Formulation and evaluation of fast dissolving tablet containing domperidone ternary solid dispersion.

INTRODUCTION: Fast dissolving tablet containing domperidone ternary solid dispersion was developed to improve the dissolution of drug and stability of solid dispersion. MATERIALS AND METHODS: Binary and ternary solid dispersions were prepared by fusion method. They were characterized by solubility study, in vitro dissolution, dissolution efficiency, and stability study. The solid state properties of solid dispersions were characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). Ternary solid dispersion was successfully incorporated into fast dissolving tablet by direct compression method. Tablets were characterized for pre-compression parameters, post-compression parameters, and stability study. RESULTS: Optimized ternary solid dispersion containing ratio 1:2:1.5 of drug: Gelucire 50/13: Poloxamer 188 gave maximum dissolution. The FTIR, DSC, and XRD studies of solid dispersions were confirmed the formation of solid dispersion. Ternary solid dispersion was more stable compared to binary solid dispersion at accelerated environment conditions for one month as confirmed by DSC study. Crospovidone as a superdisintegrant (4%) showed good result with disintegration time of 19 s and dissolution near to 100% in 0.1N HCL at 30 min. CONCLUSION: The studies indicated that the dissolution of drug and stability of solid dispersion was improved in the presence of ternary agent (surfactant) as compared to binary solid dispersion. It was concluded that fast dissolving tablet containing ternary solid dispersion was stable at accelerated environmental conditions for 1 month.

Development and validation of spectrophotometric method for simultaneous estimation of paracetamol and lornoxicam in different dissolution media.

BACKGROUND: Paracetamol and lornoxicam in combined tablet dosage form are available in the market. This combination is used to treat inflammatory diseases of the joints, osteoarthritis and sciatica. Spectrophotometric and high performance liquid chromatography (HPLC) methods have been reported for their simultaneous estimation in tablet dosage form in specific solvent. This paper presents simple, accurate and reproducible spectrophotometric method for simultaneous determination of paracetamol and lornoxicam in tablet dosage form in different dissolution media. The reported method is helpful in determination of paracetamol and lornoxicam during dissolution study. MATERIALS AND METHODS: Simple, sensitive, accurate and economical spectrophotometric method based on an absorption correction equation was developed for the estimation of paracetamol and lornoxicam simultaneously in tablet dosage form in different dissolution media at different pH. RESULTS: Paracetamol showed absorption maxima at 243 nm in 0.1N HCland phosphate buffer pH 6.8, while lornoxicam showed absorption maxima at 374 nm in 0.1N HCland phosphate buffer pH 6.8. The linearity was obtained in the concentration range of 4-12 µg/ml for paracetamol and 4-16 µg/ ml for lornoxicam. DISCUSSION: The concentrations of the drugs were determined by an absorption correction equation method. The results of analysis have been validated statistically by recovery studies.

Development and validation of a method for simultaneous estimation of ofloxacin and ornidazole in different dissolution media.

INTRODUCTION: Ofloxacin and ornidazole in a combined tablet dosage form is available in the market. This combination has gained increasing acceptance in diarrhea caused due to bacterial and protozoal infections. Ofloxacin and ornidazole are also combined in the capsule dosage form to modify its release pattern in different studies. Spectrophotometric and HPTLC methods have been reported for their simultaneous estimation in the tablet dosage form in specific solvents. This paper presents a simple, accurate, and reproducible spectrophotometric method for simultaneous estimation of ofloxacin and ornidazole in the tablet dosage form in different dissolution media. The reported method is helpful in determination of ofloxacin and ornidazole during a dissolution study. MATERIALS AND METHODS: A simple, sensitive, accurate, and economical spectrophotometric method based on the simultaneous equation was developed for the estimation of ornidazole and ofloxacin simultaneously in the tablet or capsule dosage form in different dissolution media at different pH values. RESULTS: Ofloxacin showed absorption maxima at 294 nm in 0.1 N HCl and at 287 nm in phosphate buffer pH 6.8 and phosphate buffer pH 7.4 while ornidazole showed absorption maxima at 277 nm in 0.1 N HCl and at 319 nm in two buffers, respectively. The linearity was obtained in the concentration range of 1-8 µg/ ml for ofloxacin and 4-26 µg/ml for ornidazole. DISCUSSION: The concentrations of the drugs were determined by the simultaneous equation method. The results of analysis have been validated statistically and by recovery studies.

