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Part I of this article reported general considerations of oral controlled release dosage forms and the applications of cellulose ether polymers in hydrophilic matrices. Part II of this study describes the advantages and disadvantages of limited swelling hydrophilic matrices, their preparation, mechanism, and parameters affecting drug release from these systems.
The pharmaceutical availability of metronidazole from several commercial oral and vaginal dosage forms in sink and non-sink conditions has been examined by measuring the rate of drug dissolution. The results were interpreted by means of reversible and irreversible dissolution models. For non-sink conditions the reversible model was found to better interpret the data. The values of the relative dissolution rate constant, theoretical dissolution time and dissolution efficiency were obtained and discussed.
A high-performance liquid chromatographic method and a UV spectrophotometric method for the quantitative determination of meropenem, a highly active carbapenem antibiotic, in powder for injection were developed in present work. The parameters linearity, precision, accuracy, specificity, robustness, limit of detection and limit of quantitation were studied according to International Conference on Harmonization guidelines. Chromatography was carried out by reversed-phase technique on an RP-18 column with a mobile phase composed of 30 mM monobasic phosphate buffer and acetonitrile (90:10; v/v), adjusted to pH 3.0 with orthophosphoric acid. The UV spectrophotometric method was performed at 298 nm. The samples were prepared in water and the stability of meropenem in aqueous solution at 4 and 25 degrees C was studied. The results were satisfactory with good stability after 24 h at 4 degrees C. Statistical analysis by Student's t-test showed no significant difference between the results obtained by the two methods. The proposed methods are highly sensitive, precise and accurate and can be used for the reliable quantitation of meropenem in pharmaceutical dosage form.
The gastrointestinal transit of liquid, pellet and tablet formulations was measured under fasted conditions in the domestic pig (n = 4) using the technique of gamma scintigraphy. The mean times for 50% gastric emptying for liquid and pellet systems were 1.4 and 2.2 h, respectively; tablets emptied between 1.5 and 6.0 h. Total transit times were in the order of 50 h. These data conform well to published values for the transit of liquid and solid food materials in the pig. The times are much shorter than those previously published for the transit of solid dosage forms in the pig. We conclude that the domestic pig would be a good model to study the gastrointestinal transit of pharmaceutical formulations and the absorption of drug compounds.
The mechanical properties of dry and wet polymeric films prepared from various aqueous polymeric dispersions were evaluated by a puncture test. They were studied with respect to type of polymer dispersion [cellulosic: Aquacoat and Surelease; acrylic: Eudragit NE, L, RS, and RL 30 D], plasticizer type (water-soluble or water-insoluble), drying or curing conditions, method of film preparation (pseudolatex-vs solvent casting) and ratio of Eudragit RS/RL 30 D in mixed Eudragit RS/RL films. Dry and wet mechanical strengths of the polymeric films depended primarily on the types of the colloidal polymer dispersion and the plasticizer. Films prepared from ethylcellulose dispersions resulted in very weak and brittle films when compared to the acrylic films. Pseudolatex-cast ethylcellulose films showed lower puncture strength and elongation values when compared to those of the solvent-cast films. Curing of the pseudolatex-cast ethylcellulose films had minimal effects on their mechanical properties. Eudragit L 30D, an enteric polymer dispersion, resulted in brittle films in the dry state, but in very flexible films in the wet state because of the plasticization effect of water. Wet Eudragit RS 30 D polymer films plasticized with water-insoluble plasticizers were significantly more flexible than the corresponding wet films plasticized with water-soluble plasticizers. The water-soluble plasticizers leached from the films during exposure to the aqueous medium, while the water-insoluble plasticizers were almost completely retained within the wet films. The low permeability of a water-soluble drug, chlorpheniramine maleate, and the weak mechanical properties of Aquacoat films could suggest osmotic driven/rupturing effects as the release mechanisms from Aquacoat-coated dosage forms.
A square-wave voltammetric (SWV) method and a flow injection analysis system with amperometric detection were developed for the determination of tramadol hydrochloride. The SWV method enables the determination of tramadol over the concentration range of 15-75 microM with a detection limit of 2.2 microM. Tramadol could be determined in concentrations between 9 and 50 microM at a sampling rate of 90 h(-1), with a detection limit of 1.7 microM using the flow injection system. The electrochemical methods developed were successfully applied to the determination of tramadol in pharmaceutical dosage forms, without any pre-treatment of the samples. Recovery trials were performed to assess the accuracy of the results; the values were between 97 and 102% for both methods.
Herbal drug formulation is a challenge in pharmaceutical technology due to the complex physicochemical properties of these multicomponent materials. Potential instabilities of the pharmacologically active and coactive substances as well as incompatibilities and interactions of the extracted compounds and excipients have to be considered. Microbial contamination of the applied plant material might limit the shelf life of the products. Using state of the art methods in formulation stable preparations are obtained; additionally compliance of drugs might be enhanced due to simplified application or better sensorial quality. Nowadays, besides traditional pharmacopoeial aqueous, ethanolic, or (partially) dried extracts fluid, semisolid, or solid dosage forms of these extracts are in use, for example syrups, juices, drops, liniments, gels, ointments, creams, suppositories, tablets, coated tablets (dragees) as well as soft and hard gelatine capsules.
