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Purpose: Products formulated for intramammary (IMM) infusion are intended for the delivery of therapeutic moieties directly into the udder through the teat canal to maximize drug exposure at the targeted clinical site, the mammary gland, with little to no systemic drug exposure. Currently, to our knowledge, there has been no in-vitro matrix system available to differentiate between IMM formulations. Our goal is to develop A custom tailored in-vitro "Matrix of Chemistry, Manufacturing and Control" (MoCMC) System to be a promising future tool for identifying inequivalent IMM formulations. MoCMC can detect inter and intra batch variabilities, thereby identifying potential generics versus brand product similarities or differences with a single numeric value and a specific & distinctive fingerprint., Methods: The FDA-approved IMM formulation, SPECTRAMAST Ⓡ LC, was selected as the reference product for the MoCMC. Twelve in-house test formulations containing ceftiofur hydrochloride were formulated and characterized. The MoCMC was developed to include six input parameters and three output parameters. The MoCMC system was used to evaluate and compare SPECTRAMAST Ⓡ LC with its in-house formulations., Results: Based on the MoCMC generated parameters, the distinctive fingerprints of MoCMC for each IMM formulations, and the statistical analyses of MCI and PPI values, in-house formulations, F-01 and F-02 showed consistency while the rest of in-house formulations (F-03-F-12) were significantly different as compared to SPECTRAMAST Ⓡ LC., Conclusion: This research showed that the MoCMC approach can be used as a tool for intra batch variabilities, generics versus brand products comparisons, post-approval formulations changes, manufacturing changes, and formulation variabilities., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Intramammary (IMM) formulations are locally acting and delivered intracisternally into the udder. No pharmacopeial in-vitro release method is available to differentiate between the IMM formulations. Our research aim is to develop in-vitro release methods that discriminate different IMM formulations (SPECTRAMAST® LC and in-house formulations)., Methodology: Different in-house formulations were developed to simulate SPECTRAMAST® LC generics. SPECTRAMAST® LC and the in-house formulations were characterized for physicochemical attributes, such as particle size, rheology, drug content, sedimentation rate, and flocculation rate. The in-vitro release method was optimized by evaluating drug release using USP apparatuses 1, 2 (with and without enhancer/customized cells), and 4. Various test parameters, including medium effect (whole homogenized bovine milk versus aqueous buffer), medium volume (200-900 mL), and rotational speed (50-200 rpm) were investigated., Results: Two potential in-vitro systems can be used as discriminatory methods for IMM formulations: USP apparatus 2 with the IMM formulation loaded into two containers a) customized formulation container (83.1 cm in height and 56.4 cm in width) or b) enhancer cells with their top adapted with mesh #40 (rotation speed:125 rpm and 900 mL of whole homogenized bovine milk). The release profile of SPECTRAMAST® LC at 1 h (99.8%) was not significantly different from formulations with similar physicochemical characteristics F-01 (99.1%) and F-02 (100.5%). Formulation with different physicochemical characteristics F-03 (44.3%) and F-04 (57.2%) showed slower release (1 h) than SPECTRAMAST® LC (98.8%)., Conclusion: The developed in-vitro release methods can be used as a potential tool for in-vitro comparability evaluations for IMM formulations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The focus of present work was to prepare salt of aripiprazole (APZ) with dicarboxylic acids to improve physicochemical properties the drug. Dicarboxylic acids used in the study were malonic acid, maleic acid and succinic acid. The salts were prepared with solubilization-crystallization method. The salts were characterized for pH-solubility, dissolution, and stabilities. The Fourier infrared spectroscopy, X-ray powder diffraction, differential scanning calorimetry and near infrared chemical imaging indicated formation of new solid phase. pH-solubility profiles of the salts were similar to the drug except higher solubility were observed in the salts at all tested pH. The highest solubility was observed for APZ-Malonate salt among all the prepared salts. The solubility curve was inverted 'V' shape for APZ-maleate and APZ-succinate while it was inverted 'U' shape for APZ-malonate. The water solubility of APZ, APZ-malonate, APZ-maleate and APZ-succinate were 0.07 ± 0.02, 3503.9 ± 37.4, 269.3 ± 6.9 and 729.4 ± 9.4 µg/mL, respectively. The dissolution was 2.9 ± 0.4, 18.4 ± 3.9, 19.5 ± 1.4 and 36.6 ± 4.0% in 45 min for APZ, APZ-maleate, APZ-malonate, and APZ-succinate. The stabilities of the salts were similar to the drug. Thus, salts improved the physicochemical properties of the drug, and have similar stability profiles as that of APZ.

