Cryogenic liquids, nanoparticles, and microencapsulation

The biopharmaceutical classification system (BCS) is used to group pharmaceutical actives depending upon the solubility and permeability characteristics of the drug. BCS class II compounds are poorly soluble but highly permeable, exhibiting bioavailability that is limited by dissolution. The dissolution rate of BCS class II drug substances may be accelerated by enhancing the wetting of the bulk powder and by reducing the primary particle size of the drug to increase the surface area. These goals may be achieved by nucleating drug particles from solution in the presence of stabilizing excipients. In the spray freezing into liquid (SFL) process, a drug containing solution is atomized and frozen rapidly to engineer porous amorphous drug/excipient particles with high surface areas and dissolution rates. Aqueous suspensions of nanostructured particles may be produced from organic solutions by evaporative precipitation into aqueous solution (EPAS). The suspensions may be dried by lyophilization. The particle size and morphology may be controlled by the type and level of stabilizers. In vivo studies have shown increased bioavailability of a wide variety of drugs particles formed by SFL or EPAS. For both processes, increased serum levels of danazol (DAN) were observed in mice relative to bulk DAN and the commercial product, Danocrine. Orally dosed itraconazole (ITZ) compositions, formed by SFL, produce higher serum levels of the drug compared to the commercial product, Sporanox oral solution. Additionally, nebulized SFL processed ITZ particles suspended in normal saline have been dosed via the pulmonary route and led to extended survival times for mice inoculated with Aspergillis flavus. SFL and EPAS processes produce amorphous drug particles with increased wetting and dissolution rates, which will subsequently supersaturate biological fluids in vivo, resulting in increased drug bioavailability and efficacy.     

Comparison of powder produced by evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) technologies using novel Z-contrast STEM and complimentary techniques.

The objective of this study was to compare the properties of particles formed by nucleation and polymer stabilization (e.g. evaporative precipitation into aqueous solution (EPAS)) versus rapid freezing (e.g. spray freezing into liquid (SFL)). Powders formed by EPAS and SFL, composed of danazol and PVP K-15 in a 1:1 ratio, were characterized using X-ray powder diffraction, modulated differential scanning calorimetry (MDSC), contact angle determination, dissolution, scanning electron microscopy (SEM), environmental scanning electron microscopy (ESEM), BET specific surface area, and Z-contrast scanning transmission electron microscopy (STEM). Large differences in particle morphologies and properties were observed and explained in terms of the particle formation mechanisms. Both techniques produced amorphous powders with high T(g) and low contact angle values. However, STEM analysis showed highly porous bicontinuous nanostructured 30nm particles connected by narrow bridges for SFL versus aggregated 500 nm primary particles for EPAS. The combination of STEM and other characterization techniques indicates solid solutions were formed for the SFL powders consistent with rapid freezing. In contrast, the EPAS particle cores are enriched in hydrophobic API and the outer surface is enriched in the hydrophilic polymer, with less miscibility than in the SFL powders. Consequently, dissolution rates are faster for the SFL particles, although both techniques enhanced dissolution rates of the API.     

Enhanced drug dissolution using evaporative precipitation into aqueous solution

A new process, evaporative precipitation into aqueous solution (EPAS) has been developed to coat poorly water soluble drugs, in this case carbamazepine, with hydrophilic stabilizers to enhance dissolution rates. A heated organic solution of the drug in dichloromethane is sprayed though a fine nozzle into a heated aqueous solution. The rapid evaporation of the organic solvent produces high supersaturation and rapid precipitation of the drug in the form of a colloidal suspension that is stabilized by a variety of low molecular weight and polymeric surfactants. The stabilizer adsorbs to the drug surface and prevents particle growth and crystallization during the spray process. The suspensions are dried by spray drying or ultra-rapid freezing. The high dissolution rates are a consequence of the following advantages of the EPAS process: a small primary particle size, a hydrophilic coating on the particles that enhances wetting, and low crystallinity.     

