Process variable studies for preparation of optimized system for bupropion hydrochloride using CCD

Mucoadhesive buccal film is developed as a promising dosage form, which has prominent advantages because of drug delivery through buccal mucosa. New formulation of buccal films containing rizatriptan benzoate (RB) was prepared by solvent casting method using various concentrations of hydroxypropyl methylcellulose (HPMC K4M), polyvinyl alcohol (PVA), polyethylene oxide (PEO), glycerol, stevia, and goat buccal mucosa used as a model membrane. In this work, the effect of polymers and plasticizer concentrations on drug release profile, disintegration and dissolution time, mechanical properties, and mucoadhesive characteristics of films was studied. Scanning electron microscopy analysis revealed uniform distribution of RB in film formulations. Chemical compounds and thermal analysis of the films were studied by Fourier transform infrared spectroscopy and differential scanning calorimetry, respectively. The buccal films produced were uniform in drug content and thickness. All formulations have in vitro release of 98–102% between 40 and 80 min. Also ex vivo mucoadhesion strength was in the range of 0.205 ± 0.035 to 0.790 ± 0.014 N for all formulations. A formulation consisting RB (50 mg), HPMC K4M, PVA, and PEO (63 mg), glycerol (1.5 ml), stevia (5 mg) was selected as our optimum composition. More satisfactory results were obtained in terms of disintegration and dissolution time, mechanical properties, and mucoadhesive characteristics. In addition, it showed about 99.89% RB released in 45 min. The results suggest that RB-loaded mucoadhesive buccal films could be a potential candidate to achieve optimum drug release for effective treatment of migraine.

Macro-micro structure characterization and molecular properties of emulsion-templated polysaccharide oleogels

IntroductionOrally disintegrating tablet (ODT) is a dosage form that overcomes the problem of swallowing which is prevalent in about 35% of the general population. Co-trimoxazole (CTX) is given for patients with HIV for the prophylaxis of opportunistic infection (OI), commonly for pneumocystis carinii pneumonia. It was reported that CTX was associated with a 25–46% reduction in mortality among individuals infected with HIV in sub-Saharan Africa. Esophageal candidiasis which usually comes along with HIV/AIDS is one of AIDS defining illness affecting up to 1 in 5 of people with AIDS. This opportunistic illness is manifested by painful or difficulty of swallowing. In this respect, CTX ODT offer the advantages of both liquid dosage forms in terms of easy swallowing thereby improve patient compliance and solid dosage forms in terms of dose uniformity, stability, lower production, and transportation costs. The objective of this study was to formulate, characterize and optimize CTX ODT which could overcome swallowing problem and improve patient compliance. Co-trimoxazole ODTs were prepared by direct compression technique using a semi synthetic super disintegrant (crospovidone) along with other excipients. Two taste masking techniques were employed, addition of sweetening agent, and solid dispersion by using a pH sensitive polymer, Eudragit E-100 at different ratios (1:1, 1:2 and 1:3). Taste masking was determined by comparing taste threshold value and in vitro drug release. Preliminary study was used to investigate the effect of crospovidone, compression force (CF) and Hydroxypropyl cellulose (HPC) on disintegration time, friability and wetting time (WT). Factorial design was used as it enables simultaneous evaluation of formulation variables and their interaction effect. From the preliminary study, the factors that were found significant were further optimized using central composite design. Design-Expert 8.0.7.1 software was employed to carry out the experimental design. The bitterness threshold concentration of Trimethoprim was found to be 150 μg/ml and the in vitro drug release of the three batches of drug to polymer ratio (F1:1, 1:2 and 1:3) was 2.80±0.05, 2.77±0.00 and 2.63±0.00 respectively. From the optimization study, the optimal concentration for the superdisintegrant was 8.60% w/w and a CF of 11.25 KN which gave a rapid disintegration and WT of 13.79 and 23.19 seconds respectively and a friability of 0.666%.ConclusionIn this study, co-trimoxazole ODT was formulated successfully. Central composite design was effectively used to model and optimize friability, DT and WT. The method was found effective for estimating the effect of independent variables on the dependent variables by using polynomial equation and surface plots. Optimization of the response variables was possible by using both numerical and graphical optimization and the predicted optimal conditions were confirmed experimentally and were found to be in good agreement within 5% of the predicted responses. The results of the study showed that CTX ODT had significantly rapid disintegration, less than 1% friability and enhanced dissolution profiles. The successful formulation of CTX ODT can solve difficulty of swallowing of conventional tablets for some group of patients which are unable to swallow solid oral dosage form.

