Preparation of Sustained Release Formulation of Verapamil Hydrochloride Using Ion Exchange Resins.

The purpose of this investigation was to formulate and evaluate the interaction between cation exchange resins and verapamil hydrochloride. The uptake studies were conducted using the rotating bottle apparatus. The Langmuir-like equation was applied to the experimental data and the maximum drug loading was determined from the Langmuir-like parameters. The drug-resin complexes were evaluated using XRD, SEM, and particle size analysis. Release studies were performed using USP dissolution apparatus 2. The resin with the lowest percentage of cross-linking had the highest uptake capacity. The percent increase in particle size due to complexation was found to be associated with drug loading; the highest drug loading had the highest increase in particle size. The X-ray diffraction patterns of the resins and the drug-resin complexes showed that they were both amorphous. The maximum drug release was approximately 40% when conventional dissolution testing was used. Results showed that sink conditions could not be maintained using conventional dissolution methods. Maximum drug release increased dramatically by increasing the volume of samples withdrawn and fresh dissolution medium added. Excellent correlation was obtained between sample volume and drug release rate with an R-value of 0.988. Particle diffusion-controlled model and film diffusion-controlled model were both applied to the experimental data. The results indicated that the rate-limiting step is the diffusion of the exchanging cations through the liquid film. The modified release formulation was prepared successfully and correlated very well with the USP monograph for verapamil hydrochloride extended release capsules.

The relationship between the Hammett acidity and the decomposition of cefotaxime sodium in the solid state.

It was of interest to correlate the solid-state acidity to the decomposition of a model drug namely cefotaxime sodium. Amorphous samples containing either an indicator probe (thymol blue) or a model drug (cefotaxime sodium) were prepared by freeze-drying. The prepared samples were characterized using XRPD and Karl Fischer titrimetry. The acidity in the solid state was measured using reflectance spectroscopy. The kinetics of hydrolysis of cefotaxime sodium was studied in solid state at 50 °C in the Hammett acidity range of 8.12-8.61 and at constant ionic strength. The kinetics of decomposition of cefotaxime sodium in solution was also studied in basic media in the pH range of 7.9-8.9 at 50 °C and at constant ionic strength. The degradation was monitored using a validated HPLC method. The hydrolysis was found to follow pseudo-first-order kinetics in solution and solid state. The results obtained showed that there is a good correlation between the Hammett acidity function and the base-catalyzed decomposition of cefotaxime sodium in the solid state. The Hammett acidity-rate profile for cefotaxime decomposition is similar to the pH-rate profile obtained in solution. The decomposition of cefotaxime sodium in the solid state was found to be sensitive to the ionic strength.

Solid self-nanoemulsifying drug delivery system filled in enteric coated hard gelatin capsules for enhancing solubility and stability of omeprazole hydrochloride.

Omeprazole has poor water solubility, low stability in acidic solutions, and is subject to first pass metabolism resulting in low bioavailability. The objective was to enhance the dissolution and stability by preparing a solid-self nanoemulsifying drug delivery system (SNEDDS) and filling it in enteric coated HGCs. Drug solubility in many oils, surfactants, and cosurfactants was studied. Different SNEDDS were prepared and ternary phase diagrams were constructed. The optimum SNEDDS was evaluated. It was converted into solid by adsorption onto Neusilin® US2, and evaluated. Emulsions formed using Capryol 90, Cremophor RH 40, and ethanol formed spontaneously and were clear. Droplet size was 19.11 ± 3.11 nm, PDI was 0.18 ± 0.05, and zeta potential was -3.9 ± 1.56 mV. Non-medicated SNEDDS was thermodynamically stable. Cloud point was 88 ± 2 °C. Encapsulation efficiency and drug loading of solid-SNEDDS were 98.56 ± 0.44 and 1.29 ± 0.01%, respectively. Flow properties were much enhanced. Crystalline drug was adsorbed/precipitated onto Neusilin® US2 in amorphous form. Dissolution rate was enhanced as compared to commercial products and unprocessed drug. The drug was unstable at the accelerated stability conditions. Accordingly, the traditional stability study at 25 °C should be conducted. In conclusion, the solid-SNEDDS filled in enteric coated HGCs enhanced the dissolution rate and stability in acidic pH.