Rapid dissolving high potency danazol powders produced by spray freezing into liquid process

The objective of this study was to investigate the use of organic solvents in the spray freezing into liquid (SFL) particle engineering process to make rapid dissolving high potency danazol powders and to examine their particle size, surface area and dissolution rate. The maximum drug potency produced was 91% for SFL micronized danazol/PVP K-15. XRD indicated that danazol in the high potency SFL powders was amorphous. SEM micrographs revealed that the SFL danazol/PVP K-15 nanostructured aggregates had a porous morphology and were composed of many smooth primary nanoparticles with a diameter of about 100 nm. Surface areas of SFL danazol/PVP K-15 high potency powders were in the range of 28-115 m2/g. The SFL powders exhibited significantly enhanced dissolution rates. The rate of dissolution of micronized bulk danazol was slow; only 30% of the danazol was dissolved in 2 min. However, 95% of danazol was dissolved in only 2 min for the SFL high potency powders. The SFL process offers a highly effective approach to produce high potency danazol nanoparticles contained in larger structured aggregates with rapid dissolution rates, and is especially applicable to delivery systems containing poorly water soluble drugs.     

Preparation of cyclosporine A nanoparticles by evaporative precipitation into aqueous solution

Amorphous nanoparticle suspensions of a poorly water-soluble drug, cyclosporine A, are produced by a new process, evaporative precipitation into aqueous solution (EPAS). The rapid evaporation of a heated organic solution of the drug, which is atomized into an aqueous solution, results in fast nucleation leading to nanoparticles suspensions. Hydrophilic stabilizers, introduced in the organic or aqueous phases, limit particle growth and inhibit crystallization for drug concentrations as high as 35 mg/ml, and drug/surfactant ratios up to 1.0. The suspensions may be used in parenteral formulations to enhance bioavailability or may be dried to produce oral dosage forms with the potential for high dissolution rates due to the low crystallinity, small particle size and hydrophilic stabilizer that enhances wetting.     

A mechanistic study of danazol dissolution in ionic surfactant solutions

This study examined the dissolution mechanism of the neutral drug danazol into solutions of the ionic surfactant sodium dodecyl sulfate (SDS). The effect of counterion concentration on drug dissolution was also studied by controlling the solution ionic strength (IS). The laminar flow apparatus of Shah and Nelson was chosen to measure in vitro dissolution rates for its simulation of physiological hydrodynamics. A mathematical model was developed to test the proposed mechanism for dissolution. Transport of the dissolved drug away from the tablet surface is the slow step in the process. Two major physicochemical properties, drug solubility in surfactant solutions and the effective diffusion coefficients used in the model, were measured in separate experiments for use in the transport model. Pulsed field proton nuclear magnetic resonance spectroscopy ((1)H NMR) was used to measure the drug diffusion coefficient. Actual drug dissolution rates were determined by multiplying the measured effluent drug concentration in the aqueous medium by its flow rate. The assumption of a transport-controlled dissolution rate was tested by plotting the measured dissolution rates as a function of medium flow rate in a log-log plot. A slope of 1/3 is predicted by the model and slopes of 0.26 to 0.32 were found experimentally, suggesting that the transport controlled mechanism is accurate. The model-predicted dissolution rates were compared with the experimental data. For SDS solutions without IS control, the model calculated data are 20-35% lower than the experimental results, whereas with IS control, the error is only 0.4-4%. We believe that there is significant electrostatic interaction between micelles in processes with low IS or poor IS control. In that situation, the nuclear magnetic resonance (NMR)-measured drug diffusivity would not be its actual value in the dissolution process.     

Improvement of dissolution rates of poorly water soluble APIs using novel spray freezing into liquid technology

Purpose. To develop and demonstrate a novel particle engineering technology, spray freezing into liquid (SFL), to enhance the dissolution rates of poorly water-soluble active pharmaceutical ingredients (APIs). Methods. Model APIs, danazol or carbamazepine with or without excipients, were dissolved in a tetrahydrofuran/water cosolvent system and atomized through a nozzle beneath the surface of liquid nitrogen to produce small frozen droplets, which were subsequently lyophilized. The physicochemical properties of the SFL powders and controls were characterized by X-ray diffraction, scanning electron microscopy (SEM), particle size distribution, surface area analysis, contact angle measurement, and dissolution. Results. The X-ray diffraction pattern indicated that SFL powders containing either danazol or carbamazepine were amorphous. SEM micrographs indicated that SFL particles were highly porous. The mean particle diameter of SFL carbamazepine/SLS powder was about 7 m. The surface area of SFL danazol/poloxamer 407 powder was 11.04 m²/g. The dissolution of SFL danazol/poloxamer 407 powder at 10 min was about 99%. The SFL powders were free flowing and had good physical and chemical stability after being stored at 25°C/60%RH for 2 months. Conclusions. The novel SFL technology was demonstrated to produce nanostructured amorphous highly porous particles of poorly water soluble APIs with significantly enhanced wetting and dissolution rates.     