The focus of the study was to understand the effects of formulation and process variables on the printlets quality manufactured by selective laser sintering (SLS) 3D printing. The Box-Behnken response surface methodology was used to evaluate effects of individual variables and combinations thereof. The formulation and process variables studied were printing chamber temperature (°C, X 1 ), laser scanning speed (mm/sec, X 2 ) and lactose monohydrate concentration (%, X 3 ). The responses studied were weight of printlets (mg, Y 1 ), hardness (N, Y 2 ), disintegration time (sec, Y 3 ) and dissolved drug fraction in 15 min (%, Y 4 ). The values of Y 1 , Y 2 , Y 3 and Y 4 varied from 170.2-257.0 mg, 5.5-32.0 N, 20-120 s and 64.4-97.5%, respectively. The studied factors showed statistically significant effects on the dependent variables (p < 0.04). The correlation coefficient between empirical and model predicted values for Y 1 , Y 2 , Y 3 and Y 4 were 0.999, 0.992, 0.998 and 0.983, respectively. The model was validated by an independent experiment and actual values of the responses were in close agreement with model predicted values. Fourier transformed infrared spectroscopy indicated no chemical interactions between the components of the formulation during printing process. X-ray powder diffractograms suggested a decrease in crystallinity of the drug and lactose in the printlets. Chemical images indicated uniform distribution of the drug. Scanning electron microscopy and X-ray micro-CT scanning showed a very porous microstructure of the printlets with a porosity of about 37.89%. In conclusion, the SLS method of manufacturing provides a feasible and flexible avenue for fabricating dosage forms with tailored characteristics., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The commercial product of rifaximin (RFX) contains α form. The α form can change to β form on exposure to high humidity that can occur during manufacturing, stability, and in-use period. It is critical to maintain α form of the drug in a drug product to avoid variability in clinical response. U.S. Food and Drug Administration dissolution method was found to be nondiscriminatory for RFX formulations containing either 100% α or β form. The objective of this study was to develop a discriminatory dissolution method that can detect low levels of α to β transformation in RFX products. Formulations containing a variable fraction of α and β forms were prepared by using direct compression method. Dissolution parameters investigated were type of dissolution medium (water and phosphate buffer), volume (500, 900, and 1000 mL), and paddle speed (50, 75, and 150 rpm). Dissolution in water with 0.2% sodium lauryl sulfate was less than 80% and nondiscriminatory. However, dissolution tested in a phosphate buffer pH 7.4 with 0.2% sodium lauryl sulfate at 50 rpm was discriminatory with more than 17.5% difference in dissolution profile between formulations containing α and β forms. The developed method can detect polymorphic transformation if there is 25% or more β form conversion., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Carbamazepine (CBZ) exists in anhydrous and dihydrate forms. These forms differ in their solubility, dissolution rate, and subsequently in their oral bioavailability. The objective of this study is to develop multivariate chemometric models for estimation of the low level of carbamazepine dihydrate (CBZ-DH) in the CBZ formulations containing excipients of the commercial formulation. The selected excipients were mixed in proportions to make sample matrices ranging from 0% to 50% CBZ-DH. Fourier transform infrared (FTIR), near infrared (NIR), and hyperspectral imaging data were mathematically pretreated before the development of partial least square and principal component analysis regression models. The developed partial least squares regression and principal component analysis models demonstrated predictability of CBZ and CBZ-DH by multiple scattering correction and standard normal variate processing methods. Among the spectroscopic techniques used the model performance parameters such as root-mean-square error, standard error, and bias were found to be low for NIR compared to FTIR. The treated data have shown better model fitting than without treatment, which was demonstrated by correlation coefficient of 0.9778, 0.9824, and 0.9852 for FTIR, NIR, and hyperspectral imaging, respectively. Furthermore, the predicted values were found to be very close to the selected low level of independent samples having 5% CBZ-DH in tablet formulation., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Understanding the impact of pharmaceutical processing, formulation excipients and their interactions on the solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuring consistent product performance. This study reports the effect of polymer viscosity, diluent type, granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition of theophylline anhydrous (THA) in controlled release formulations as well as the implications of this transition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using a full factorial screening design and monitored over a 3 month period at 40 °C and 75%. Physicochemical characterization revealed a drastic drop in tablet hardness accompanied by a very significant increase in moisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD) indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueous wet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, the hydration-dehydration process induced during aqueous wet granulation hastened the pseudopolymorphic conversion of theophylline during storage through a cascade of events. On the other hand, no solid state transformation was observed in directly compressed formulations and formulations in which isopropanol was employed as a granulating fluid even after the twelve weeks study period. The transition of THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed in directly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphic transition of theophylline on dissolution in controlled release formulations may be the net result of two opposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolution and hydration of theophylline which decreases the drug dissolution., (Published by Elsevier B.V.)