Design and evaluation of colon targeted modified pulsincap delivery of 5-fluorouracil according to circadian rhythm.

INTRODUCTION: A modified pulsincap dosage form of 5-fluorouracil was developed to target drug to colorectal carcinoma according to daily oscillations of rate-limiting metabolizing enzyme dihydropyrimidine dehydrogenase. MATERIALS AND METHODS: The capsule body was made water insoluble by exposing the body to formaldehyde vapor. A mixture of granules containing drug, superdisintegrant, and osmogen was filled in the capsule body. A hydrogel plug was fitted to the mouth of the treated body, and the untreated cap was fitted to the body which was coated with Eudragit S100. Developed formulations were evaluated for in vitro drug release in 1.2 pH (2 h), 6.8 pH (3 h), and 7.4 pH (up to 12 h) buffer solutions. A 2(3) full factorial design was used for optimization in which the type of hydrogel plug (X1), the type of osmogen (X(2)), and the type of superdisintegrant (X(3)) were selected as independent variables while, cap opening time, percentage drug released in 5(Q(5)), 6(Q(6)), and 12(Q(12)) h were taken as dependent variables. RESULTS: Dissolution data were fitted to various models to ascertain the kinetic of drug release. Regression analysis and analysis of variance were performed for dependent variables. The results of the F-statistics were used to select the most appropriate model. CONCLUSION: Formulation F(1) containing sodium starch glycolate, potassium chloride, and hydroxypropyl methylcellulose K4M plug was considered optimum since it showed more similarity to the theoretical predicted dissolution profile (f(2) = 77.33). The studies indicate that the formulation was effective in providing in vitro colon targeted release and controlled release after predetermined lag time.

Formulation and evaluation of mixed matrix gastro-retentive drug delivery for famotidine.

INTRODUCTION: Present investigation describes an influence of ratio of Gelucire 43/01(hydrophobic) to hydroxypropyl methylcellulose K4M (HPMC K4M) (hydrophilic) and different fillers on release of famotidine from gastro-retentive tablets using 3(2) full factorial design. Ratio of Gelucire 43/01 to HPMC K4M (X(1)) and the type of filler (X(2)) were selected as independent variables while buoyancy lag time (BLT), drug release at 1h (Q(1)), 6h (Q(6)), and the 12h (Q(12)) were selected as dependent variables. MATERIALS AND METHODS: Gastro-retentive tablets of famotidine were prepared by a solvent free melt granulation technique using Gelucire 43/01 as a hydrophobic meltable binder. HPMC K4M and sodium bicarbonate were used as matrixing agent and gas-generating agent, respectively. Prepared tablets were evaluated for in vitro dissolution, in vitro buoyancy, friability, hardness, drug content and weight variation. Dissolution data were fitted to various models to ascertain kinetics of drug release. The data were analyzed using regression analysis and analysis of variance. RESULTS: All formulations (F(1)-F(9)) showed floating within 3min and had total floating time of more than 12h. It was observed that a type of filler and the ratio of Gelucire 43/01 to HPMC K4M had significant influence on buoyancy lag time (P = 0.037) and Q(6) (P = 0.011), respectively without significant influence on Q(1) and Q(12). CONCLUSION: Formulation F(5) was selected as an optimum formulation as it showed more similarity in dissolution profile with theoretical profile (Similarity factor, f(2) = 83.01). The dissolution of batch F(5) can be described by zero order kinetics (r(2) = 0.9914) with anomalous (non-Fickian) diffusion as a release mechanism (n = 0.559). The difference observed in in vitro release profile after temperature sensitivity study at 40°C for 1 month was insignificant.

Formulation and evaluation of floating oral in situ gelling system of amoxicillin.

