The decomposition of benzodiazepines during analysis by capillary gas chromatography/mass spectrometry

A capillary gas chromatography column directly interfaced to a mass spectrometer was used for the analysis of sixteen benzodiazepines. The thermal stability of the drugs was found to be related to their chemical structure. Nine of the benzodiazepines were thermally unstable indicating that care should be taken in the interpretation of gas chromatographic data from this class of drugs. The unstable benzodiazepines were: ketazolam which decomposes to diazepam; N-4 oxides (chlordiazepoxide and demoxepam) which lose an oxygen radical; aromatic 7-nitro compounds (nitrazepam and clonazepam) which are partially reduced to the corresponding amine; alpha-hydroxy ketones (lorazepam and oxazepam) which decompose with the loss of water and N-methyl-alpha-hydroxy ketones (lormetazepam and temazepam) which partially decompose with the loss of a hydrogen molecule to produce the corresponding alpha, beta-diketones. Few problems were encountered in distinguishing the drugs by their mass spectra, the exceptions being ketazolam which decomposes to diazepam and demoxepam which decomposes to desmethyldiazepam. In general, good spectra were obtained from 20-50 ng of drug injected. However, for those compounds where the decompositions were not quantitative (nitrazepam, clonazepam, lormetazepam, temazepam) detection limits were poor.     

A novel procedure for preparation of submicron liposomes-lyophilization of oil-in-water emulsions

A novel liposome preparation method is described involving the freeze-drying of oil-in-water emulsions containing sucrose in the aqueous phase as a lyoprotectant and phospholipids in the oil as emulsifiers. The oil-in-water emulsions can be prepared by emulsification and then lyophilized to obtain dry products that will, upon rehydration, form unilamellar liposomes with a mean size of less than 200 nm, as proved by dynamic light scattering, atomic force micrographs, freeze-fracture electron micrographs, and small-angle X-ray scattering (SAXS). With or without combination with active loading, this method can be used successfully to encapsulate amphiphilic or lipophilic drugs into liposomes, although it cannot be applied to hydrophilic drugs. The lyophilized products are stable and can be rehydrated to form liposomes, even after a storage period of 10 months. Based on the encapsulation efficiency for hydrophilic drugs, as well as the scanning electron micrograph and SAXS of the freeze-dried products, a unique liposome formation mechanism is proposed.     

Synthesis and Characterization of PLGA Shell Microcapsules Containing Aqueous Cores Prepared by Internal Phase Separation

The preparation of microcapsules consisting of poly(d,l-lactide-co-glycolide) (PLGA) polymer shell and aqueous core is a clear challenge and hence has been rarely addressed in literature. Herein, aqueous core-PLGA shell microcapsules have been prepared by internal phase separation from acetone-water in oil emulsion. The resulting microcapsules exhibited mean particle size of 1.1?±?0.39 μm (PDI?=?0.35) with spherical surface morphology and internal poly-nuclear core morphology as indicated by scanning electron microscopy (SEM). The incorporation of water molecules into PLGA microcapsules was confirmed by differential scanning calorimetry (DSC). Aqueous core-PLGA shell microcapsules and the corresponding conventional PLGA microspheres were prepared and loaded with risedronate sodium as a model drug. Interestingly, aqueous core-PLGA shell microcapsules illustrated 2.5-fold increase in drug encapsulation in comparison to the classical PLGA microspheres (i.e., 31.6 vs. 12.7%), while exhibiting sustained release behavior following diffusion-controlled Higuchi model. The reported method could be extrapolated to encapsulate other water soluble drugs and hydrophilic macromolecules into PLGA microcapsules, which should overcome various drawbacks correlated with conventional PLGA microspheres in terms of drug loading and release.     

银耳粗多糖对桉叶油的乳化性研究

对不同浓度、温度、pH、NaCl浓度条件下,银耳粗多糖对桉叶油的乳化能力,以及乳化体系的稳定性进行了研究。结果表明,银耳粗多糖对桉叶油的乳化性随浓度增大上升,在浓度1%时达到最大,随后呈下降趋势;在pH 4.0~8.0之间;有较好的乳化性及乳化稳定性,在此范围以外,随pH的升高、降低,银耳粗多糖的乳化和乳化性均呈下降趋势;随着温度和NaCl浓度升高,银耳粗多糖的乳化活性和乳化稳定性有所降低。     

Delivery of fluorescent-labeled cyclodextrin by liposomes: role of transferrin modification and phosphatidylcholine composition