This study is the second in a series that examines the characterizing and selection of suitable grades of lactose for capsule formulation development. Based upon the previous study, four grades were selected for further study. The effects of drug load and operational variables on formulations derived from these four lactose types were evaluated for physicochemical and mechanical attributes of plugs and their capsules on an instrumented dosing-disc capsule filling machine (H&H KFM/3) using acetaminophen as a model, highly soluble and poorly compressible drug. The results obtained were as follows: (1) flowability reduced upon increasing drug load; (2) powder bed height (PBH) and compression force (CF) had positive significant effect on plug weight (p < 0.05); (3) ejection force was positively and significantly correlated with increasing speed and CF (p < 0.05); (4) AL capsule plugs had the highest plug crushing force which was followed by DCL15; (5) the crushing strength of plugs made from DCL11 increased with increasing acetaminophen concentration; (6) higher CF had a significant negative impact on acetaminophen release at 15 min time point (p < 0.05); (7) at 10% and 40% drug load, formulations containing AL showed the quickest drug release; and (8) increased drug load had a significant negative impact on the release rate at 15 and 45 min time points (p < 0.05). Overall, the results from this study provides information on risk based assessment of filler selection based on drug load and the range of machine operating variables which will help in defining criteria for meeting key quality attributes for capsule formulation development.

Warfarin sodium (WS) is a narrow therapeutic index drug and its product quality should be thoroughly understood and monitored in order to avoid clinical performance issues. This study was focused on understanding the effect of manufacturing and formulation variables on WS product critical quality attributes (CQAs). Eight formulations were developed with lactose monohydrate (LM) or lactose anhydrous (LA), and were either wet granulated or directly compressed. Formulations were granulated either with ethanol, isopropyl alcohol (IPA) and IPA-water mixture (50:50). Formulations were characterized for IPA, water content, hardness, disintegration time (DT), assay, dissolution and drug physical forms (scanning electron microscopy (SEM), near infrared chemical imaging (NIR-CI), X-ray powder diffraction (XRPD) and solid state nuclear magnetic resonance (ssNMR)), and performed accelerated stability studies at 40°C/75% RH for three days. The DT and dissolution of directly compressed formulations were faster than wet granulated formulations. This was due to phase transformation of crystalline drug into its amorphous form as indicated by SEM, NIR-CI, XRPD and ssNMR data which itself act as a binder. Similarly, LM showed faster disintegration and dissolution than LA containing formulations. Stability results indicated an increase in hardness and DT, and a decrease in dissolution rate and extent. This was due to phase transformation of the drug and consolidation with particles' bonding. In conclusion, the CQAs of WS product were significantly affected by manufacturing and formulation variables., (Published by Elsevier B.V.)

The purpose of this research was to develop an orally disintegrating tablet (ODT) dosage form containing taste-masked beads of clindamycin HCl. Several formulation strategies were evaluated and a taste-masked ODT of clindamycin HCl was prepared without the use of a waxy cushioning agent. Clindamycin HCl (ca. 46% w/w) was coated onto microcrystalline cellulose beads (Cellets® 200) followed by the addition of a taste-masking layer of amino methacrylate copolymer, NF (Eudragit EPO® (EPO)) coating suspension. The efficiency of both the drug coating process and the taste-masking polymer coating process, as well as the taste masking ODTs was determined using potency and drug release analysis. Magnesium stearate was found to be advantageous over talc in improving the efficiency of the EPO coating suspension. A response surface methodology using a Box-Behnken design for the tablets revealed compression force and levels of both disintegrant and talc to be the main factors influencing the ODT properties. Blending of talc to the EPO-coated beads was found to be the most critical factor in ensuring that ODTs disintegrate within 30 s. The optimized ODTs formulation also showed negligible (<0.5%) drug release in 1 min using phosphate buffer, pH 6.8 (which is analogous to the residence time and pH in the oral cavity). By carefully adjusting the levels of coating polymers, the amounts of disintegrant and talc, as well as the compression force, robust ODTs can be obtained to improve pediatric and geriatric patient compliance for clindamycin oral dosage forms.

