Complete Drug Dissolution Research Articles

In-line monitoring of solid dispersion preparation in small scale extrusion based on UV–vis spectroscopy

The poor solubility of a large number of active pharmaceutical ingredients (APIs) is a major challenge in pharmaceutical research. Therefore, the extrusion of amorphous solid dispersions (ASDs) is one promising approach to enhance the dissolution rate by molecularly dissolving the API in an amorphous carrier polymer. During ASD extrusion, crucial parameters as the dissolution of the API in the carrier polymer need to be monitored. Within this study, a small scale twin screw extruder was coupled with special ColVisTec UV–vis probes that are characterized by their small dimensions. This setup enables a systematic formulation design and optimization based on in-line monitoring of drug dissolution using small material quantities. In fact, sample quantities of about 5 mg were evaluated for each measurement, representing 50% of the material inside the die. The amount of undissolved drug particles was determined based on the lightness of the extrudates. It was shown that the temperature has a significant effect on the drug dissolution in the polymer. Furthermore, complete drug dissolution was shifted to lower temperatures if higher residence times were applied. Based on the courses of lightness, regime maps were modeled that specify the process conditions where ASDs are successfully manufactured.

Lipid/Clay-Based Solid Dispersion Formulation for Improving the Oral Bioavailability of Curcumin.

This study was conducted to develop a lipid/clay-based solid dispersion (LSD) formulation to enhance the dissolution and oral bioavailability of poorly soluble curcumin. Krill oil and aminoclay were used as a lipid and a stabilizer, respectively, and LSD formulations of curcumin were prepared by an antisolvent precipitation method combined with freeze-drying process. Based on the dissolution profiles, the optimal composition of LSD was determined at the weight ratio of curcumin: krill oil: aminoclay of 1:5:5 in the presence of 0.5% of D-α-tocopherol polyethylene glycol succinate. The structural and morphological characteristics of the LSD formulation were determined using X-ray powder diffraction, differential scanning calorimetry, and scanning electron microscopy. Crystalline curcumin was changed to an amorphous form in the LSD formulation. At the pH of acidic to neutral, the LSD formulation showed almost complete drug dissolution (>90%) within 1 h, while pure curcumin exhibited minimal dissolution of less than 10%. Furthermore, the LSD formulation had significantly improved oral absorption of curcumin in rats, where Cmax and AUC of curcumin were 13- and 23-fold higher for the LSD formulation than for the pure drug. Taken together, these findings suggest that the krill oil-based solid dispersion formulation of curcumin effectively improves the dissolution and oral bioavailability of curcumin.

Front Cover: Development and Validation of Reverse‐Phase High‐Performance Liquid Chromatography Method for Estimation of Itraconazole through Hydroxypropyl Methylcellulose Acetate Succinate based Polymeric Films using Quality by Design principles

DOI: 10.1002/sscp.202100037 The cover picture shows a reverse phase HPLC method development for Itraconazole using principles of analytical QbD with surface response curves indicating the results of multivariate analysis in present method conditions, where the retention time (RT) was impacted with mobile phase concentration and flow rate with negligible impact of pH of mobile phase and a non-linear correlation amongst the experimental variables. On the other hand, the response for theoretical plates indicated a linear correlation with the pH of water used in the mobile phase without much impact of other variables. To evaluate the suitability of the test method for rapid screening of formulations, polymeric amorphous dispersion films were prepared for Itraconazole using the solvent evaporation method at different drug concentrations and using two different grades of polymer HPMCAS. It was observed that amongst the drug concentrations and polymer grades studied, the highest clarity of the film was achieved at 10% drug loading with HPMCAS 912G which also resulted in a rapid and complete drug dissolution in less than 30 minutes indicative of supersaturation and prevention of recrystallization after formation of the polymeric amorphous dispersion film.

Investigation of tablet disintegration pathways by the combined use of magnetic resonance imaging, texture analysis and static light scattering.