Effect of Moisture Content of Chitin-Calcium Silicate on Rate of Degradation of Cefotaxime Sodium.

Assessment of incompatibilities between active pharmaceutical ingredient and pharmaceutical excipients is an important part of preformulation studies. The objective of the work was to assess the effect of moisture content of chitin calcium silicate of two size ranges (two specific surface areas) on the rate of degradation of cefotaxime sodium. The surface area of the excipient was determined using adsorption method. The effect of moisture content of a given size range on the stability of the drug was determined at 40°C in the solid state. The moisture content was determined at the beginning and the end of the kinetic study using TGA. The degradation in solution was studied for comparison. Increasing the moisture content of the excipient of size range 63-180 µm (surface area 7.2 m2/g) from 3.88 to 8.06% increased the rate of degradation of the drug more than two times (from 0.0317 to 0.0718 h-1). While an opposite trend was observed for the excipient of size range < 63 µm (surface area 55.4 m2/g). The rate of degradation at moisture content < 3% was 0.4547 h-1, almost two times higher than that (0.2594 h-1) at moisture content of 8.54%, and the degradation in solid state at both moisture contents was higher than that in solution (0.0871 h-1). In conclusion, the rate of degradation in solid should be studied taking into consideration the specific surface area and moisture content of the excipient at the storage condition and it may be higher than that in solution.

The Effect of Specific Surface Area of Chitin-Metal Silicate Coprocessed Excipient on the Chemical Decomposition of Cefotaxime Sodium.

Chitin-metal silicates are multifunctional excipients used in tablets. Previously, a correlation between the surface acidity of chitin-calcium and chitin-magnesium silicate and the chemical decomposition of cefotaxime sodium was found but not with chitin-aluminum silicate. This lack of correlation could be due to the catalytic effect of silica alumina or the difference in surface area of the excipients. The objective of this study was to investigate the effect of the specific surface area of the excipient on the chemical decomposition of cefotaxime sodium in the solid state. Chitin was purified and coprocessed with different metal silicates to prepare the excipients. The specific surface area was determined using gas adsorption. The chemical decomposition was studied at constant temperature and relative humidity. Also, the degradation in solution was studied. A correlation was found between the degradation rate constant and the surface area of chitin-aluminum and chitin-calcium silicate but not with chitin-magnesium silicate. This was due to the small average pore diameter of this excipient. Also, the degradation in solution was slower than in solid state. In conclusion, the stability of cefotaxime sodium was dependent on the surface area of the excipient in contact with the drug.

Determination of solid-state acidity of chitin-metal silicates and their effect on the degradation of cephalosporin antibiotics.

It was of interest to determine the solid-state acidity of chitin-metal silicate coprocessed excipients and to correlate this acidity to the chemical stability of cefotaxime sodium in the presence of the aforementioned excipients. The solid-state acidities of chitin aluminum silicate, chitin magnesium silicate, and chitin calcium silicate were determined by reflectance spectroscopy using structurally different dye molecules. The chemical stability of cefotaxime sodium was assessed at 50 °C in a 4% (w/v) slurry system in the pH range 6.6-10.5 and in the solid-state in the Hammett acidity range 6.1-7.8. The solid-state acidity was found to be reproducible because one or more structurally different dye molecules gave reliable solid-state acidity values. A significant discrepancy in pH stability profile of cefotaxime sodium between the solid-state and the slurry system was observed. Furthermore, chitin aluminum silicate showed minimum drug stability in the solid-state, close to where the maximum drug stability in the slurry was observed. This unexpected effect might be ascribed to the catalytic properties of chitin aluminum silicate. The slurry method was not able to predict efficiently the solid-state surface acidity and stability of cefotaxime sodium. Moreover, the solid-state chemical stability might be influenced by factors other than the solid-state acidity.

Determination of factors affecting kinetics of solid-state transformation of fluconazole polymorph II to polymorph I using diffuse reflectance Fourier transform spectroscopy.

