Paddle Method Research Articles

Development of time controlled chronomodulated tablet with swelling and rupturable layers: Optimization of factors influencing lag-time and drug release

Introduction:A tablet system consisting of cores coated with two layers of swelling and rupturable coatings was prepared and evaluated as time controlled chronomodulated tablet.Materials and Methods:Cores containing Montelukast sodium as model drug were prepared by direct compression and then coated sequentially with an inner swelling layer containing a HPMC E 5 and an outer rupturable layer of Eudragit RL/RS (1:1). A three-factor, two-level, full factorial design was used to investigate the influence of amount of HPMC E 5 and Eudragit RL/RS (1:1) on the responses, i.e., lag time to release and time required for 80% of drug to releases. The dissolution tests were studied using the USP paddle method at 50 rpm in 0.1 N HCL for 2 hr and than in phosphate buffer pH 6.8.Methods:Cores containing Montelukast sodium as model drug were prepared by direct compression and then coated sequentially with an inner swelling layer containing a HPMC E 5 and an outer rupturable layer of Eudragit RL/RS (1:1). A three-factor, two-level, full factorial design was used to investigate the influence of amount of HPMC E 5 and Eudragit RL/RS (1:1) on the responses, i.e., lag time to release and time required for 80% of drug to releases. The dissolution tests were studied using the USP paddle method at 50 rpm in 0.1 N HCL for 2 hr and than in phosphate buffer pH 6.8.Result:The lag time of the drug release decreased by increasing the inner swelling layer and increased by increasing the rupturing layer level.Conclusion:The results obtain from present study suggest that swelling come reputable coating approach gives desire drug release after lag time.

Bioequivalence Evaluation of Two Brands of Lisinopril Tablets by in vitro Comparative Dissolution Test and in vivo Bioequivalence Test

The bioequivalence of a test formulation (Nanopril, "test") and a reference formulation ("reference") of lisinopril (CAS 83915-83-7) was demonstrated by in vivo and in vitro tests. The in vivo bioequivalence study in 26 healthy volunteers was designed as a single dose, randomized, double-blind trial with a 2-week washout period between the doses. Prior to the in vivo study, an in vitro comparative dissolution test was performed by the paddle method following the bioequivalence guidance of the Korea Food and Drug Administration (KFDA). By the results of the dissolution test it was demonstrated from the similar and rapidly dissolving patterns of the two lisinopril tablets that the two formulations were pharmaceutically equivalent. However, the in vivo bioequivalence study was required to fully evaluate the bioequivalence of the two drug products. In the in vivo bioequivalence study, the plasma samples drawn from the volunteers were analyzed utilizing a sensitive LC-MS-MS analysis method and the bioequivalence between the two drug products was assessed by statistical analysis of the log transformed mean ratios of Cmax,AUC(0-t) and AUC(0-infinity). The mean maximum concentration (Cmax) of the test and reference were found to be 60.41 +/- 20.07 ng/mL and 61.11 +/- 19.36 ng/mL, respectively. The 90% confidence intervals (C.I.) of Cmax were in the range from 0.91 to 1.08. As for the AUC(0-t) and the AUC(0-infinity), test values were 792.73 +/- 273.41 ng x mL(-1) x h, 862.74 +/- 303.81 ng x mL(-1) x h and the reference values were 841.66 +/- 286.07 ng . mL(-1) x h, 906.97 +/- 318.72 ng x mL(-1) x h, respectively. The 90% C. I. of AUC(0-t) were 0.86 to 1.01 and of AUC(0-infinity), 0.87 to 1.02 and thus were within the 80-125% interval proposed by the FDA. In addition to the 90% C.I. of the pharmaceutical parameters, a two-way ANOVA showed no significant difference between the two formulations. Based upon these statistical analyses, it was concluded that the test formulation is bioequivalent to the reference.