This work evaluated the influence of oil type (sunflower vs. fish oil) and hydroxypropyl methylcellulose (HPMC) concentration on the properties of oleogels obtained by the emulsion-templated method. Oil-in-water emulsions were prepared and air-dried to produce oleogels containing 2.9-5.8% (w/w) HPMC. All oleogels exhibited solid-like behaviour, with viscoelastic moduli increasing with polymer concentration, and showed a high thermal stability. At a comparable HPMC content, fish oil oleogels developed stiffer networks than those obtained with sunflower oil. Texture analysis indicated a linear increase in hardness with HPMC content across both oils, while cohesiveness and adhesiveness were more influenced by oil nature. Oil-binding capacity (OBC) increased markedly with polymer content, exceeding 90% in most systems. However, fish oil oleogels consistently showed lower retention. Colour parameters were only slightly affected by HPMC concentration and were mainly determined by the intrinsic colour of each oil. Overall, both oil type and polymer concentration were shown to be critical factors determining the structural, mechanical, and functional characteristics of HPMC-based oleogels, providing useful information for the development of structured lipid systems as potential substitutes for conventional solid fats.

Cassava starch fermentations were conducted in batch cultures to optimize the effect of divalent cations on ethanol production with Saccharomyces pastorianus using the central composite rotatable response surface design. Divalent cations used were magnesium (Mg 2+ ), zinc (Zn 2+ ) and calcium (Ca 2+ ). Maximum ethanol concentration of 11.12% v/v was obtained with cationic concentration combination of 64, 0.48 and 30 mg/l for Mg 2+ , Zn 2+ and Ca 2+ , respectively, after 96 h of the fermentations. Minimum ethanol concentration of 7.53% (v/v) was obtained at a variable combination of 64, 0.48 and 76 mg/l for Mg 2+ , Zn 2+ and Ca 2+ , respectively. Thus response surface methodology was used in a central composite design to optimize the process variables of Mg 2+ , Zn 2+ , Ca 2+ in the fermentation medium, thereby increasing the ethanol production from 10.5% in the control to 11.12%. There were significant linear and quadratic effects of Zn 2+ as well as a significant (P 0.05) negative quadratic effect of Ca 2+ on ethanol production, which are confirmed in the response surface plots. Keywords: Ethanol, Saccharomyces pastorianus , cassava starch, hydrolyzates, central composite design, response surface methodology African Journal of Biotechnology Vol. 9(33), pp. 5423-5429, 16 August, 2010

Abstract: Objectives: The present work was designed to formulate extended-release tablets of clarithromycin by means of central composite design. To assess the systematic considerate of input and output variables and to construct design space, the central composited design was used. Methods: The concentrations of tamarind kernel powder (X1), ethyl cellulose (X2) and polyvinyl pyrrolidone (X3) remained as independent variables and responses were drug release in 2 h, 8 h and t50%. Polynomial equations were employed to forecast the quantitative result of nondependent constraints at different levels on responses. The model stood nonlinear and the curvature outcome was significant. Henceforth the study employed central composite design for optimization. Wet granulation method was used to prepare the tablets and were evaluated for pharmacotechnical properties. Results: FTIR and DSC studies signposted that drug and excipients were compatible. Precompression constraints specified respectable flow properties. The in vitro drug release of entire formulations at the end of 12 h was found to be 96.14% - 98.23%. Increase in the concentration of tamarind kernel powder, ethyl cellulose decreased percentage drug release. Contour plots were utilized to assess the relationship between independent variables and dependent variables. Conclusion: The statistical model is scientifically effective as the investigational estimates and foreseen estimates proposed by the model were relatively close to each other. The outcomes confirmed the success of the anticipated design for development of clarithromycin extended-release tablets with optimized properties. Key words: Tamarind kernel powder, Ethyl cellulose, Polyvinyl pyrrolidone, Clarithromycin, Central composite design, Extended release.