BACKGROUND: It was of interest to investigate the factors affecting kinetics of transformation of fluconazole polymorph II (the metastable form) to fluconazole polymorph I (the stable form) using diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). METHOD: Fluconazole polymorphs I and II both were prepared by crystallization in dichloromethane. The two forms were characterized using differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction, solubility, and DRIFTS. Transformation of polymorph II to polymorph I was also studied under different isothermal temperatures using DRIFTS. Kinetic analyses of the data were done using model-dependent and model-independent methods. Eighteen solid-state reaction models were used to interpret the experimental results. RESULTS: Based on statistics, the Prout-Tompkins model provided the best fit for the transformation. The activation energy (E(a)) value derived from the rate constants of the Prout-Tompkins model was 329 kJ/mol. Model-independent analysis was also applied to the experimental results. The average values calculated using both methods were not significantly different. Factors affecting kinetics of transformation such as mechanical factors, relative humidity, and the effect of seeding were also studied. Mechanical factors, which included trituration and compression, proved to enhance transformation rate significantly. Relative humidity proved to transform both polymorphs to monohydrate form. The presence of seed crystals of polymorph I was proved not to affect the transformation process of polymorph II to polymorph I. Effect of solvent of crystallization (dichloromethane) was studied. A significant change of the rate of transformation was proved in the presence of solvent vapors, and a change on the mechanism was proposed.

Influence of solid-state acidity on the decomposition of sucrose in amorphous systems II (effect of buffer).

It was of interest to investigate the solid-state acidity using indicator probe molecules and sucrose degradation. Amorphous samples containing lactose, sucrose, buffers (citrate, malate, tartarate, or phosphate) with different pH values, and sodium chloride (to adjust the ionic strength) were prepared by freeze-drying. The lyophiles were characterized using powder X-ray diffraction, differential scanning calorimetry, and Karl Fischer titrimetry. The solid-state acidity of all lyophiles was measured using diffuse reflectance spectroscopy and suitable indicators (thymol blue or bromophenol blue). Selected lyophiles were subjected to a temperature of 60 degrees C and were analyzed for sucrose degradation using the Trinder kit. The results obtained from this study have shown that good correlation can be obtained between the solid-state acidity and the molar ratio of the salt and the acid in solution. The degradation of sucrose in the lyophiles is extremely sensitive to the solid-state acidity and might be able to provide a better estimate for the acidity than the indicator probe molecules. The Hammett acidity-rate profile for sucrose degradation in the lyophiles (using four different buffers) was also obtained. The profile showed similarity to the pH-rate profile in solution, and no buffer catalysis for sucrose degradation was detected in this study.

Determination of the mechanism of uptake of organic vapors by chitoasn.

It was of interest to investigate the possible interactions that might occur between chitosan and various compounds of different polarities using solvent vapor sorption and Fourier Transform Infrared Spectroscopy (FTIR). The sorption system was composed of a gas inlet, a 2 meter gas cell and a gas outlet. The experimental set up allowed quantification of the free vapor and therefore the amount of the sorbed vapor by chitosan powder. The BET equation was applied to the experimental data to obtain the apparent monolayer sorption capacity (Sm) and the parameter C, which is related to the heat of interaction. Results demonstrated that the surface areas obtained for chitosan from the BET analyses for heptane, 1,4-dioxane and methanol were 421, 379 and 58 m(2)/g, respectively. These values were extremely higher than the value obtained from nitrogen vapor adsorption isotherm (4.56 m(2)/g). The difference is attributed to the partitioning of these compounds into the chitosan particles. The large difference in the Sm values between the nonpolar (heptane and 1,4-dioxane) and the semipolar compounds (methanol) also suggested that the polarity of the solvent might have a significant effect on the partitioning of the these compounds into the chitosan particles. The results obtained from this study also confirmed what was previously described regarding the ability of chitosan to act as a 'fat magnet' or a 'fat sponge'.

The sorption of ketotifen fumarate by chitosan.

The purpose of this investigation was to determine the mechanism of interaction between ketotifen fumarate and chitosan at different pH values. The specific surface area of chitosan was determined using gas sorption analyzer. The sorption experiments were conducted at pH 7 and 10 using two different particle size ranges of chitosan. The solutions were prepared at constant ionic strength and buffer concentration, with only varying the pH. The rotating bottle method was used for measuring the sorption. The average specific surface areas for the two different particle size ranges of chitosan were found to be 4.56 and 0.74 m(2)/g. The Langmuir-like equation and a model independent equation were both applied to the sorption experimental data. The extent of ketotifen uptake at pH 7 for small and large particles of chitosan was found to be 1,073 and 2,204 mg/g respectively. While the extent of ketotifen uptake at pH 10 for small and large particles of chitosan was found to be 4 and 11 mg/g respectively. The aforementioned results indicated that sorption of ketotifen fumarate at pH 7 is extremely high compared to pH 10 and that the sorption increases by decreasing the specific surface area of chitosan. Based on the results obtained, the following conclusions were reached. Ketotifen might be absorbed into the bulk structure of chitosan in addition to being adsorbed on the surface and the ability of chitosan to swell at pH 7 has a significant role in increasing its uptake.