Efficient tablet disintegration is a pre-requisite for fast and complete drug dissolution from immediate release formulations. While the overall tablet disintegration time is a routinely measured quality attribute of pharmaceutical products, little attention is usually paid to the analysis of disintegration fragments and the cascade of elementary steps that lead to their formation. In this work, we investigate the disintegration pathways of directly compressed tablets by a unique combination of three methods: (i) magnetic resonance imaging (MRI), to gain insight into structural changes of tablets during disintegration; (ii) texture analysis, to measure the disintegration kinetics; and (iii) static light scattering, to characterise the size distribution of disintegration fragments. By systematically varying the tablet composition (50-90% of ibuprofen as a model active ingredient, 0-4% of croscarmellose sodium disintegrant, 6-50% of lactose monohydrate filler), a relationship between the tablet formulation, the size distribution of the disintegration fragments and the dissolution rate of the active ingredient has been established. To interpret the experimental observations, we analyse the disintegration fragments by Raman mapping and relate their composition and structure to the micro-scale arrangement of individual formulation components inside the tablet.

Investigation of drug dissolution and uptake from low-density DPI formulations in an impactor–integrated cell culture model

Besides deposition, pulmonary bioavailability is determined by dissolution of particles in the scarce epithelial fluid and by cellular API uptake. In the present work, we have developed an experimental in vitro model, which is combining the state-of-the-art next generation impactor (NGI), used for aerodynamic performance assessment of inhalation products, with a culture of human alveolar A549 epithelial cells to study the fate of inhaled drugs following lung deposition. The goal was to investigate five previously developed nano-milled and spray-dried budesonide formulations and to examine the suitability of the in vitro test model. The NGI dissolution cups of stages 3, 4, and 5 were transformed to accommodate cell culture inserts while assuring minimal interference with the air flow. A549 cells were cultivated at the air–liquid interface on Corning® Matrigel® -coated inserts. After deposition of aerodynamically classified powders on the cell cultures, budesonide amount was determined on the cell surface, in the interior of the cell monolayer, and in the basal solution for four to eight hours. Significant differences in the total deposited drug amount and the amount remaining on the cell surface at the end of the experiment were found between different formulations and NGI stages. Roughly 50% of budesonide was taken up by the cells and converted to a large extent to its metabolic conjugate with oleic acid for all formulations and stages. Prolonged time required for complete drug dissolution and cell uptake in case of large deposited powder amounts suggested initial drug saturation of the surfactant layer of the cell surface. Discrimination between formulations with respect to time scale of dissolution and cell uptake was possible with the present test model providing useful insights into the biopharmaceutical performance of developed formulations that may be relevant for predicting local bioavailability. The absolute quantitative result of cell uptake and permeation into the systemic compartment is unreliable, though, because of partly compromised cell membrane integrity due to particle impaction and professed leakiness of A549 monolayer tight junctions, respectively.

Orodispersible Carbamazepine/Hydroxypropyl-β-Cyclodextrin Tablets Obtained by Direct Compression with Five-in-One Co-processed Excipients.

The development of orodispersible tablets (ODTs) for poorly soluble and poorly flowable drugs via direct compression is still a challenge. This work aimed to develop ODTs of poorly soluble drugs by combining cyclodextrins that form inclusion complexes to improve wetting and release properties, and directly compressible co-processed excipients able to promote rapid disintegration and solve the poor flowability typical of inclusion complexes. Carbamazepine (CBZ) and hydroxypropyl-β-cyclodextrin (HPβCD) were used, respectively, as a model of a poorly soluble drug with poor flowability and as a solubilizing agent. Specifically, CBZ-an antiepileptic and anticonvulsant drug-may benefit from the studied formulation approach, since some patients have swallowing difficulties or fear of choking and are non-cooperative. Prosolv® ODT G2 and F-Melt® type C were the studied five-in-one co-processed excipients. The complex was prepared by kneading. Flow properties of all materials and main properties of the tablets were characterized. The obtained results showed that ODTs containing CBZ/HPβCD complex can be prepared by direct compression through the addition of co-processed excipients. The simultaneous use of co-processing and cyclodextrin technologies rendered ODTs with an in vitro disintegration time in accordance with the European Pharmacopoeia requirement and with a fast and complete drug dissolution. In conclusion, the combination of five-in-one co-processed excipients and hydrophilic cyclodextrins may help addressing the ODT formulation of poorly soluble drugs with poor flowability, by direct compression and with desired release properties.