Purpose. Effective Helicobacter pylori eradication requires delivery of the antibiotic locally in the stomach. High dose of amoxicillin (750 to 1000 mg) is difficult to incorporate in floating tablets but can easily be given in liquid dosage form. Keeping the above facts in mind, we made an attempt to develop a new floating in situ gelling system of amoxicillin with increased residence time using sodium alginate as gelling polymer to eradicate H. pylori. Methods. Floating in situ gelling formulations were prepared using sodium alginate, calcium chloride, sodium citrate, hydroxypropyl methyl cellulose K100, and sodium bicarbonate. The prepared formulations were evaluated for solution viscosity, floating lag time, total floating time, and in vitro drug release. The formulation was optimized using a 3(2) full factorial design. Dissolution data were fitted to various models to ascertain kinetic of drug release. Regression analysis and analysis of variance were performed for dependent variables. Results. All formulations (F(1)-F(9)) showed floating within 30 s and had total floating time of more than 24 h. All the formulations showed good pourability. It was observed that concentration of sodium alginate and HPMC K100 had significant influence on floating lag time, cumulative percentage drug release in 6 h and 10 h. The batch F(8) was considered optimum since it showed more similarity in drug release (f(2) = 74.38) to the theoretical release profile. Conclusion. Floating in situ gelling system of amoxicillin can be formulated using sodium alginate as a gelling polymer to sustain the drug release for 10 to 12 h with zero-order release kinetics.

Rapid quantification of lamotrigine in human plasma by two LC systems connected with tandem MS.

A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method has been developed and validated for the determination of lamotrigine in human plasma using multiplexing technique (two HPLC units connected to one MS-MS). Lamotrigine was extracted from human plasma by solid-phase extraction technique using Oasis Hydrophilic Lipophilic Balance (HLB) or N-vinylpyrrolidone and divinylbenzene cartridge. A structural analog, 3,5-diamino-6-phenyl-1,2,4-triazine, was used as an internal standard (IS). A BetaBasic C(8) column was used for the chromatographic separation of analytes. The mass transition [M+H](+) ions used for detection were m/z 256.0 --> 211.0 for lamotrigine and m/z 188.0 --> 143.0 for IS. The method involved a simple multiplexing, rapid solid-phase extraction without evaporation and reconstitution. The proposed method has been validated for a linear range of 0.025 to 10.000 microg/mL with a correlation coefficient > or = 0.9991. The limit of quantification for lamotrigine was 0.025 microg/mL, and limit of detection was 50.000 pg/mL. The intra-run and inter-run precision and accuracy were within 10.0% for intra-HPLC runs and inter-HPLC runs. The overall recoveries for lamotrigine and IS were 97.9% and 92.5%, respectively. Total MS run time was 1.4 min per sample. The validated method has been successfully used to analyze human plasma samples for applications in pharmacokinetic, bioavailability, bioequivalence, or in vitro in vivo correlation studies.

In vitro-in vivo correlation of modified release dosage form of lamotrigine.

The plasma concentration profile of lamotrigine was predicted from the dissolution test data of the modified release 100 mg lamotrigine tablet by applying the in vitro-in vivo correlation (IVIVC). Three different release formulations (L-1, L-2 and L-3) and its profiles of in vitro data were generated in different dissolution media. Pharmacokinetics evaluation of these formulations was carried out in 12 healthy volunteers. In vitro-in vivo correlation was established from the generated dissolution and bioavailability data. A good correlation between the percentages dissolved vs absorbed (r2>0.989) was obtained using level A correlation. Evaluation of the internal predictability of level A correlation was calculated in terms of percent prediction error, which was found to be below 15%.

Rapid determination of losartan and losartan acid in human plasma by multiplexed LC-MS/MS.