Influence of solid-state acidity on the decomposition of sucrose in amorphous systems. I.

It was of interest to develop a method for solid-state acidity measurements using pH indicators and to correlate this method to the degradation rate of sucrose. Amorphous samples containing lactose 100mg/ml, sucrose 10mg/ml, citrate buffer (1-50mM) and sodium chloride (to adjust the ionic strength) were prepared by freeze-drying. The lyophiles were characterized using powder X-ray diffraction, differential scanning calorimetry and Karl Fischer titremetry. The solid-state acidity of all lyophiles was measured using diffuse reflectance spectroscopy and suitable indicators (thymol blue or bromophenol blue). The prepared lyophiles were subjected to a temperature of 60 degrees C and were analyzed for degradation using the Trinder kit. The results obtained from this study have shown that the solid-state acidity depends mainly on the molar ratio of the salt and the acid used in buffer preparation and not on the initial pH of the solution. The degradation of sucrose in the lyophiles is extremely sensitive to the solid-state acidity and the ionic strength. Reasonable correlation was obtained between the Hammett acidity function and sucrose degradation rate. The use of cosolvents (in the calibration plots) can provide good correlations with the rate of an acid-catalyzed reaction, sucrose inversion, in amorphous lyophiles.

Effect of surfactant on dissolution of spherical particles in micellar systems.

The influence of micelle-drug solubilization on the dissolution rate of monodisperse particles of benzocaine has been investigated. A model describing and predicting the initial dissolution rates of spherical particles was derived starting from the boundary layer theory. The dissolution rate of benzocaine spherical particles was determined in water and in solutions of sodium lauryl sulfate (SLS) under static conditions. The derived model was applied to the experimental data. The diffusion coefficients and the aqueous diffusion layer values were estimated from the experimental results and the aforementioned model. The diffusion coefficients and the boundary layer thickness values were also obtained experimentally from the rotating disk method and were used to predict the initial dissolution rates. Excellent correlations were obtained between the experimental and the calculated values at low micellar concentrations. However, obvious deviation was observed at high micellar concentrations. The results obtained from this study suggest that it is possible to predict the initial dissolution rates of monodisperse particles in micellar systems.

Comparison between dehydration and desolvation kinetics of fluconazole monohydrate and fluconazole ethylacetate solvate using three different methods.

It was of interest to study the dehydration and the desolvation of fluconazole monohydrate and ethyl acetate solvate respectively and also to determine the kinetics of dehydration and desolvation using thermogravimetry (TGA). Fluconazole monohydrate and ethyl acetate solvate were prepared by crystallization in water and in ethyl acetate solvent respectively. The dehydration and the desolvation processes were characterized by differential scanning calorimetry, thermogravimetry, powder X-ray diffractometry, and Fourier transform infrared spectroscopy. The weight changes of the fluconazole monohydrate and ethyl acetate solvate samples were monitored by isothermal TGA. Kinetic analyses of isothermal TGA data were done using model dependent and model independent methods. Various heating rates were also employed in different TGA samples, in order to apply the Ozawa method to determine the kinetic parameters. Eighteen solid-state reaction models were used to interpret the isothermal TGA experiments. Based on statistics, the three-dimensional phase boundary reaction model provided the best fit of the monohydrate data while the three-dimensional diffusion model provided the best fit for the ethyl acetate solvate data. The activation energy (E(a)) values derived from rate constants of the aforementioned models were 90 +/- 11 and 153 +/- 11 kJ/mol for fluconazole monohydrate and ethyl acetate solvate respectively. Model independent analysis and the Ozawa method were also applied to the experimental results. Based on the results obtained from the model dependent, model independent and the Ozawa method, the mechanisms of the dehydration and the desolvation were determined.