Drug-in-CD-in-liposome (DCL) systems which encapsulate the drug/CD inclusion complexes into inner aqueous phase of liposomes have been applied as a novel strategy to improve efficacy of lipophilic antitumor drugs. The aim of this work was to assess the role of transferrin (Tf) modification and phosphatidylcholine (PC) composition on the properties of liposomes containing hydroxypropyl-β-cyclodextrin (HP-β-CD). Fluorescence dye, FITC, was conjugated with HP-β-CD to facilitate the analysis. The resulting FITC-HP-β-CD was further encapsulated into liposomes and then the liposomes were modified with Tf. The FITC-HP-β-CD-loaded liposomes with different PC compositions were compared in terms of particle size, zeta potential, FITC content, FITC-HP-β-CD leakage, phase transition temperature (T_m) and cellular uptake. The apparent partition coefficient values of different PCs were also determined. Compared to PEGylated liposomes, FITC-HP-β-CD-loaded liposomes modified with Tf had been proved to significantly increase vesicle stability and specific cellular uptake. Moreover, PC composition affected the properties of liposomes. Soybean phosphatidylcholine (SPC) liposomes modified with Tf were found to be more easily internalized into tumor cells than 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and hydrogenated soybean phosphatidylcholine (HSPC) while Tf density on the liposomal surface was similar. And the lipophilicity of SPC was found to be much higher than DPPC and HSPC. Collectively, by the optimization of PC composition, the development of DCL modified with Tf might represent a potential strategy for the antitumor application of lipophilic drugs.     

Preparation of gelatin microbeads with a narrow size distribution using microchannel emulsification

The purpose of this study was to prepare monodisperse gelatin microcapsules containing an active agent using microchannel (MC) emulsification, a novel technique for preparing water-in-oil (W/O) and oil-in-water (O/W) emulsions. As the first step in applying MC emulsification to the preparation of monodisperse gelatin microcapsules, simple gelatin microbeads were prepared using this technique. A W/O emulsion with a narrow size distribution containing gelatin in the aqueous phase was created as follows. First, the aqueous disperse phase was fed into the continuous phase through the MCs at 40°C (operating pressure: 3.9 kPa). The emulsion droplets had an average particle diameter of 40.7 μm and a relative standard deviation of 5.1%. The temperature of the collected emulsion was reduced and maintained at 25°C overnight. The gelatin microbeads had a smooth surface after overnight gelation; the average particle diameter was calculated to be 31.6 μm, and the relative standard deviation, 7.3%. The temperature was then lowered to 5°C by rapid air cooling and finally dried. The gelatin beads were dried and could be resuspended well in iso-octane. The had an average particle diameter of 15.6 μm, and a relative standard deviation of 5.9%. Using MC emulsification, we were able to prepare gelatin microbeads with a narrow size distribution. Since this emulsification technique requires only a low-energy input, it may create desirable experimental conditions for microencapsulation of unstable substances such as peptides and proteins. This method is promising for making monodisperse microbeads.     

Attenuating the size and molecular carrier capabilities of polyacrylate nanoparticles by a hydrophobic fluorine effect

This study investigates the effect of introducing alkyl chain fluorination on the properties of polyacrylate nanoparticles prepared in aqueous solution by emulsion polymerization. For this, 2,2,3,3,4,4,4-heptafluorobutyl acrylate (1) and methyl trifluoroacrylate (2) were tested as monomers as a means to prepare fluorinated polyacrylate nanoparticles to evaluate how side chain fluorination may affect nanoparticle size and drug carrier properties. Our results show that as fluorine content within the polyacrylate matrix increases, the size of the nanoparticle systematically diminishes, from 45nm (for nanoparticles containing no fluoroacrylate) to ～7nm (for nanoparticles constructed solely of fluoroacrylate). We also observe that as fluoroacrylate content and hydrophobicity increases, the nanoparticles decrease their ability to incorporate lipophilic molecules during the process of emulsification. These findings have meaningful implications in the implementation of fluorinated nanoparticles in molecular delivery.     

Development and Evaluation of Emulsions from <Emphasis Type="Italic">Carapa guianensis</Emphasis> (Andiroba) Oil

Carapa guianensis, a popular medicinal plant known as “Andiroba” in Brazil, has been used in traditional medicine as an insect repellent and anti-inflammatory product. Additionally, this seed oil has been reported in the literature as a repellent against Aedes aegypti. The aim of this work is to report on the emulsification of vegetable oils such as “Andiroba” oil by using a blend of nonionic surfactants (Span 80® and Tween 20®), using the critical hydrophilic–lipophilic balance (HLB) and pseudo-ternary diagram as tools to evaluate the system’s stability. The emulsions were prepared by the inverse phase method. Several formulations were made according to a HLB spreadsheet design (from 4.3 to 16.7), and the products were stored at 25°C and 4°C. The emulsion stabilities were tested both long- and short-term, and the more stable one was used for the pseudo-ternary diagram study. The emulsions were successfully obtained by a couple of surfactants, and the HLB analysis showed that the required HLB of the oil was 16.7. To conclude, the pseudo-ternary diagram identified several characteristic regions such as emulsion, micro-emulsion, and separation of phases.     