Clinical performance of an amorphous solid dispersion (ASD) drug product is related to the amorphous drug content because of the greater bioavailability of this form of the drug than its crystalline form. Therefore, it is paramount to monitor the amorphous and the crystalline fractions in the ASD products. The objective of the present investigation was to study the feasibility of using a standardized X-ray powder diffraction (XRPD) in conjunction with chemometric methods to quantitate the amorphous and crystalline fraction of the drug in several tacrolimus ASD products. Three ASD products were prepared in which drug to excipients ratios ranged from 1:19 to 1:49. The amorphous and crystalline drug products were mixed in various proportions so that amorphous/crystalline tacrolimus in the samples vary from 0 to 100%. XRPD of the samples of the drug products were collected, and PLSR and PCR chemometric methods were applied to the data. The R(2) was greater than '0.987' for all the models and bias in the models were statistically insignificant (p>0.05). RMSEP and SEP values were smaller for PLSR models than PCR models. The models prediction capabilities were good and can predict as low as 10% when drug to excipient ratio is as high as 1:49. In summary, XRPD and chemometric provide powerful analytical tools to monitor the crystalline fractions of the drug in the ASD products., (Copyright © 2014. Published by Elsevier B.V.)

The study objective was to evaluate the thermodynamic stability of iron sucrose complexes as determined by molecular weight (m.w.) changes. The first part of the study focused on the effect of thermal stress, pH, electrolyte or excipient dilution on the stability of a colloidal iron drug product. Part two focused on the physical and chemical evaluation of the colloidal nature of iron sucrose using a series of characterization experiments: ultracentrifugation, dialysis, particle size, zeta potential, and osmotic pressure analysis. A validated Taguchi-optimized high performance gel permeation chromatography method was used for m.w. determinations. Results indicate m.w. of the iron sucrose complex remained unchanged after excipient dilution, ultracentrifugation, dialysis, and electrolyte dilution. Electrolyte dilution studies indicated the lyophilic nature of the iron sucrose colloid with a particle size of 10nm and zeta potential of 0 mV. The complex deformed at low pH and reformed back at the formulation pH. The complex is stable under mild-to-moderate temperature <50°C but aggregates following prolonged exposure to high temperatures >70°C. In conclusion, the resistance of the complex to breakdown by electrolytic conditions, excipient dilution, ultracentrifugation and the reversible complexation after alteration of formulation pH suggest iron sucrose is a lyophilic colloid in nature and lyophilic colloidals are thermodynamically stable., (Published by Elsevier B.V.)

Crystallization of nimodipine in liquid-filled soft gelatin capsule during storage was reported for some commercial products, resulting in product recalls due to product quality and more importantly safety concerns. In this study, a real time particle monitoring tool, focused beam reflectance measurement, was used to evaluate the precipitation conditions of nimodipine in co-solvents. Upon water addition, two particle populations were discovered, appearing at different percentage of water content. Two transitions (i.e. sudden increase in particle counts) were observed, possibility related to nucleation and crystal growth of nimodipine. Furthermore, lowering storage temperature increased the tendency of nimodipine precipitation. Most critically, it was determined that with certain excipient, the drug precipitation occurred at approximately 7% (w/w) water content. Considering that all the orally administered liquid filled soft gelatin capsule shells contain residue water content as plasticizer, moisture transfer from the shell to the formulation may occur during long term storage, resulting in drug precipitation, particularly under cold temperature conditions., (Published by Elsevier B.V.)