Preparation and crystal characterization of a polymorph, a monohydrate, and an ethyl acetate solvate of the antifungal fluconazole.

The preparation and solid-state characterization of three crystalline modifications of the antifungal agent fluconazole [2-(2,4-difluorophenyl)-1,3-bis-(1H-124-triazol-1-yl)-propan-2-ol] are reported. Recrystallization of fluconazole from propan-2-ol yielded a polymorph (Form III), whereas the solvents water and ethyl acetate yielded the solvated products fluconazole monohydrate and fluconazole. (ethyl acetate)(0.25), respectively. These species were analyzed by thermogravimetry (TGA), differential scanning calorimetry (DSC), FTIR spectroscopy, powder X-ray diffractometry (PXRD), and single crystal X-ray diffraction. Availability of the hitherto unknown crystal structures facilitated interpretation of the thermal data and clarified previous findings relating to the polymorphism of this compound. Fluconazole was found to exist as a centrosymmetric hydrogen bonded dimer in Form III. For the solvated phases, the solvent locations within the drug host matrices were established as isolated sites for water molecules and constricted channels for ethyl acetate molecules. Desolvation of the monohydrate and ethyl acetate solvate yielded polymorphic Form I. Reference PXRD patterns computed from the refined single-crystal X-ray data for the title compounds are presented.

Prediction of the adsorption of diazepam by activated carbon in aqueous media.

Adsorption isotherms for the diazepam-activated carbon system in simulated intestinal fluid (SIF), without pancreatin, and in SIF with different percentages of ethanol were determined as were the solubilities of diazepam in SIF and in SIF with different percentages of ethanol. The surface area of the activated carbon was also evaluated. The results from the experimental work provided information on the relationship between adsorption and solubility. An excellent logarithmic relationship was observed between the adsorption affinity and the solubility of diazepam in the ethanol-SIF mixtures. This relationship was explained by a linear relationship between the differential free energy of displacement and the differential free energy of solution. Excellent correlations were also observed between the amounts of diazepam adsorbed by activated carbon and the solubilities of diazepam in the ethanol-SIF mixtures. This relationship was used to predict the complete isotherm, which was in excellent agreement with the experimental work.

The application of the convective diffusion model and the film equilibrium model to surfactant-facilitated dissolution of gliclazide.

Gliclazide is practically insoluble in water, and has low dissolution rate. Therefore, it was of interest to improve its dissolution rate using anionic and cationic surfactants. The intrinsic dissolution rates of gliclazide in solutions of sodium dodecyl sulfate (SDS) and in solutions of tetradecyltrimethyl ammonium bromide (TDTMAB) were measured using the rotating disk method to study the convective diffusion transport of drug-loaded micelles. Two different approaches were applied to the experimental data; the convective diffusion model and the film equilibrium model. The two approaches are based on the same fundamental assumptions differing only in their interpretation of the diffusional boundary layer. The results obtained from the film equilibrium model were less satisfactory, and in case of TDTMAB the model was inapplicable (negative diffusion coefficient). While excellent results were obtained from the convective diffusion model. The free solute diffusion coefficient (D(s)) obtained experimentally was 2.47 x 10(-5) cm(2)/s, and the diffusion coefficient of the drug-loaded SDS micelle (D(sm)) estimated was 1.74 x 10(-6) cm(2)/s. The drug-loaded SDS micelle radius was 14 A. The thickness of the diffusional boundary layer was 54 and 22 microm for the free solute and the drug-loaded SDS micelle, respectively. TDTMAB showed lower effect in improving the dissolution rate of gliclazide than SDS. The drug-loaded TDTMAB micelle diffusion coefficient was 1.03 x 10(-6) cm(2)/s. The radius of the drug-loaded TDTMAB micelle and the boundary layer thickness were 24 A and 19 microm, respectively.

Study of multiple-component adsorption on the surface of activated carbon using a model system of benzyl alcohol and phenobarbital.