Enhanced bioproduction of carvone in a two-liquid-phase partitioning bioreactor with a highly hydrophobic biocatalyst

The microbial biotransformation of (-)-trans-carveol to the flavor and fragrance compound (R)-(-)-carvone by Rhodococcus erythropolis DCL14 was carried out in a 3 L two phase partitioning bioreactor with an immiscible liquid second phase in an effort to improve upon the reactor performance achieved in a single aqueous phase system. The purpose of employing the liquid second phase is to minimize biotransformation rate inhibition due to the accumulation of the toxic substrate (cis-carveol) and product (carvone) in the aqueous phase. 1-Dodecene was chosen as the solvent for this application because it is biocompatible, non-biodegradable and has a superior affinity for the target product (carvone) relative to the other solvents tested. However, when 1-dodecene was used in the biotransformation, the extremely hydrophobic R. erythropolis DCL14 created an emulsion with the organic solvent with significant sequestering of the cells into the organic phase and negligible substrate conversion. To overcome these operational difficulties, silicone oil, which is considered a liquid polymer, was used with the aim of preventing emulsification and sequestration of cells in the non-aqueous phase. Although some emulsification of the water-silicone oil was again created by the cells, operability was improved and, in fed-batch mode, the system was able to convert approximately 2(1/2) times more carveol than a benchmark single aqueous phase system before substrate/product toxicity caused the biotransformation to stop. This study has demonstrated enhancement of a microbial biotransformation for the production of a high value nutraceutical compound via the use of a second partitioning phase, along with operational challenges arising from the use of a highly hydrophobic organism in such systems.     

Formation of Fine Oil-in-Water Emulsions by the Gel Emulsification Method with Saccharide and Protein

An emulsification method using a gel-like phase of a saccharide and protein mixture has been developed. In the method, which is called a gel emulsification method, an oil is added to the highly concentrated saccharide solution containing protein to form a clear gel-like phase, which followed by dilution with water to form a fine oil-in-water emulsion. This emulsion was investigated as to its emulsifying activity and emulsion stability as compared with that obtained by high-shear equipment, which was called a homomixer method. The emulsifying activity of the emulsions prepared by the gel emulsification method was much higher than that of the emulsions prepared by the homomixer method.

The emulsions prepared by both methods were highly stable in terms of the stability against coalescence. On the other hand, the stability against creaming of the emulsions prepared by the gel emulsification method was much higher than that of the emulsions prepared by the homomixer method.

The surface hydrophobicity of the protein and the unfreezable water content in the highly concentrated saccharide solution containing protein were not correlated to the emulsifying properties of the emulsions prepared by the gel emulsification method, which appeared to be dependent on the viscosity of the highly concentrated saccharide solution containing protein.     

Spontaneous Emulsification of Nifedipine-Loaded Self-Nanoemulsifying Drug Delivery System

Self-nanoemulsifying drug delivery system (SNEDDS) can be used to improve dissolution of poorly water-soluble drugs. The objective of this study was to prepare SNEDDS by using ternary phase diagram and investigate their spontaneous emulsifying property, dissolution of nifedipine (NDP), as well as the pharmacokinetic profile of selected SNEDDS formulation. The results showed that the composition of the SNEDDS was a great importance for the spontaneous emulsification. Based on ternary phase diagram, the region giving the SNEDDS with emulsion droplet size of less than 300 nm after diluting in aqueous medium was selected for further formulation. The small-angle X-ray scattering curves showed no sharp peak after dilution at different percentages of water, suggesting non-ordered structure. The system was found to be robust in different dilution volumes; the droplet size was in nanometer range. In vitro dissolution study showed remarkable increase in dissolution of NDP from SNEDDS formulations compared with NDP powders. The pharmacokinetic study of selected SNEDDS formulation in male Wistar rats revealed the improved maximum concentration and area under the curve. Our results proposed that the developed SNEDDS formations could be promising to improve the dissolution and oral bioavailability of NDP.KEY WORDS: nifedipine, poorly water-soluble drug, self-emulsifying drug delivery system, spontaneous emulsification     

Solubilizing poorly soluble antimy cotic agents by emulsification via a solvenent-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.     