Physical stability of micronized powders produced by spray-freezing into liquid (SFL) to enhance the dissolution of an insoluble drug

PURPOSE: The objective of this study was to investigate the physical stability of micronized powders produced by the spray-freezing into liquid (SFL) particle engineeringtechnology. MATERIALS AND METHODS: Danazol was formulated with polyvinyl alcohol (MW 22,000), poloxamer 407, and polyvinylpyrrolidone K-15 to form a cosolvent solution that was SFL processed. The dried micronized SFL powders were sealed in glass vials with desiccant and exposed to 25 degrees C/60% RH for 3 and 6 mo, 40 degrees C/75% RH for 1, 2, 3, and 6 mo, and conditions where the temperature was cycled between -5 and +40 degrees C (6 cycles/24 hr) with constant 75% RH for 1, 2, 3 and 4 wk. The samples were characterized by using Karl-Fisher titration, differential scanning calorimetry, x-ray diffraction, specific surface area, scanning electron microscopy, and dissolution testing. RESULTS: Micronized SFL powders consisting of porous aggregates with small-particle domains were characterized as having high surface areas and consisted of amorphous danazol embedded within a hydrophilic excipient matrix. Karl-Fischer titration revealed no moisture absorption over the duration of the stability studies. Differential scanning calorimetry studies demonstrated high degrees of molecular interactions between danazol, PVA, poloxamer, and PVP. Scanning electron microscopy studies confirmed these interactions, especially those between danazol and poloxamer. These interactions facilitated API dissolution in the aqueous media. Powder surface area remained constant during storage at the various stability conditions, and danazol recrystallization did not occur during the entirety of the stability studies. Micronized SFL powders containing danazol dissolved rapidly and completely within 5 min in aqueous media. No differences were observed in the enhanced dissolution profiles of danazol after exposure to the storage conditions investigated. Physically stable micronized powders produced by the SFL particle engineering technology were produced for the purpose of enhancing the dissolution of an insoluble drug. CONCLUSIONS: The potential of the SFL particle-engineering technology as a micronization technique for enhancing the dissolution of hydrophobic drugs was demonstrated in this study. The robustness of the micronized SFL powders to withstand stressed storage conditions was shown.     

Use of conventional surfactant media as surrogates for FaSSIF in simulating in vivo dissolution of BCS class II drugs

The usefulness of selected conventional surfactant media to enhance dissolution of BCS class II drugs similarly to fasted state simulated intestinal fluid (FaSSIF) and to predict the absorption of drugs in vivo was evaluated. Dissolution behavior of danazol (Danol®), spironolactone (Spiridon®) and N74 (phase I compound) was compared between FaSSIF, containing physiological levels of sodium taurocholate (STC) and lecithin, and dissolution media containing various concentrations of anionic surfactant, sodium lauryl sulfate (SLS) or non-ionic surfactant, polysorbate (Tween) 80. Although these media differed largely in their solubilization ability, micelle size, diffusivity and surface tension, similar dissolution enhancing levels were achieved between FaSSIF and drug-specific concentrations of conventional surfactants. The dissolution enhancement was shown, however, to be important only for danazol and N74, molecules that are characterized by high hydrophobicity. An in vivo pharmacokinetic dog study was carried out with N74. Comparison of observed plasma profiles with simulated profiles obtained using compartmental absorption and transit model (CAT) indicated that 0.1% SLS medium was the best to predict in vivo plasma profiles and pharmacokinetic parameters (C_max and AUC). This study demonstrates the potential of substituting FaSSIF with more simple and cost-effective conventional surfactant media. Use of in vivo prognostic amounts of synthetic surfactants in dissolution testing could largely assist in industrial drug development as well as in quality control purposes.     