The purpose of this work was to characterize the surface of activated carbon and to study the specificity of interactions using multicomponent adsorption. The competition between phenobarbital and benzyl alcohol was studied by conducting multicomponent-adsorption experiments. Benzyl alcohol and phenobarbital were combined to form a bisolute system. The adsorption of the bisolute system from simulated intestinal fluid (without pancreatin) by activated carbon was studied by using the rotating bottle method. The concentrations, both before and after the attainment of equilibrium, were determined with the aid of an HPLC system using a reversed-phase column. The modified competitive Langmuir-like model was fit to the data. A good correlation was obtained between the experimental and the calculated data, which indicates that benzyl alcohol and phenobarbital are competing for the same binding sites. The competition between benzyl alcohol and phenobarbital was not expected, and it suggests that benzyl alcohol is not interacting with the site having the theoretically highest enthalpy of interaction (carbonyl group on the activated carbon surface), due to the blockage of this site by the solvent (water). This unexpected result also indicates that the hydroxyl group is likely to be the most important group when the adsorption occurs from aqueous solution.

Study of the solubilization of gliclazide by aqueous micellar solutions.

It was of interest to increase the solubility of gliclazide in aqueous media. Therefore, solubilization of gliclazide in a variety of surfactants was investigated. Anionic and cationic surfactants exhibited dramatic solubilizing ability for gliclazide, whereas nonionic surfactants showed significantly lower solubilizing ability. It was found that gliclazide solubility increases with increasing the carbon chain length of cationic surfactants and decreases with increasing the carbon chain length of anionic surfactants. The solubilization data were analyzed on the basis of a pseudo-phase model with gliclazide exhibiting moderate partition coefficients into the micellar phase. The possible sites of solubilization of gliclazide in the micelle were examined by studying the effect of NaCl on solubilization and by comparing the absorption spectra of gliclazide in different solvents. The results obtained from these two experiments indicated that gliclazide is solubilized mainly in the inner core of the cationic surfactant micelles and in the outer regions of the anionic surfactant micelles.

Solid-state characterization of fluconazole.

Two polymorphs and three solvates of fluconazole were isolated and characterized by x-ray powder diffractometry, IR spectroscopy, differential scanning calorimetry (DSC), thermogravimetry, and their dissolution rates. The different forms were prepared by crystallization of the original powder in different solvents at different cooling rates. X-ray diffraction patterns of the five solid modifications exhibited substantial differences in both the intensity and position of the peaks. FTIR spectra of the five different solid-state modifications also exhibited differences in the peaks' positions and intensities. DSC thermogram of anhydrate form I showed a single melting point at 139.2 degrees C. Anhydrate form II showed two endothermic peaks at 136.5 and 139.2 degrees C and one exothermic peak in between. The DSC thermogram of acetone 1/4 solvate exhibited two endothermic peaks at 75.5 and 139.2 degrees C. Benzene 1/7 solvate exhibited two endothermic peaks at 131.5 and 138.8 degrees C. Hydrate E exhibited two endothermic peaks at 102.7 and 139.2 degrees C. The DSC thermogram of anhydrate form II showed that this form is sensitive to the application of a mechanical force. The solubility study showed that anhydrate form II and acetone 1/4 solvate have higher solubilities than anhydrate form I while benzene 1/7 solvate and monohydrate have lower solubilities than anhydrate form I. The intrinsic dissolution study confirmed these results.

Prediction of adsorption from multicomponent solutions by activated carbon using single-solute parameters. Part II--Proposed equation.

Prediction of multicomponent adsorption is still one of the most challenging problems in the adsorption field. Many models have been proposed and employed to obtain multicomponent isotherms from single-component equilibrium data. However, most of these models were based on either unrealistic assumptions or on empirical equations with no apparent definition. The purpose of this investigation was to develop a multicomponent adsorption model based on a thermodynamically consistent equation, and to validate that model using experimental data. Three barbiturates--phenobarbital, mephobarbital, and primidone--were combined to form a ternary system. The adsorption of these barbiturates from simulated intestinal fluid (without pancreatin) by activated carbon was studied using the rotating bottle method. The concentrations, both before and after the attainment of equilibrium, were determined with a high-performance liquid chromatography system employing a reversed-phase column. The proposed equation and the competitive Langmuir-like equation were both fit to the data. A very good correlation was obtained between the experimental data and the calculated data using the proposed equation. The results obtained from the original competitive Langmuir-like model were less satisfactory. These results suggest that the proposed equation can successfully predict the trisolute isotherms of the barbituric acid derivatives employed in this study.