The aim of present research was to design and evaluate orally disintegrating tablet (ODT) of novel lamotrigine-cyclamate salt. Box-Behnken response surface methodology was selected to design the optimized formulation. The independent factors selected were tablet hardness (X1), disintegrant (X2) and lubricant (X3) levels, and responses chosen were disintegration time (DT, Y1), friability (Y2), T50 (Y3), and T90 (Y4). The tablets were also characterized for drug uniformity by near infrared chemical imaging (NIR-CI) and taste masking evaluation by electronic tongue. All the selected independent variables were statistically (p<0.05) effect the Y1 while Y2, Y3, and Y4 affected only by X2. The optimized ODT was found to meet the regulatory requirement of DT and friability specification. The NIR-CI images indicated uniform distribution of active and inactive ingredients within the tablets. The electronic tongue results were analyzed by principle component analysis (PCA). It indicated that novel salt of lamotrigine and its ODT formulation have a taste similar to cyclamic acid which is indicated by close proximity on PCA score plot, lower Euclidean distance, and high discrimination index values. Furthermore, these parameters were very close to ODT placebo formulation. On the other hand, lamotrigine, its ODT, and placebo formulation were far from each other. In summary, lamotrigine salt provides another avenue for pediatric friendly formulation for children and will enhance patience compliance., (Published by Elsevier B.V.)

Various adverse events including esophagus irritations have been reported with the use of alendronate tablets, likely attributed to the rapid tablet disintegration in the mouth or esophagus. Accordingly, the disintegration of six alendronate tablet drug products was studied using a newly developed testing device equipped with in-line sensors, in addition to the official compendial procedure for measuring the disintegration time. The in-line sensors were used to monitor the particle count and solution pH change to assess the onset and duration of disintegration. A relatively large variation was observed in the disintegration time of the tested drug products using the compendial method. The data collected using the in-line sensors suggested that all tested drug products exhibited almost instantaneous onset of disintegration, under 2 s, and a sharp drop in solution pH. The drop in pH was slower for tablets with slower disintegration. The in-house prepared alendronate test tablets also showed similar trends suggesting rapid solubilization of the drug contributed to the fast tablet disintegration. This research highlights the usefulness of the newly developed in-line analytical method in combination with the compendial method in providing a better understanding of the disintegration and the accompanying drug solubilization processes for fast disintegrating tablet drug products., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: The purpose of this work was to investigate the effect of preparation methods and the drug-to-resin ratio on complex formation between risperidone and amberlite resin., Methods: The existence of such resin complex may provide taste-masking properties to the dosage forms. It is important to determine when and how the complex forms. Therefore, in this study, the complexes of risperidone and amberlite resin were prepared by granulation, solution, and freeze-drying methods at various drug-to-resin ratios. The physical mixtures of drug-resin were used to compare the results of complexes prepared by granulation, solution, and freeze drying. The complexes were evaluated by various methods of characterization including differential scanning calorimetry, X-ray diffraction, spectroscopy (near infrared, Fourier transform infrared, and Raman), drug release, and binding studies., Results: Complexation between risperidone and amberlite was investigated for various preparation methods. It was found that complexation occurred at lower amounts of amberlite resin (drug-to-resin ratios of 1:1 and 1:2) when solution form of drug was contacted with the resin as in the case of solution and freeze-drying techniques compared with granulation (drug-to-resin ratios of 1:4 and 1:6). Characterization studies such as differential scanning calorimetry, X-ray diffraction, spectroscopic techniques, and drug release studies differentiated complexes from the physical mixtures. Binding studies between them revealed that the binding was linear with solubility of the drug limiting the adsorption capacity., Conclusions: Results of the study highlighted the importance of the preparation methodologies to formulate complexes. When the drug and the resin were simply mixed physically, no complexation occurred. Thus, a careful evaluation of manufacturing procedure would indicate the nature and extent of complexation.

The objective of this study was to develop an integrated process monitoring approach for evaluating powder blending process kinetics and determining blending process end-point. A mixture design was created to include 26 powder formulations consisting of ibuprofen as the model drug and three excipients (HPMC, MCC, and Eudragit L100-55). The mixer was stopped at various time points to enable near-infrared spectroscopy scan of the powder mixture for obtaining the time course of the blending process. The evaluation of the blending process kinetics and process end-point was studied through three quantitative approaches: (1) Spectra linear superposition method; (2) Characteristic peak method; (3) Moving block standard deviation method. It was found that the powder blending experienced an initial rapid process to reach a quasi- end point within the first few minutes. Afterwards, a demixing occurred. Then, a real blending end-point was reached as characterized by an inflection point. ANOVA shows that the compositions of ibuprofen and MCC are the most statistically significant variables that impact the time required to reach the blending end-point. This highlighted the critical importance of developing quantitative chemometric approaches to extract critical process information and generate essential process knowledge to enable real-time release of the blending process., (Copyright 2009 Wiley-Liss, Inc.)