A rapid LC-MS/MS method has been developed and validated for the determination of losartan (LOS) and its metabolite losartan acid (LA) (EXP-3174) in human plasma using multiplexing technique (two HPLC units connected to one MS/MS). LOS and LA were extracted from human plasma by SPE technique using Oasis HLB cartridge without evaporation and reconstitution steps. Hydroflumethiazide (HFTZ) was used as an internal standard (IS). The analytes were separated on Zorbax SB C-18 column. The mass transition [M-H] ions used for detection were m/z 421.0 --> 127.0 for LOS, m/z 435.0 --> 157.0 for LA, and m/z 330.0 --> 239.0 for HFTZ. The proposed method was validated over the concentration range of 2.5-2000 ng/mL for LOS and 5.0-3000 ng/mL for LA with correlation coefficient > or = 0.9993. The overall recoveries for LOS, LA, and IS were 96.53, 99.86, and 94.16%, respectively. Total MS run time was 2.0 min/sample. The validated method has been successfully used to analyze human plasma samples for applications in 100 mg fasted and fed pharmacokinetic studies.

A rapid and specific approach for direct measurement of donepezil concentration in human plasma by LC-MS/MS employing solid-phase extraction.

A selective, rapid and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is described for assay of donepezil in human plasma using escitalopram as an internal standard. Chromatographic separation was achieved on a Betabasic-C(8), 5 microm, 100 x 4.6 mm column using methanol:water:formic acid (90:9.97:0.03, v/v/v) as mobile phase. Detection of donepezil and internal standard was achieved by ESI MS/MS in positive ion mode using 380.20/91.10 and 325.13/262.00 transitions, respectively. The linearity over the concentration range of 0.15-50 ng/mL for donepezil was obtained and the lower limit of quantification was 0.15 ng/mL. For each level of quality control samples, inter-day and intra-day precisions (RSD) were < or =8.92 and 10.35% and accuracy (%RE) were < or =7.33% and 9.33%, respectively. The recovery was more than 88.50% for both donepezil and internal standard by solid-phase extraction, eliminating evaporation and reconstitution steps.

Gastric floating matrix tablets: design and optimization using combination of polymers.

The purpose of the present study was to develop an optimized gastric floating drug delivery system (GFDDS) containing domperidone as a model drug. Box-Behnken design was employed in formulating the GFDDS with three polymers: hydroxypropyl methylcellulose K4M (HPMC K4M) (X1), Carbopol 934P (X2) and sodium alginate (X3), as independent variables. Floating lag time (FLT), total floating time (TFT), time required to release 50% of the drug (t50) and diffusion exponent (n) were selected as dependent variables. Seventeen formulations were prepared, dissolution data obtained was fitted to the power law and floating profiles were analyzed. HPMC loading was found to be significant for floating properties. Carbopol loading had a negative effect on floating properties but was found helpful in controlling the release rate of the drug. No significant effect of sodium alginate on floating properties was observed but it was important for gel formation. The quadratic mathematical model developed could be used to predict formulations with desired release and floating properties.

Floating granules of ranitidine hydrochloride-gelucire 43/01: formulation optimization using factorial design.

The purpose of this research was to develop and optimize a controlled-release multiunit floating system of a highly water soluble drug, ranitidine HCl, using Compritol, Gelucire 50/13, and Gelucire 43/01 as lipid carriers. Ranitidine HCl-lipid granules were prepared by the melt granulation technique and evaluated for in vitro floating and drug release. Ethyl cellulose, methylcellulose, and hydroxypropyl methylcellulose were evaluated as release rate modifiers. A 3(2) full factorial design was used for optimization by taking the amounts of Gelucire 43/01 (X (1)) and ethyl cellulose (X (2)) as independent variables, and the percentage drug released in 1(Q(1)), 5(Q(5)), and 10 (Q(10)) hours as dependent variables. The results revealed that the moderate amount of Gelucire 43/01 and ethyl cellulose provides desired release of ranitidine hydrochloride from a floating system. Batch F4 was considered optimum since it contained less Gelucire and was more similar to the theoretically predicted dissolution profile (f(2) = 62.43). The temperature sensitivity studies for the prepared formulations at 40 degrees C/75% relative humidity for 3 months showed no significant change in in vitro drug release pattern. These studies indicate that the hydrophobic lipid Gelucire 43/01 can be considered an effective carrier for design of a multiunit floating drug delivery system for highly water soluble drugs such as ranitidine HCl.