Different Approaches for Enhancement of Curcumin Aqueous Solubility and Dissolution rate

Curcumin (CUR) is a nature polyphenolic phytoingredient. CUR showed anti-inflammatory, anti-oxidant, anti-fungal and anti-cancer activities. The therapeutic efficacy of CUR was limited due to its poor aqueous solubility, poor oral bioavailability. Poor solubility of drugs is the major challenge associated with formulation development. Therefore, the aim of present work was to enhance CUR aqueous solubility and dissolution rate using Physical mixture and its solid dispersion. CUR solid dispersions were prepared by solvent evaporation and Freeze drying techniques using different polymers, such as cyclodextrins, polyvinyl pyrrolidone (PVP K30), polyethylene glycol 6000 and Pluronic®F-127. The prepared physical mixtures, solid dispersions were characterized using different techniques such as (DSC), (FTIR) and (XRD). Furthermore, the solubility and the dissolution rate of the drug in its different systems were explored. The results of physical characterization of the different systems show no interaction between them. Dissolution studies of CUR solid dispersions showed that the highest drug dissolution rate was achieved at CUR/ Pluronic®F-127 weight ratio of 1:3. Also, complete drug dissolution was obtained for CUR/Pluronic F-127 solid dispersion after 30 min compared to 35% dissolution for CUR alone after the same time. Also, CUR permeability coefficient through rat skin for Pluronic®F-127 micelles and solid dispersion were two times higher than that of the CUR alone. The obtained results concluded that, the preparation of solid dispersion of Pluronic®F-127 solid dispersions by freeze drying method is a promising one to overcome CUR shortcomings through enhancing its aqueous solubility, dissolution rate and skin permeability.

Poly(methyl methacrylate) salt as film forming material to design orodispersible films

This work aims to evaluate the possible use of a poly(sodium methacrylate, methyl methacrylate) (NaPMM2) plasticized by PEG400 in the design of orodispersible films (ODF). Placebo ODF prepared by solvent casting were intended to study the impact of the polymer/plasticizer ratio and residual moisture on disintegration time, stickiness and mechanical properties. The drug loading capacity was assessed using ketoprofen and paracetamol. Placebo ODF containing PEG400 in the 10–30% w/w range and 10–15% of residual moisture content were easy-to-handle, packed without failures and completely dissolved within 30 s.NaPMM2/PEG400 in 80/20 ratio allowed up to 70% of paracetamol loading, which appeared as the largest value described in literature. This ODF showed good mechanical properties and disintegration time. The same formulation loaded with 25% or 50% ketoprofen (pKa = 4.45) swelled without disintegrating, because of a partial protonation of NaPMM2, as verified by ATR-FTIR spectroscopy. However, the addition of 5% surfactants allowed the formulation of ODF containing 25% ketoprofen that disintegrated within one minute and guaranteed the complete drug dissolution within 5 min. All the presented data, discussed in the framework of information available on such copolymer, highlighted its versatility in the design of orodispersible dosage forms.

Solubilization and Enhancement of Ex Vivo Vaginal Delivery of Progesterone Using Solid Dispersions, Inclusion Complexes and Micellar Solubilization.