Dynamic changes in size distribution of emulsion droplets during ethyl acetate-based microencapsulation process

This study investigated the dynamic effect of the emulsification process on emulsion droplet size in manufacturing microspheres using ethyl acetate as an organic solvent. A dispersed phase consisting of poly(lactide-co-glycolide) and ethyl acetate was emulsified in a poly(vinyl alcohol) aqueous solution for a predetermined time ranging from 2 to 9, 16, 23, 30, 40, 50, or 60 minutes. Ethyl acetate was then quickly extracted to transform emulsion droplets into solidified microspheres, and their size distribution was determined. This experimental design allowed quantification of the size distribution of emulsion droplets over the course of emulsification. When emulsification time was extended from 2 to 60 minutes, the emulsion droplets decreased in size from 98.1 to 50.3 microm and their surface area increased from 0.07 to 0.29 m2/g. Overall, prolonging emulsification time up to 60 minutes resulted in the progressive evolution of smaller emulsion droplets (1-60 microm) and the simultaneous disappearance of larger ones (> 81 microm). Increases in the total number of microspheres and their surface area were caused mainly by continuous fragmentation of emulsion droplets before ethyl acetate extraction. The increase in the smaller microsphere population might also be due in part to shrinkage of microspheres. These results show that the onset of ethyl acetate extraction influenced the kinetics of the breakup and formation of emulsion droplets, thereby affecting to a great extent the size distribution of microspheres.     

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.     

Formulation development and optimization using nanoemulsion technique: A technical note

Summary and Conclusion  Ramipril nanoemulsion formulations were successfully prepared by the spontaneous emulsification method (titration method). Sefsol 218 was selected as the oil phase for the development of the formulation on the basis of the solubility studies. The differences in the droplet size between the formulations selected from the phase diagram was not statistically significant, although the polydispersity was at a minimum for the formulation containing 20% oil, 27% Smix, and 53% vol/vol aqueous phase. The droplet size was found to be 34.5 nm. Therefore, nanoemulsion, a multipurpose technology, can be exploited in drug delivery for poorly soluble drugs. Nanoemulsions have a higher solubilization capacity than simple micellar solutions, and their thermodynamic stability offers advantages over unstable dispersions, such as emulsions and suspensions, because they can be manufactured with little energy input (heat or mixing) and have a long shelf life. This technical note explains the basis for calculation and construction of pseudoternary phase diagrams and, most important, explains selection of the formulations from the phase diagrams to avoid metastable formulations having minimum surfactant concentration in the least possible time. Published: April 6, 2007     

Method to recover a lipophilic drug from hydroxypropyl methylcellulose matrix tablets

A reverse-phase high-performance liquid chromatographic (HPLC) method for recovery of the lipophilic drug, alprazolam, from matrix tablets containing the hydrophilic polymer hydroxypropyl methylcellulose (HPMC) was developed. Lipophilic drugs, such as alprazolam, are difficult to completely extract and quantitate from tablets containing HPMC polymer. The percentage of recoveries of alprazolam from placebo powder spiked with alprazolam stock solution and from placebo powder mixed with alprazolam powder were about 100% and 85% to 95%, respectively. The validated method using water to completely dissolve HPMC before the addition of a strong solvent to dissolve and extract the drug from the HPMC solution was shown to be the most reproducible method. Different molecular weight distributions of the HPMC polymer, such as HPMC-K4M and HPMC-K100LV, did not influence the dissolution results of alprazolam using this validated method. Similarly, the excipients composing the matrix tablet formulations, such as dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, calcium sulfate dihydrate, sucrose, dextrose, and lactose monohydrate, did not influence the percent recovery of alprazolam. The recovery method reported herein was shown to be the most efficient to achieve complete recovery of alprazolam from powder blends and tablets containing a variety of excipients and different grades of HPMC.     

Phosphatidyl choline-based colloidal systems for dermal and transdermal drug delivery

In this study we have prepared various phosphatidyl choline based colloidal systems, namely liposomes, transfersomes, microemulsions and micelles, using similar excipients and compared their ability to deliver drugs into and through the skin under occlusive and non-occlusive conditions. Hydrophilic propranolol hydrochloride (PHCl) and lipophilic propranolol base (PB) were used as model drugs. All tested parameters, that is formulation composition, drug characteristics and testing conditions, influenced skin permeability and skin retention. A trend was observed showing that the skin permeation as well as skin retention decreases with the amount of phosphatidyl choline in the formulations for both tested model drugs (micelles > transfersomes > liposomes > microemulsion). The lipophilic model drug had higher skin permeability especially when incorporated into the systems containing mainly hydrophilic excipients. Skin retention, however, was not affected by the drug hydrophilicity to the same extent as skin permeability. Occlusion increased both skin retention and skin permeation for both model drugs.     