Present investigation describes statistically the influence of viscosity of hydroxypropyl methylcellulose and types of filler on dipyridamole release from floating matrix tablets using 3 2 full factorial design. Tablets were prepared using direct compression technique. Tablets were evaluated for in vitro floating ability and drug release study using USP 24 types II paddle apparatus using 0.1 N HCl (pH 1.2) at rotation of 100 rpm and temperature of 37±0.5°. Multiple regression analysis was performed for dependent variables studied and to evaluate contribution of factors with their levels two way ANOVA was performed followed by Tukey test. Polynomial equations and response surface plots were generated for all dependent variables. It was observed that both the factors had significant influence on all dependent variable studied (p<0.05). It was observed that as viscosity of polymer increases the release rate constant was decreased. Release rate obtained was highest when microcrystalline cellulose was employed as filler followed by dicalcium phosphate and lactose. Mechanism of drug release was anomalous types and depends upon viscosity of polymer and types of filler used. Microcrystalline cellulose gave release mechanism nearer to diffusion mechanism while dicalcium phosphate and lactose gave anomalous release. It was observed that both the factors had significant contribution on all dependent variables studied. A major controlling factor for kinetics of drug release was viscosity of polymer and it can be modified by incorporation of different types of filler. In initial phase of drug release viscosity of polymer and types of filler both governs the drug release while in later phase only the viscosity of polymer predominates

The fungus Candida albicans is one of the causes of mouth ulcer whose growth can be inhibited through the activity of saga leaf extract which contains saponin and flavonoid compounds. One of the efforts to facilitate the use of ethanolic extract of saga leaves is to make it into edible film candy preparations. This study aims to evaluate the physical properties of edible film candies containing an ethanol extract of saga leaf with varying concentrations of hydroxypropyl methylcellulose (HPMC). The ethanol extract of saga leaves was prepared using the maceration method with 70% alcohol, resulting in a 5% concentration of ethanol extract of saga leaves. The HPMC concentrations used varied between 3.5%, 2.5%, and 1.5%. Subsequently, the resulting edible film underwent physical property tests, including organoleptic evaluations, moisture content, pH, thickness, weight determination, and dissolution time. The analysis revealed that the edible film exhibited a thin shape and a blackish-green color, along with a distinctive aroma of the extracts and sweet, bitter, and minty flavors. The pH of the edible film was 6, with a moisture content of less than 20%, and a fold resistance of less than 100. Moreover, it only melted without dissolving. Statistical analysis demonstrated a significant difference in the thickness and weight of the edible film among the variations in HPMC concentration. In conclusion, the comparison of HPMC concentration affects the physical properties of edible film candy containing ethanol extract of saga leaves, and HPMC concentration of 2.5% is a suitable choice to meet the requirements of edible film according to the Indonesian National Standard (SNI).