A selective, precise and accurate isocratic RP-HPLC method has been developed and validated for the simultaneous determination of metronidazole benzoate (MB), diloxanide furoate (DF), methyl paraben (MPn) and propyl paraben (PPn) in suspension. The cis/trans isomerization phenomenon for DF has also been presented. The method uses as stationary phase a Supelco LC-18 DB (15 cm x 4.6 mm) 5 microm column and as a mobile phase a buffer-acetonitrile mixture (70:30, v/v) adjusted to pH of 2.5 at a flow rate of 2.0 mLmin(-1). The buffer is a 0.005 M KH2PO4 solution. The four analytes were well resolved from the degraded solutions peaks. The excepients present in the formulation do not interfere with the assay procedure. The linearity range (n=3) is (0.20130-1.20779 mgmL(-1)) for MB with R of 0.99985; (0.15790-0.94740 mgmL(-1)) for DF with R of 0.99987; (0.01131-0.06788 mgmL(-1)) for MPn with R of 0.99987 and (0.00126-0.00756 mgmL(-1)) for PPn with R of 0.99991. Precision (n=6) was 0.87% for MB; 1.15% for DF; 1.32% for MPn and 1.27% for PPn. The percentage recoveries (n=3) were 99.1% for MB; 99.6% for DF; 99.1% for MPn and 98.7% for PPn. The proposed method can be utilized for the routine analysis of the four analytes in pharmaceutical dosage form.
The hypocalcemic effects of salmon calcitonin (SCT) after oral administration in rats by means of SCT-loading double liposomes (DL) which consist of liposomes containing small liposomes were investigated. SCT-loading DL consisted of four types of the inner liposomes such as neutral liposomes (NL) and cationic charged liposomes (CL) prepared using Coatsome, and neutral (VET) and cationic charged (c-VET) liposomes prepared using a mechanochemical method and sizing to 100 nm by the extrusion procedure were prepared. DL could be prepared by a combination of mechanochemical and glass-beads methods at a high efficiency. DL produced the increase in bioavailability in all groups treated with SCT-loading liposomes except for c-VET. The bioavailability of VET-DL was not significantly different but the greatest among the samples used in this study regardless of the similar size of NL-DL and CL-DL, and was approx. 6.8-fold higher than that of SCT solution when taken orally. The group treated with c-VET showed the strongest hypocalcemic effects among the inner liposomes examined (P>0.05). Therefore, it is speculated that not only the size of liposomes but also the cationic charge plays an important role in the intestinal absorption of DL. These findings suggested the utility of DL as an oral dosage form of SCT.
A highly sensitive polarographic method was developed for the determination of EDTA added as a preservative in certain pharmaceutical preparations. The method involved chelation with Eu(III) followed by polarographic measurement of the chelate formed. A well-defined cathodic wave was developed in Britton-Robinson buffers over the pH range 2-12. The wave was characterized as being quasi-reversible and diffusion controlled. The current-concentration relationship was found to be rectilinear over the ranges 8-160 and 2-120 micrograms ml-1, using DCt and DPP modes, respectively, with limit of detection of 0.1 microgram ml-1 using the DDP technique. The mechanism of the electrode reaction was verified. The proposed method was applied for the determination of EDTA in certain pharmaceutical dosage forms, and the results obtained were in agreement with those obtained by a reference method.
The objective of this investigation was to develop a HPTLC method for the determination of ceftriaxone, cefixime and cefotaxime, cephalosporins widely used in clinical practice. High performance TLC of cephalosporins was performed on pre-coated silica gel HPTLC plates with concentrating zone (2.5 x 10 cm) by development in mobile phase ethyl acetate-acetone-methanol-water (5:2.5:2.5:1.5 v/v/v/v). A TLC scanner set at 270 nm was used for direct evaluation of the chromatograms in reflectance/absorbance mode. The calibration curves were established as dependence of peak height (linear and polynomial regression) and peak area (polynomial regression) versus ng level (125-500 ng for all cephalosporins investigated). Relative standard deviations obtained from calibration curves was compared. Precision (RSD: 1.12-2.91% (peak height versus ng) and RSD: 1.05-2.75% (peak area versus ng)), and detection limits (ng level) was validated and found to be satisfactory. The method was found to be reproducible and convenient for quantitative analysis of ceftriaxone, cefixime and cefotaxime in their raw materials and their dosage forms.