Effect of formulation variables on preparation and evaluation of gelled self-emulsifying drug delivery system (SEDDS) of ketoprofen

The purpose of this study was to formulate a gelled self-emulsifying drug delivery system (SEDDS) containing ketoprofen as an intermediate in the development of sustained release solid dosage form. Captex 200 (an oil), Tween 80 (a surfactant), and Capmul MCM (a cosurfactant) were used to formulate SEDDS. Silicon dioxide was used as a gelling agent, which may aid in solidification and retardation of drug release. Effect of concentrations of cosurfactant and gelling agent on emulsification process and in vitro drug diffusion was studied using 3² factorial design. Multiple regression analysis data and response surfaces obtained showed that liquid crystal phase viscosity increased significantly with increasing amount of silicon dioxide, which in turn caused an increase in average droplet size of resultant emulsion and slower drug diffusion. Drug release from the formulation increased with increasing amount of cosurfactant.     

Stability of CoQ10-Loaded Oil-in-Water (O/W) Emulsion: Effect of Carrier Oil and Emulsifier Type

Co-enzyme Q10 (CoQ10), a lipophilic compound that widely used in the food and pharmaceutical products was formulated in a κ-carrageenan coated oil-in-water (O/W) emulsion. In this work, we examined the solubility of CoQ10 in different carrier oils and effects of emulsifier type on the formation and stability of CoQ10-loaded O/W emulsion. Nine vegetable oils and four types of emulsifiers were used. CoQ10 was found significantly (p?<?0.05) more soluble in medium chain oils (coconut oil and palm kernel oil) as compared to other vegetable oils. The O/W emulsions were then prepared with 10 % (w/w) coconut oil and palm kernel oil containing 200 g CoQ10/L oil stabilized by 1 % (w/v) emulsifiers (sucrose laurate (SEL), sodium stearoyl lactate (SSL), polyglycerol ester (PE), or Tween 80 (Tw 80)) in 1 % (w/v) κ-carrageenan aqueous solution. Particle size distribution and physical stability of the emulsions were monitored. The droplet sizes (surface weighted mean diameter, D[3,2]) of fresh O/W emulsion in the range of 2.79 to 5.83 μm were observed. Irrespective of the oil used, results indicated that complexes of SSL/κ-carrageenan provided the most stable CoQ10-loaded O/W emulsion with smaller and narrower particle size distribution. Both macroscopic and microscopic observations showed that O/W emulsion stabilized by SSL/κ-carrageenan is the only emulsion that exhibited no sign of coalescence, flocculation, and phase separation throughout the storage period observed.     

Application of Ultra-Centrifugation and Bench-Top <Superscript>19</Superscript>F NMR for Measuring Drug Phase Partitioning for the Ophthalmic Oil-in-Water Emulsion Products

Generic drug products are expected to have the same active pharmaceutical ingredient (API) (Q1) with the same content (Q2) and microstructure arrangement (Q3) as the innovator product. In complex oil-in-water emulsion drugs, the hydrophobic API is mainly formulated in oil droplets stabilized by surfactant and micelles composed of extra surfactant molecules. The API phase partition in oil and water (mainly micelle) is a critical quality attribute (CQA) of emulsion product in demonstrating physicochemical equivalence using difluprednate (DFPN) emulsion product Durezol® as a model, we developed a novel low-field benchtop NMR method to demonstrate its applicability in measuring DFPN phase partition for ophthalmic oil-in-water emulsion products. Low-field ¹⁹F spectra were collected for DFPN in formulation, in water phase and oil phase after separation from ultra-centrifugation. The NMR data showed the mass balance of DFPN before and after phase separation. The average water phase content of different Durezol® lots was 32 ± 3% with 1% variation from method reproducibility test. The partition results were 52 ± 2% for the in-house control products prepared in Q1/Q2 equivalence to Durezol® but by a different process. The significant difference in DFPN-phase partition between Durezol® and the in-house formulation demonstrated manufacture difference readily changed the API partition. The newly developed ultra-centrifugation and ¹⁹F NMR by benchtop instrument is a simple, robust, and sensitive analytical method for ophthalmic emulsion drug product development and control.