Simultaneous production and co-mixing of microparticles of nevirapine with excipients by supercritical antisolvent method for dissolution enhancement

Microparticles of a poorly water-soluble model drug, nevirapine (NEV) were prepared by supercritical antisolvent (SAS) method and simultaneously deposited on the surface of excipients such as lactose and microcrystalline cellulose in a single step to reduce drug–drug particle aggregation. In the proposed method, termed supercritical antisolvent-drug excipient mixing (SAS-DEM), drug particles were precipitated in supercritical CO₂ vessel containing excipient particles in suspended state. Drug/excipient mixtures were characterized for surface morphology, crystallinity, drug–excipient physico-chemical interactions, and molecular state of drug. In addition, the drug content uniformity and dissolution rate were determined. A highly ordered NEV–excipient mixture was produced. The SAS-DEM treatment was effective in overcoming drug–drug particle aggregation and did not affect the crystallinity or physico-chemical properties of NEV. The produced drug/excipient mixture has a significantly faster dissolution rate as compared to SAS drug microparticles alone or when physically mixed with the excipients.     

Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs

Danazol is a poorly water soluble compound (10 μg/ml) that demonstrates poor bioavailability. The impact on bioavailability of increasing the area for dissolution by decreasing drug crystal particle size to less than 200 nm and stabilizing the particles to prevent agglomeration in the GI tract has been evaluated. A randomized three-way crossover study was conducted in fasted male beagle dogs to compare absolute oral bioavailability of danazol from three formulations. The three formulations examined were: A, an aqueous dispersion of nanoparticulate danazol (mean particle size 169 nm); B, danazol-hydroxypropyl-β-cyclodextrin (HPB) complex; C, an aqueous suspension of conventional danazol particles (mean particle size 10 μm). The three formulations were administered (200 mg) at 1 week intervals, and a fourth leg was conducted using intravenous danazol-HPB at a dose of 3 mg/kg. Plasma samples were obtained over the course of 24 h and analyzed by SPE-HPLC. Absolute oral bioavailability of each formulation was determined by comparison of oral AUC values to intravenous AUC values in the same dog, normalized to a 20 mg/kg dose. Absolute bioavailabilities of the three formulations were: nanoparticulate danazol, 82.3 ± 10.1%; cyclodextrin complex, 106.7 ± 12.3%; conventional danazol suspension, 5.1 ± 1.9%. The bioavailabilities of nanoparticle dispersion and cyclodextrin complex are not significantly different (P = 0.05) suggesting that the nanoparticle dispersion had overcome the dissolution rate limited bioavailabilty observed with conventional suspensions of danazol. This approach should have general applicability to many poorly soluble drugs with dissolution rate-limited absorption.     

Melt granulation using a twin-screw extruder: a case study

The purpose of this study was to use a twin-screw extruder for melt granulation. Polyethylene glycols (PEG 400 and 4000) were used as binders for the development of a drinking water formulation with immediate drug release. The effect of drug content, PEG 400/4000-ratio, surfactant (type and concentration) and granulation temperature on granule properties and dissolution characteristics was determined. The granulation temperature had an important influence on the granule formation. High yield (95% of the granules <1400 microm) was obtained only at a temperature near the melting point of PEG 4000. During granulation the drug of BCS class II was finely dispersed in the PEGs, creating a micro-environment around the drug particles enhancing the dissolution rate. To obtain complete drug release within 10 min for a formulation containing 10% drug, the addition of 2% (w/w) surfactant (polysorbate 80 or Cremophor RH40) was required. At a higher drug content (20%), the PEG 4000 concentration had to be increased to 20% to improve granule properties and 4% polysorbate 80 was required to obtain 100% drug release. X-ray diffractograms showed distinct peaks of crystalline drug, the crystallinity of the drug did not change after 50 days, independent of the storage conditions.     

Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles

The slow dissolution rate exhibited by poorly water-soluble drugs is a major challenge in the drug development process. Following oral administration, drugs with slow dissolution rates generally show erratic and incomplete absorption which may lead to therapeutic failure. The aim of this study was to improve the dissolution rate and subsequently the oral absorption and bioavailability of a model poorly water-soluble drug. Microparticles containing the model drug (griseofulvin) were produced by spray drying the drug in the absence/presence of a hydrophilic surfactant. Poloxamer 407 was chosen as the hydrophilic surfactant to improve the particle wetting and hence the dissolution rate. The spray dried particles were characterized and in vitro dissolution studies and in vivo absorption studies were carried out. The results obtained showed that the dissolution rate and absolute oral bioavailability of the spray dried griseofulvin/Poloxamer 407 particles were significantly increased compared to the control. Although spray drying griseofulvin alone increased the drug's in vitro dissolution rate, no significant improvement was seen in the absolute oral bioavailability when compared to the control. Therefore, it is believed that the better wetting characteristics conferred by the hydrophilic surfactant was responsible for the enhanced dissolution rate and absolute oral bioavailability of the model drug.     