Background: Due to short-lasting action, fast clearance and enzymatic instability of anti-diabetic drugs result in low bioavailability as they are mainly absorbed from the stomach and the lower part of the gastrointestinal tract. The bioavailability of antidiabetic drugs can be significantly increased by enhancing the gastric residence time using gastroretentive drug delivery systems such as floating microspheres.
 Objectives: The present investigation deals with the development and optimization of floating microspheres for gastroretentive delivery containing repaglinide using Box-Behnken design and also investigates the effect of different process variables on the formation of the microsphere. Thereby, increasing the bioavailability and reducing the mentioned side effects of repaglinide.
 Materials and methods: Floating microspheres of repaglinide formulated by ionic gelation method and optimized using Box-Behnken design. The independent variables were the concentration of Hydroxy methylcellulose (HPMC) (A), Sodium alginate (B), and calcium chloride (C) while entrapment efficiency (R1), swelling index (R2), and in vitro drug release (R3) were considered as dependent variables. The optimized formulation of floating microspheres was characterized by various physicochemical properties, surface morphology, drug excipient interaction, in vitro release, and buoyancy studies.
 Results: Based on obtained 3D response surface plot factors A, B, and C were found to give a synergistic effect on R1, while factor A has a negative effect on R2. Interaction of AC was negative on R1 and R2 but positive on R3. The interaction of AC and BC was negative in all the responses. Scanning electron microscopy (SEM) revealed that microspheres were spherical with nearly smooth surface morphology. Good entrapment and buoyancy were observed for 12 h. The in vitro drug release was found to be controlled for more than 12 hours and followed the Higuchi model. The validations of response surface methodology (RSM) for three dependent variables were 100.09%, 99.68%, and 97.02%.
 Conclusion: Repaglinide floating microspheres were prepared and optimized by use of Box – Behnken process optimization software. The quantitative responses of particle size, entrapment efficiency, and in vitro drug release for different combinations of independent variables, sodium alginate as release retarding polymer, HPMC K100M as floating polymer, and calcium chloride as a cross-linking agent were obtained experimentally, and the results were found to fit the design model. The quantitative effect of these factors at different levels on the responses could be predicted using polynomial equations, and high linearity was observed between predicted and actual values of response variables. The results of the present study showed that the responses i.e, particle size, entrapment efficiency, and in vitro release are significantly affected by the concentration of polymer and a cross-linking agent. The formulation OF1 was found to be the optimum formulation predicted by the point prediction of the design expert software. The in vitro drug release was found to be controlled for more than 12 h and followed the Higuchi model. The validations of RSM for three dependent variables were 100.09%, 99.68%, and 97.02%. Therefore, it can be concluded that a floating microsphere for repaglinide was developed and optimized using a three-factor, three-level Box – Behnken design.

The purpose of this study was to develop an extended release tablet formulation containing gliclazide as a model drug by optimization technique. A central composite design was employed with pH-dependent matrix forming polymers like keltone®-HVCR (X1) and eudragit®-EPO (X2) as independent variables. Five dependent variables were considered: hardness, percent drug release after 1 hr, percent drug release after 6 hr, diffusion exponent and time required for 50% of drug release. Response surface methodology and multiple response optimization utilizing a quadratic polynomial equation were used to obtain an optimal formulation. The results indicate that Factor X1 along its interaction with Factor X2 was found to be significantly affecting the studied response variables. An optimized formulation, containing 8 mg of keltone®-HVCR and 14.10mg of eudragit®-EPO, provides a sufficient hardness (> 4.5 kg/cm2) and optimal release properties. The desirability function was used to optimize the response variables, each having a different target and the observed responses were highly agreed with experimental values. The release kinetics of gliclazide from optimized formulation followed zero-order release pattern. The dissolution profiles of optimized formulation before and after stability studies were evaluated by using similarity factor (f2) and were found to be similar. The results demonstrate the feasibility of the model in the development of extended release dosage form.

Background: Sumatriptan is one of the most essential drugs for treating migraine. However, dosage-related side effects are still a worry despite its 14 % oral bioavailability and recurrence of migraine-associated diseases. Methodology: The fundamental focus of the study is to develop the sumatriptan intra-nasal nano-ethsomal gel by film hydration technique with the aid of QbD principles that govern the varied compositions and blends of polymers like HPMC K100M and Phospolipon 90G to develop a sustained release dosage form. Results and discussion: The preliminary FT-IR and DSC studies revealed no interactions between the drug and their physical mixtures. The present study considered three observable responses: vesicle size, zeta potential, and percent drug release after 24 h, taken into consideration during the optimization of the ethosomal formulations utilizing 32 central composite designs (CCD). The vesicle size (122.23 nm), zeta potential (-40.2 mV), and drug release percentage (92.61 %) for all formulations were seen in the F12 batch after 24h. The p-XRD and SEM studies indicated that the nano-ethosomal gel was stable. The stability studies indicated the preparation of a more stable formulation for the parameters under the study protocol. Conclusion: Using a novel intra-nasal brain targeting approach by adapting the film hydration technique, the current issues might be addressed, and the drug's duration of residence at the absorption site uptake substantially increase. To efficiently modify the drug's residence through the intra-nasal route, this work focuses on developing a nano-ethosomal gel loaded with sumatriptan.


