5, 5-7, and 10-25 times in Na-CMC, SSG, PGS, and HPMC solid dispersions, respectively; whereas wettability of solid dispersions was found in the order of Na-CMC>HPMC>PGS>SSG. Angle of repose was found to be in the range of 29 degrees to 35 degrees for all solid dispersions, which shows good flowability characteristics. HPMC showed increase in drug dissolution up to an optimized level; however, further increase in its concentration decreased drug dissolution.

Preparation and characterisation of liposomes encapsulating ketoprofen–cyclodextrin complexes for transdermal drug delivery

Multilamellar vesicle (MLV) liposomes containing ketoprofen–cyclodextrin complexes intended for drug topical delivery were prepared, with the aim of simultaneously exploiting the favourable properties of both carriers. Drug complexes with β-cyclodextrin (βCyd) and hydroxypropyl-βCyd (HPβCyd), prepared by coevaporation and sealed-heating methods, were characterised by differential scanning calorimetry, hot stage microscopy, scanning electron microscopy and tested for dissolution properties. The coevaporated system with HPβCyd was the most effective, enabling an about 11-fold increase in drug dissolution. Drug and drug-Cyd systems were incorporated in MLV liposomes prepared by the thin layer evaporation technique. All liposomal formulations were characterised for encapsulation efficiency, particle size and morphology, using dialysis, light scattering and transmission electron microscopy techniques, respectively. MLV formation was negatively influenced by the presence of Cyd; nevertheless, it was possible to prepare stable MLVs containing ketoprofen-Cyd complexes. The presence of the Cyd complex affected MLV dimensions but not their lamellar structure. The complex with HPβCyd, in virtue of its greater stability than the βCyd one, allowed higher percentages of encapsulation and gave rise to more stable MLV systems. Permeability studies of drug and drug-Cyd complexes, as such or incorporated in liposomes, performed both across artificial membranes and rat skin, highlighted a favourable effect of Cyd on drug permeation rate, due to its solubilizing action; by contrast, unexpectedly, no skin-permeation enhancer property of liposomes has been evidenced. Confocal laser scanning microscopy studies carried out with the rhodamine-Cyd complex as fluorescent marker, confirmed such results, showing that the label permeated deeper across rat skin layers when it was in solution than when entrapped in liposomes.