Progesterone (PG), a natural female sex hormone is used clinically in menopausal hormone replacement therapy and to control reproductive functions. Its very limited aqueous solubility results in reduced oral bioavailability and low patient compliance when administered in high doses. The aim of this study was to enhance PG aqueous solubility and vaginal delivery using solid dispersion, inclusion complex and micellar solubilization techniques. PG solid dispersions and inclusion complexes were prepared by solvent evaporation method using different polymers, such as cyclodextrins, polyvinyl pyrrolidone (PVP), poly (ethylene glycol) 6000, Pluronic® F-127 and Pluronic® F-68. PG was also incorporated into polymeric micelles of Pluronic® F-127, Pluronic® F- 68, Brij®35 and Myrj®52. The prepared solid dispersions, inclusion complexes and micelles were characterized using different techniques. Drug permeability across rabbit vaginal mucosa was also studied. Dissolution studies of PG solid dispersions showed that the highest drug dissolution rate was achieved at PG/polymer weight ratio of 5:5. Further, complete drug dissolution was obtained for PG/Pluronic® F-127 solid dispersion after 15 min compared to 42% dissolution for the drug alone. Brij®35 micelles had a drug loading capacity ~15%, which increased the drug aqueous solubility by more than 20 folds. PG permeability coefficients through rabbit vaginal mucosa for PG/Brij®35 micelles and PG/Pluronic® F-127 micelles were ~ two times higher than that of the drug alone. These results confirm that Brij®35 and Pluronic® F-127 micelles are promising carriers to overcome PG shortcomings through enhancing its aqueous solubility and vaginal permeability.

PREPARATION AND EVALUATION OF IBUPROFEN LIQUID FILL FORMULATIONS FOR SOFT GELS

The present investigation was undertaken with an objective to prepare and evaluate liquid fill formulations of non-steroidal anti-inflammatory drug, ibuprofen (IBU), in order to improve its dissolution properties and thereby its bioavailability. Liquid fill formulations were prepared by employing different co-solvents and surfactants like polyethylene glycol 400 (PEG 400), propylene glycol (PG) and polyvinylpyrrolidone (PVP K-30). The liquid fills were characterized by assay, rheology, clarity, in vitro dissolution studies and FTIR. More than 90% of the drug was released within 5 min from PVP K30 based formulations. Formulations containing PVP K 30 gave better dissolution properties when compared to formulations without PVP K 30, and complete drug dissolution was observed within 5min. Compatibility studies of IBU PEG 400, PG and PVP by IR method indicated that the excipients are compatible.

Controlled in Vitro Release of Levodopa from Sodium Alginate Membranes

Levodopa (LD) plays a central role in Parkinson’s Disease therapeutics. In this study, we aimed to encapsulate LD in sodium alginate (SA) membranes, and to study its dissolution profiles. Two types of SA membranes, loaded with two different amounts of LD were prepared and compared (M1: 85 mg per 50 ml SA/LD; M2: 127.5 mg per 75 ml SA/LD); membranes production followed a solvent-casting methodology. Calcium chloride was used as a crosslinking agent. LD solubility tests were performed to predict sink conditions required for complete drug dissolution. LD dissolution assays were carried out and UV spectrophotometry was used for cumulative release percentage determination. The obtained data were mathematically evaluated and fitted into mathematical dependent models; the difference factor (f1), the similarity factor (f2) and other parameters like dissolution efficiency (DE) were also used. No differences in the dissolution profiles of both membranes were noticed. Thus, increasing the amount of LD, but keeping the same concentration, led to a similar controlled release. The membranes presented in this work are expected to be a promising contribution in the development of a new controlled drug delivery system for LD administration.

Development and characterization of fast-dissolving tablet formulations of glyburide based on solid self-microemulsifying systems