The objective of this study was to develop an integrated multivariate approach to quantify the constituent concentrations of both drug and excipients of powder blends. A mixture design was created to include 26 powder formulations consisting of ibuprofen as the model drug and three excipients(HPMC, MCC, and Eudragit L100-55). The mixer was stopped at various time points to enable near infrared(NIR) scan of the powder mixture and sampling for UV assay. Partial least square (PLS), principal component regression (PCR), and multiple linear regression (MLR) models were established to link the formulation concentrations with the Savitzky-Golay 1st derivative NIR spectral data at various characteristic wavelengths of each component. PLS models based on the NIR data and UV data were calibrated and validated. They predicted the main components' concentrations well in the powder blends, although prediction errors were larger for minor components. As expected from the complete random-mixture (CRM) model, the measurement uncertainties were higher for minor components in the powder formulations. The prediction performance differences between the NIR model and UV model were explained in the context of scale of scrutiny and model applicability. The importance of understanding excipient variability in powder blending and its implication for blending homogeneity assessment is highlighted.

The objective of this study was to examine the effects of testing parameters and formulation variables on the segregation tendency of pharmaceutical powders measured by the ASTM D 6940-04 segregation tester using design of experiments (DOE) approaches. The test blends consisted of 4% aspirin (ASP) and 96% microcrystalline cellulose (MCC) with and without magnesium stearate (MgS). The segregation tendency of a blend was determined by measuring the last/first (L/F) ratio, the ratio of aspirin concentrations between the first and last samples discharged from the tester. A 2(2) factorial design was used to determine the effects of measurement parameters [amount of material loaded (W), number of segregation cycles] with number of replicates 6. ANOVA showed that W was a critical parameter for segregation testing. The L/F value deviated further from 1 (greater segregation tendency) with increasing W. A 2(3) full factorial design was used to assess the effects of formulation variables: grade of ASP (unmilled, milled), grade of MCC, and amount of lubricant, MgS. MLR and ANOVA showed that the grade of ASP was the main effect contributing to segregation tendency. Principal Component Regression Analysis established a correlation between L/F and the physical properties of the blend related to ASP and MCC, the ASP/MCC particle size ratio (PSR) and powder cohesion. The physical properties of the blend related to density and flow were not influenced by the grade of ASP and were not related to the segregation tendency of the blend. The direct relationship between L/F and PSR was determined by univariate analysis. Segregation tendency increased as the ASP to MCC particle size increased. This study highlighted critical test parameters for segregation testing and identified critical physical properties of the blends that influence segregation tendency., ((c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association)

Purpose: To prepare a self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate, with enhanced dissolution and better chance of oral absorption., Method: All-trans-retinol acetate SNEDDS was prepared using different concentrations of soybean oil (solvent) Cremophor EL (surfactant) and Capmul MCM-C8 (co-surfactant). Particle size and turbidity of the SNEDDS were determined after adding water to the oily solution. Dissolution profile of SNEDDS filled in hydroxyl propyl methyl cellulose (HPMC) capsules was determined by using water in USP apparatus 2. Ternary phase diagrams were constructed to identify the self-nanoemulsified region. The SNEDDS were evaluated by the visual observation, turbidity in nephrometric turbidity units (NTU), mean particle size (microm) and Fourier transformed-infrared spectroscopy (FT-IR). SNEDDS were thermally characterized using differential scanning calorimetry (DSC) to ensure the compatibility of the SNEDDS ingredient., Results: From the data obtained in this work, it was clear that surfactant to co-surfactant ratio has the main impact on the physical characteristics of the emulsion formed. The optimum surfactant to co-surfactant ratio was found to be 2:1 (37.5-50% for Cremophor EL, and 18.75-25% for Capmul MCM-C8). With this ratio, the resultant nanoemulsions obtained have a particle size range of 0.103-0.051 microm, turbidity range of 18.12-2.18 NTU and t30 values (cumulative% all-trans-retinol acetate dissolved in 30 min) of 90.42-99.5. Also the thermograms obtained from DSC experiments showed that there is no incompatibility or interaction between the SNEDDS ingredients (soybean oil, Cremophor EL, and Capmul MCM-C8) and all-trans-retinol acetate., Conclusion: The present study revealed that the self-nanoemulsified drug delivery system of all-trans-retinol acetate increased its dissolution rate and has the potential to enhance its bioavailability without interaction or incompatibility between the ingredients., (copyright 2004 Elsevier B.V.)