Effect of crystallinity of microcrystalline cellulose on the compactability and dissolution of tablets.

Microcrystalline cellulose (MCC) was pulverized with a vibrational rod mill. The degree of crystallinity of MCC decreased from 65.5 to 12.1% with pulverization time due to mechanochemical effect. Pulverized MCCs were compressed at 155.6 MPa using a compression test apparatus, and the two parameters relating to compactability, the B value and yield pressure, were calculated using a Heckel plot. These values were lowered as the degree of crystallinity of MCC became smaller. These results suggest that the crystal region and the amorphous region in MCC particles may be mainly fractured and deformed plastically during compression, respectively. Then the dissolution test was performed for the acetaminophen-MCC (10:90) tablets. Dissolution profiles showed an interesting phenomenon, namely, the dissolution rate of acetaminophen from MCC tablet decreased when the degree of crystallinity of MCC was in the range from 65.5 to 37.6%, however, it increased markedly when the degree of crystallinity of MCC was in the range from 25.8 to 12.1%. The amount of water absorbed into tablets changed in accord with the dissolution rates of acetaminophen from tablets. The dissolution data indicate that drug release can be modified by changing the degree of crystallinity of MCC.     

Preparation of a chemically stable quercetin formulation using nanosuspension technology

In the present study the evaporative precipitation into aqueous solution (EPAS) process and the high homogenization press (HPH) process were compared to evaluate their feasibility to form a chemically stable quercetin nanosuspension. The particle size and Zeta potential of the EPAS nanosuspension were similar to those of the HPH nanosuspension. Differences in results of differential scanning calorimetery and X-ray measures were observed between the two processes. The crystalline-to-amorphous phase transition was shown in the profile of EPAS dried powder. On the contrary the initial crystalline state of drug was maintained throughout the HPH process. Dissolution test results indicated that the EPAS process showed a higher improvement in the drug solubility and dissolution rate than the HPH process. At last the high performance liquid chromatography (HPLC) analysis proved the superiority of both nanosuspensions over QCT solution formulation for the chemical and photo-stability. As a result, it can be concluded that the EPAS and HPH techniques were feasible to prepare a chemically stable QCT nanosuspension with significantly enhanced dissolution rate.     

Simultaneous micronization and surface modification for improvement of flow and dissolution of drug particles

Simultaneous micronization and surface modification of drug particles is considered in order to mitigate disadvantages of micronization, e.g., agglomeration, poor flowability, marginal increase in surface area and low bulk density. Particles of ibuprofen (102 μm), a model drug, pre-blended with hydrophilic nano-silica, are micronized down to 10 and 5 μm in a continuous fluid energy mill (FEM) to obtain fine surface modified particles. The solid feeding rate and the grinding pressure are shown as critical parameters for achieving the desired particle size and size distribution. The powder properties were characterized via SEM, laser scattering, powder rheometer with shear-cell, and dissolution test. Significant improvement in flow properties and dissolution rate was observed when micronization accompanied surface modification. Additionally, co-grinding with water-soluble polymer during micronization led to further increase in bulk density and more enhanced dissolution rate improvement, which is attributed to improved wettability. XRD, DSC and Raman were used to examine crystallinity, indicating minimal detectable physical transformation with FEM processed ibuprofen. The surface modified, micronized powders also showed improved dispersion, higher bulk densities (>0.4 g/ml), reduced electrostatic, and higher flowability (FFC ≥ 6) compared to just micronized powder (0.19 g/ml, FFC=1.0), indicating they may be used in high drug loaded formulations amenable to direct compression.     

Characterization of calcium fenoprofen 1. Powder dissolution rate and degree of crystallinity

Samples of calcium fenoprofen crystals have been prepared on laboratory, pilot and production scales, some by conventional aqueous precipitation, others under conditions designed to increase or decrease the degree of crystallinity. They were characterized by X-ray powder diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, surface area by nitrogen sorption, agglomerate size by Coulter counter, true density, sodium content, powder dissolution rates and heats of solution. No evidence of polymorphic variation was found. Most precipitation conditions gave partially fused agglomerates of primary crystals. Relative degrees of crystallinity were assessed from heats of solution. The more perfectly crystalline samples gave relatively high endothermic heats of solution coupled with low powder dissolution rates. Lattices with high levels of disruption, or low crystallinity, gave lower heats of solution coupled with enhanced powder dissolution rates. Heats of solution make a significant contribution to the overall characterization and to understanding batch-to-batch variation, and they relate well to the observed powder dissolution rates.     