The aim of this work was to develop effective fast-dissolving tablet formulations of glyburide, endowed with improved dissolution and technological properties, investigating the actual effectiveness of the Solid-Self MicroEmulsifying Drug Delivery System (S-SMEDDS) approach. An initial screening aimed to determine the solubility of the drug in different oils, Surfactants and CoSurfactants allowed the selection of the most suitable components for liquid SMEDDS, whose relative amounts were defined by the construction of pseudo-ternary phase diagrams. The selected liquid SMEDDS formulations (Capyol 90 as oil, Tween 20 as Surfactant and Glycofurol or Transcutol as CoSurfactant) were converted into Solid-SMEDDS, by adsorbing them onto Neusilin (1:1 and 1:0.8w/w S-SMEDDS:carrier), and fully characterized in terms of solid state (DSC and X-ray powder diffraction), morphological (ESEM) and dissolution properties, particle size and reconstitution ability. Finally, the 1:1 S-SMEDDS containing Glycofurol as CoSurfactant, showing the best performance, was selected to prepare two final tablet formulations. The ratio test (t10 min ratio and DE60 ratio) and pair-wise procedures (difference (f1) and similarity (f2) factors) highlighted the similarity of the new developed tablets and the marked difference between their drug dissolution profiles and those of formulations based on the micronized drug. The S-SMEDDS approach allowed to develop fast-dissolving tablets of glyburide, endowed with good technological properties and able to achieve the complete drug dissolution in a time ranging from 10 to 15min, depending on the formulation composition.

Novel instantly-soluble transmucosal matrix (ISTM) using dual mechanism solubilizer for sublingual and nasal delivery of dapoxetine hydrochloride: In-vitro/in-vivo evaluation

Dapoxetine (D) suffers from poor oral bioavailability (42%) due to extensive first pass metabolism. The usefulness of transmucosal (sublingual and intranasal) drug delivery to improve bioavailability of D, a weak basic drug, has been hampered by its poor solubility in the neutral pH of the body fluids. In this study, instantly-soluble transmucosal matrices (ISTMs) of D, containing dual mechanism solubilizer (Pluronic F-127/citric acid mixture), were prepared by lyophilization technique to enhance matrix disintegration, dissolution and transmucosal permeation. The matrices were evaluated for in-vitro disintegration, wetting time, in-vitro dissolution, ex vivo transmucosal permeation, scanning electron microscopy and in-vivo studies. Dissolution studies confirmed the higher ability of ISTMs to enhance the early time point dissolution and maintain complete drug dissolution in pH 6.8 compared to conventional lyophilized matrices. The optimized ISTM gave approximately 77.54 and 88.40 folds increase of D dissolution after 1 and 3min relative to the drug powder in pH 6.8. ISTMs containing the highest F127 concentration (2%) and the lowest gelatin and mannitol concentrations (1%) exhibited the shortest in-vitro disintegration times (<10s), the fastest dissolution in the neutral pH of body fluids (∼99% in 3min) and the highest enhancement of transmucosal permeation. The relative bioavailabilities of D after sublingual and intranasal administration of ISTMs to rabbits were about 124.58% and 611.15%, respectively, in comparison to the oral market tablet. The significant increase of drug dissolution in nasal fluids, rapid permeation rate together with the improved bioavailability propose that ISTMs could be promising for intranasal delivery of drugs suffering from oral hepatic metabolism and have limited solubility in nasal fluids.

Evaluation of powder, solution and suspension layering for the preparation of enteric coated pellets

Gastro-resistant pellets were prepared by use of three different drug loading techniques (powder layering, solution layering and suspension layering) and two different enteric coating techniques (powder layering and suspension layering). Pellets produced by different layering techniques were compared in terms of morphological characteristics, content of drug, release properties and stability. Drug loaded pellets produced by the use of powder layering had much more pronounced surface roughness in comparison to other tested techniques. Higher weight gains of enteric polymer were needed to achieve the same level of gastric resistance when powder layering was employed to apply enteric layer than when it was applied by suspension layering. Both tested techniques of enteric coating application enabled complete dissolution of drug in buffer stage of dissolution test. Suspension layering proved to be superior to other techniques both in drug loading and enteric layering phase.