 The present study was aimed to prepare a time-dependent pulsed release system for the programmed release of losartan potassium for the treatment of hypertension. The core tablets of losartan potassium were prepared using wet granulation containing a superdisintegrant. The design was based on 32 full factorial design containing 2 factors evaluated at 3 levels and the experimental trials were performed on coating of the core tablets. Eudragit S100 and Eudragit L100 were used as pH dependent polymers for coating of the tablets. Factors influenced the lag time and In-vitro drug release of formulations, called as dependent factors. Dissolution studies of coated tablets in media with pH (1.2 and 6.8) showed that drug release could be modulated by optimizing the concentration of Eudragit L100: Eudragit S100. Polynomial mathematical model generated for various response variable using multiple linear regression analysis, were found to be statistically significant. Contour plots and response surface plots were drawn and optimum formulation were selected by feasibility and desirability function. The experimental values obtained from the optimized formulation highly agreed with the predicted values. The results of in vitro dissolution studies indicated that formulation P5 is the most successful formulation of the study and exhibited lag time 5.5 h and drug release 95.23 % in 12 h. The total release pattern was very close to the theoretical release profile of pulsed release system. The study showed that lag time prior to drug release was highly affected by the coating level. The dissolution data revealed that the level of coating and the ratio of polymers are very important to achieve an optimum formulation. Stability study of the optimized formulation indicates no significant difference in release profile after a period of one month.

Fabrication of silver nanoparticles-loaded chitosan-polylactic acid based biofilms was successfully employed for investigating the optimal of mechanical properties (i.e. tensile strength and elongation at break) of biofilms using central composite design (CCD), response surface methodology (RSM). In this study, only two factors that influences the biofilm mechanical properties were selected namely concentration of polyethelene glycol 400 (PEG) and percentage volume of polylactic acid (PLA)/chitosan. Analysis of results was performed by using response surface methodology (RSM) to avoid the traditional one-factor-at-a-time experiments. Common statistical tools such as analysis of variance (ANOVA) and response surface plot were used to determine the optimal tensile strength and elongation at break responses. Central composite design (CCD) builds a response surface for mechanical properties of biofilms optimization. From the results of statistical analysis, it could be concluded that the optimal conditions for mechanical properties of biofilms were 7.93% w/w concentration of polyethylene glycol (PEG) and 28.79%/71.21% percentage volume of polylactic acid (PLA)/chitosan. At this optimum stage, 7.99 MPa of tensile strength and 32.6 % elongation at break were obtained. Then, results of verification process have shown that the percentage errors are 2.08% for tensile strength and 3.89% elongation at break, respectively.

Attempting to prepare a convenient bioavailable formulation of vitamin B12 (cyanocobalamin), 17 tablet formulations were prepared by direct compression. Different concentrations of hydroxypropyl methyl cellulose (HPMC), carbopol 971p (CP971p), and chitosan (Cs) were used. The tablets were characterized for thickness, weight, drug content, hardness, friability, surface pH, in vitro drug release, and mucoadhesion. Kinetic analysis of the release data was conducted. Vitamin B12 bioavailability from the optimized formulations was studied on rabbits by the aid of enzyme-linked immunosorbent assay. Neurotone® I.M. injection was used for comparison. HPMC (F1-F4), CP971p (F5-F8), and HPMC/CP971p (F12-F15)-based formulations showed acceptable mechanical properties. The formulated tablets showed maximum swelling indices of 232 ± 0.13. The surface pH values ranged from 5.3 ± 0.03 to 6.6 ± 0.02. Bioadhesive force ranged from 66 ± 0.6 to 150 ± 0.5 mN. Results showed that CP971p-based tablets had superior in vitro drug release, mechanical, and mucoadhesive properties. In vitro release date of selected formulations were fitted well to Peppas model. HPMC/CP971p-based formulations showed bioavailability up to 2.7-folds that of Neurotone® I.M. injection.

Extraction optimization, preliminary characterization, and in vitro antioxidant activities of crude polysaccharides from finger citron