NanoClusters Surface Area Allows Nanoparticle Dissolution with Microparticle Properties

Poorly water-soluble drugs comprise the majority of new drug molecules. Nanoparticle agglomerates, called NanoClusters, can increase the dissolution rate of poorly soluble compounds by increasing particle surface area. Budesonide and danazol, two poorly soluble steroids, were studied as model compounds. NanoCluster suspensions were made using a Netzsch MiniCer media mill with samples collected between 5 and 15 h and lyophilized. Differential scanning calorimetry (DSC) and powder X-ray Diffraction were used to evaluate the physicochemical properties of the powders, and Brunauer, Emmett and Teller (BET) analysis was used to determine surface area. Scanning electron microscopy confirmed NanoClusters were between 1 and 5 μm. NanoCluster samples showed an increase in dissolution rate compared with the micronized stock and similar to a dried nanoparticle suspension. BET analysis determined an increase in surface area of eight times for budesonide NanoClusters and 10–15 times for danazol NanoClusters compared with the micronized stock. Melting temperatures decreased with increased mill time of NanoClusters by DSC. The increased surface area of NanoClusters provides a potential micron-sized alternative to nanoparticles to increase dissolution rate of poorly water-soluble drugs. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1787–1798, 2014     

Development of Fully Redispersible Dried Nanocrystals by Using Sucrose Laurate as Stabilizer for Increasing Surface Area and Dissolution Rate of Poorly Water-Soluble Drugs

There is much interest in converting poorly water-soluble drugs into nanocrystals as they provide extremely high surface area that increases dissolution rate and oral bioavailability. However, nanocrystals are prepared as aqueous suspensions, and once the suspensions are dried for development of solid dosage forms, the nanocrystals agglomerate as large particles to reduce the excess surface energy. For successful development of drug products, it is essential that any agglomeration is reversible, and the dried nanocrystals regain original particle sizes after redispersion in aqueous media. We have established that sucrose laurate serves as a superb stabilizer to ensure complete redispersion of dried nanocrystals in aqueous media with mild agitation. Nanocrystals (150–300 nm) of three neutral drugs (fenofibrate, danazol and probucol) were produced with sucrose laurate by media milling, and suspensions were dried by tray drying under vacuum, spray drying, and lyophilization. Dried solids and their tablets redispersed into original particle sizes spontaneously. Preliminary studies showed that sucrose laurate can also redisperse acidic and basic drugs, indicating its versatile application. Fatty acid ester of another disaccharide, lactose laurate, also performed like sucrose laurate. Thus, we have developed a method of retaining high dissolution rate and, by implication, high bioavailability of nanocrystals from solid formulations.     

Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs

Lipid-based formulations of danazol with varying quantities of included surfactant have been examined in vitro and in vivo. Formulations comprising fatty acid ester surfactants were readily hydrolysed during in vitro digestion, although Cremophor RH40 (CrRH) was less effectively hydrolysed than Cremophor EL (CrEL). Formulations comprising high quantities of digestible surfactant also appeared to less effectively prevent danazol precipitation during in vitro evaluation. These trends were replicated in vivo where danazol bioavailability in beagle dogs was higher after oral administration of self-emulsifying formulations employing 55% (w/w) CrRH when compared with CrEL. The oral bioavailability of danazol after administration of drug formulated in surfactant alone, however, was poor. Studies using predispersed and encapsulated formulations of CrRH subsequently suggested that the low bioavailability of the single surfactant formulations reflected poor dispersion. Mixtures of surfactants, improved dispersion and good oral bioavailability of danazol was evident after administration of formulations comprising CrRH and either Pluronic L121 or Gelucire 44-14, in spite of evidence of danazol precipitation during in vitro digestion of the Gelucire formulation. These data suggest that effective dispersion and resistance to precipitation during both dispersion and digestion are key design parameters for lipid-based formulations comprising high proportions of surfactant.