Fast dissolving cyclodextrin complex of piroxicam in solid dispersion Part I: Influence of β-CD and HPβ-CD on the dissolution rate of piroxicam

Sublingual drug delivery is an interesting route for drug having significant hepatic first-pass metabolism or requiring rapid pharmacological effect as for patients suffering from swallowing difficulties, nausea or vomiting. Sublingual absorption could however be limited by the kinetic of drug dissolution. This study evaluated influences of cyclodextrins (β-CD or HP-β-CD) and their different inclusion process (spray-drying or freeze-drying) on the drug dissolution kinetic of solid dispersions in poly(ethylene glycol) (PEG, Mw 6000Da) of piroxicam, used as poor hydrosoluble drug model. A secondary objective was to determine influences of drug dispersion process in PEG (evaporation or melting methods) on the drug dissolution kinetic of piroxicam. Piroxicam solid dispersions containing or not cyclodextrins were characterized by different scanning calorimetry (DSC), Thermogravometry analyser (TGA) and Fourier transform-infrared spectroscopy (FT-IR) spectroscopy. In vitro drug dissolution study of these solid dispersions was then performed. The results demonstrated the high potential and interest of solid dispersions of drug previously included in cyclodextrins for sublingual delivery of hydrophobic drugs. This study also showed the advantages of evaporation method on the melting ones during drug dispersion in PEG. Indeed, drug complexation with cyclodextrins as dispersion by melting prevented the presence in solid dispersions of drug in crystalline form which can represent up to 63%. Moreover, dispersion in PEG by evaporation method gave more porous drug delivery system than with melting methods. This allowed complete (limited at most at 80–90% with melting methods) and quick drug dissolution without rebound effect like with melting ones.

Unexpected Performance of Physical Mixtures over Solid Dispersions on the Dissolution Behavior of Benznidazole from Tablets

This work investigated the feasibility of developing benznidazole (BZL) tablets, allowing fast, reproducible, and complete drug dissolution, by compressing BZL-Polyethylene Glycol (PEG) 6000 physical mixtures (PMs) and solid dispersions (SDs). SDs were prepared by the solvent evaporation method at different drug:polymer ratios (w/w). BZL-PEG 6000 formulations were characterized by X-ray diffraction (XRD), scanning electron microscopy, and dissolution studies. The preparation of SD-based BZL tablets by the wet granulation method was carried out and the influence of pregelatinized starch (PS) and starch (S) on the disintegration time and drug dissolution rate was analyzed. SDs showed a significant improvement in the release profile of BZL as compared with the pure drug. As demonstrated by XRD, the crystalline character of BZL remained almost unaltered in both PMs and SDs. BZL release from the PEG 6000 tablets increased by the presence of PS instead S. Unexpectedly, the BZL release from tablets containing PMs was almost equal as compared with the BZL release from tablets containing SDs. In conclusion, the results suggest that PEG 6000 and PS are suitable additives for the development of BZL tablets with enhanced dissolution behavior through the preparation of ordinary PMs, instead the laborious SDs.

Preparation and Evaluation of Valsartan Liquid Filling Formulations for Soft Gels.

The present investigation includes the preparation of liquid filling formulations for soft gels using an antihypertensive drug, valsartan (VAL), in order to improve its dissolution properties and thereby its bioavailability. Formulations were prepared using excipients like polyethylene glycol 400 (PEG 400), propylene glycol (PG), polyvinylpyrrolidone (PVP K-30), antioxidants, ethanol, and purified water. Prepared formulations were evaluated for appearance, pH, drug content percentage, viscosity, stability, and in vitro dissolution studies. The compatibility between the drug and excipients in formulations was confirmed by FTIR spectra. The drug contents were in the range of 99.62-99.63 and the viscosity was in the range of 60.9–591.7 cps with all the formulations developed. Formulations containing 10 mg PVP K 30 gave better dissolution properties when compared to formulations without PVP K 30, and a complete drug dissolution was observed within 10 min and followed the first-order release kinetics. Stability studies were conducted for selected formulations (F4–F9) for a period of 6 months at room temperature (~30°C/65% RH). From the studies, it can be concluded that VAL liquid filling formulations for soft gels were successfully prepared with in vitro dissolution properties superior when compared to VAL itself.