The hygroscopicity of the contents of clorazepate dipotassium (Mendon) capsules (CM) was investigated by storage at various relative humidities (RHs). The CM adsorbed water vapor significantly at more than 75% RH. At the same time, a marked discoloration of CM from white to yellow was also observed during storage. On the basis of differential scanning calorimetry (DSC) and Fourier transform (FT) Raman spectroscopy, the discoloration seemed to be due to the change in clorazepate dipotassium to nordiazepam and other substances. It was found that, when opening of the Mendon capsule is necessary to prepare the powdered dosage form, the CM should be stored below 60% RH to avoid the adsorption of water vapor and discoloration.
The reproducibility of drug absorption within a given subject as well as the evaluation of bioavailability of two digoxin dosage forms were studied. The data showed (a) a higher initial plasma digoxin concentration after the soft elastic gelatin (SEG) capsule; (b) a more irregular absorption after the tablet; (c) on the average, the coefficients of variation of individual plasma concentrations were lower after the capsule; and (d) for the capsule, the intrasubject variations of the peak plasma concentrations, time of peak, area under plasma concentrations-versus-time curve (AUC), and amount digoxin excreted in urine (Ae) were on the average 60 per cent of the variations in the tablet parameters. The ratios of AUC and Ae for capsule/tablet were essentially unity, indicating that the amount digoxin absorbed from the 0.4-mg digoxin SEG capsule is identical to that from a 0.5-mg standard reference tablet.
A simple, specific GLC procedure is described for the analysis of one sedative and six anticonvulsant drugs in pharmaceutical dosage forms. Sample aliquots of ethotoin, glutethimide, mephenytoin, methsuximide, and phensuximide were shaken with or extracted into ethyl acetate, diluted with the internal standard (diphenyl phthalate) solution, injected into a gas chromatograph, and eluted from a methylsilicon column. Primidone and phenytoin samples (extracted as the free acid) required derivatization with N,O-bis(trimethylsilyl)acetamide prior to chromatography. The same temperature programming conditions and flow rate settings were used for all seven drugs. The GLC results agreed well with those obtained using the pharmacopeial methods.
Four sensitive methods are described for the direct determination of telmisartan (TELM) and hydrochlorothiazide (HCT) in combined dosage forms without prior separation. The first method is a first derivative spectophotometry (1D) using a zero- crossing technique of measurement at 241.6 and 227.6 nm for TELM and HCT, respectively. The second method is the first derivative of ratio spectrophotometry (1DD) where the amplitudes were measured at 242.7 nm for TELM and 274.9 nm for HCT. The third method is based on TLC separation of the two drugs followed by the densitometric measurements of their spots at 295 and 225 nm for TELM and HCT, respectively. The separation was carried out on silica gel 60 F254 using butanol: ammonia 25% (8:2 v/v) as mobile phase. The fourth method is spectrofluorimetric determination of TELM, depending on measuring the native fluorescence of the drug in 1 M sodium hydroxide at lambda excitation 230 nm and emission at 365 nm. The proposed methods were applied successfully for the determination of the two drugs in bulk powder and in pharmaceutical formulations. The spectrofluorimetric method was utilized for the analysis of TELM in human plasma.
Three Dimensional Printing is a novel technique used in the fabrication of complex oral dosage delivery pharmaceuticals. It is possible to engineer devices with complicated internal geometries, varying densities and diffusivities, and multiple actives and excipients. Samples were fabricated using this technique using standard pharmaceutical materials. Erosion mechanism delayed-release tablets were constructed with varying polymer content from 8.9 to 17. 9%. Lag times varied between 25 and 50 min with a corresponding decrease in release rate as polymer content increased. Diffusion mechanism tablets were constructed with varying polymer content from 9.0 to 16.7%. The peak release rate decreased and the time to exhaustion increased with polymer content, whereas lag time was not affected. Active delivery studies with fluorescein indicated that Three Dimensional Printing is capable of accurately constructing dosage forms with active content as low as 10(-12) moles per tablet. Hardness and friability testing indicated that samples fabricated with this technique are comparable to other standard pharmaceutical products.
Two different ultraviolet (UV) spectroscopic methods were developed for determination of Lansoprazole in pharmaceutical dosage forms. The solutions of the standard and the sample were prepared in 0.1 M NaOH and phosphate buffer pH 6.6. Both UV spectrophotometric and derivative spectroscopic techniques were applied. Second-order derivative spectra were generated between 200 and 400 nm at N = 9, deltalambda = 31.5. The linear range for the UV spectrophotometric method was 3.0-25.0 microg ml(-1) and that for the derivative spectroscopic method was 0.5-25.0 microg ml(-1). The developed methods were applied to three different pharmaceutical preparations. The percentage recovery was 100.2%.
Seven sustained/controlled-release dosage forms were designed for gastrointestinal delivery of lovastatin or simvastatin, two potent HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. The in vivo performance of these formulations was evaluated in dogs and healthy volunteers in terms of the cholesterol lowering efficacy and/or systemic concentrations of HMG-CoA reductase inhibitors. Results from the present and previous studies suggest that, through the controlled release of HMG-CoA reductase inhibitors, sustained lower plasma concentrations of HMG-CoA reductase inhibitors may result in an equal or better therapeutic efficacy.