Is premedication with midazolam more effective by the sublingual than the oral route?

Background:In this study, we compared the sedative effects of sublingual midazolam solution with the oral tablet as premedication. Sixty pediatric patients of ASA physical status I and II were randomly selected to receive either 0.5 mg/kg of tablet or 0.5 mg/kg of sublingual solution of midazolam as premedication, about 45 min before elective surgery.Materials and Methods:There were 30 patients in each group. In Group I, the patients received premedication in the form of oral midazolam tablet 0.5 mg/kg. In Group II, the patients received midazolam solution 0.5 mg/kg. The degree of sedation and ease of separation was assessed according to the Niall C. Wilton scale and the procedure of Davis Peter, respectively. The time for complete drug dissolution was noted in both the groups. Then, the patients were interviewed regarding their acceptance of taste.Results:The sedation scores in the sublingual group were higher than in the oral group at 30 and 45 min after drug administration (P=0.0134 and P=0.0157). 66.6% of the patients in the sublingual group found it satisfactory as compared to 53.3% in the case of group receiving tablet.Conclusion:Thus, from the present study, it is concluded that premedication with midazolam is more effective by the sublingual than the oral route in children.

Fast-Dissolving Tablets of Glyburide Based on Ternary Solid Dispersions with PEG 6000 and Surfactants

Marketed glyburide tablets present unsatisfying dissolution profiles that give rise to variable bioavailability. With the purpose of developing a fast-dissolving tablet formulation able to assure a complete drug dissolution, we investigated the effect of the addition to a reference tablet formulation of different types (anionic and nonionic) and amounts of hydrophilic surfactants, as well as the use of a new technique, based on ternary solid dispersions of the drug with an hydrophilic carrier (polyethylene glycol [PEG] 6000) and a surfactant. Tablets were prepared by direct compression or previous wet granulation of suitable formulations containing the drug with each surfactant or drug:PEG:surfactant ternary dispersions at different PEG:surfactant w/w ratios. The presence of surfactants significantly increased (p<0.01) the drug dissolution rate, but complete drug dissolution was never achieved. On the contrary, in all cases tablets containing ternary solid dispersions achieved 100% dissolved drug within 60 min. The best product was the 10:80:10 w/w ternary dispersion with PEG 6000 and sodium laurylsulphate, showing a dissolution efficiency 5.5-fold greater than the reference tablet formulation and 100% drug dissolution after only 20 min.

Solubilizing poorly soluble antimycotic agents by emulsification via a solvent-free process.

The purpose of this study was to formulate itraconazole and ketoconazole as oil/water emulsions for parenteral delivery by using a solvent-free homogenization process, namely SolEmuls (solubilization by emulsification) technology. The drugs were incorporated in the commercial emulsion Lipofundin MCT 20%, composed of a medium-chain triglyceride/long-chain triglyceride (MCT/LCT) oil phase (1:1) and stabilized with 1.2% lecithin. Different parameters such as drug-loading capacity, long-term physical stability, and completeness of drug dissolution were investigated. Up to 10.0 mg/mL complete drug dissolution was achieved with itraconazole; at 20 mg/mL hybrid dispersion was obtained. Itraconazole-loaded emulsions were physically stable for 9 months (data up to now). Ketoconazole showed physical instability in the Lipofundin emulsion, which was stabilized with only 1.2% lecithin. Stabilization of ketoconazole-loaded emulsions was achieved using additionally Tween 80 as steric stabilizer. Higher concentrations of ketoconazole (ie, 10.0 mg/mL concentrated ketoconazole emulsions) were also produced with additional 2.0% Tween 80. Ketoconazole-loaded emulsions, 1 mg/mL, which were stabilized with 2.0% Tween 80, were stable for a period of 6 months. It can be concluded, after formulating amphotericin B and carbamazepine with SolEmuls technology, that SolEmuls was also applicable to the antimycotic agents itraconazole and ketoconazole, yielding IV-applicable emulsions with cost-effective production technologies.