In vitro Dissolution and in vivo Bioequivalence Evaluation of Two Brands of Cefuroxime Axetil Tablets

The bioequivalence of two brands of 250 mg cefuroxime axetil (CAS 64544-07-6) tablets was evaluated by in vitro dissolution tests and in vivo bioequivalence tests. The in vitro dissolution test was performed by the paddle method following the guidance of the Korea Food and Drug Administration (KFDA). The in vivo bioequivalence study was designed to be a single dose, randomized, double-blind trial with a 1-week washout period between the doses in 26 healthy volunteers. The results of the dissolution test showed comparable and rapidly dissolving profiles of the two cefuroxime axetil tablets, which were pharmaceutically equivalent. The in vivo study was conducted to evaluate the bioequivalence of the two drug products in humans. In the in vivo bioequivalence study, the plasma samples drawn from the volunteers were analyzed utilizing a sensitive HPLC analysis method with ultraviolet detection. The evaluation of bioequivalence between test and reference products was accomplished by statistical analysis of the log transformed mean ratios of Cmax, AUC0–t and AUC0–8. The mean maximum concentration (Cmax) of the test and the reference were found to be 8.5 ± 2.0 µg/mL and 8.6 ± 2.1 µg/mL, respectively. The 90% C. I. of Cmax was 0.95 to 1.03. As for the AUC0–t and the AUC0–8, test values were 22.6 ± 5.7 µg mL−1 h, 23.5 ± 6.3 µg mL−1 h and the reference values were 25.6 ± 6.6 µg mL−1 h, 26.7 ± 6.8 µg mL−1 h, respectively. The 90% C. I. of AUC0–t was 0.83 to 0.94 and AUC0–8, 0.82 to 0.94. Consequently, all the results fulfilled the standard criteria of bioequivalence, being within the 0.80 to 1.25% range. In addition to the 90% C. I. of the parameters, a two-way ANOVA showed that there was no significant difference between the two products. Based on these statistical analyses, it is concluded that the test product is bioequivalent to the reference product.

Enhancement of dissolution rate and bioavailability of sulfamethoxazole by complexation with β-cyclodextrin

The purpose of this study was to improve the solubility and dissolution rate of sulfamethoxazole (SMZ) with inclusion compound of β-cyclodextrin (β-CD). The interaction between SMZ and β-CD in solution was studied by the phase-solubility method. The phase-solubility studies revealed the formation of inclusion complexes with poor solubility with an inclusion complex of 1:1 molar ratio and a stability constant of 122.3 M−1. The solid complexes of SMZ with β-CD were prepared by using kneading and coprecipitation methods. The physical mixture of these chemicals was also prepared for comparison. Inclusion complexation was confirmed by the results from the studies of infrared spectoroscopy (IR) and differential scanning calorimetry (DSC). The effect of water-soluble polymers i.e., polyethylene glycol 20000 and non-ionic surfactants i.e., polysorbate 20 on the complexation of SMZ with β-CD was also investigated by the same methods. The rates of release of the active material from the complexes were determined from dissolution studies using USP XXII paddle method. The formulation, that provided delivery of active material near to the target value in six healthy volunteers and in vivo tests, clearly revealed that the bioavailability of active material was found to be enhanced by preparing ternary mixtures.

Comparison of Dissolution Behavior of Scopolamine Butylbromide between Ethical and Over-the-counter Drugs

Marketing authorization holders do not disclose any information on the pharmaceutical properties of over-the-counter drugs (OTC). When a drug is switched from a prescription drug to OTC, pharmacists can acquire that information from the corresponding ethical drug (ED) through the package insert, interview form, and so on. However, the pharmaceutical equivalence between ED and OTC is unclear. In this study, we examined the drug dissolution behavior of both ED and OTCs containing scopolamine butylbromide. Dissolution tests were performed by the paddle method using Japanese Pharmacopeia (JP) XV test fluids at pH 1.2, 4.0 and 6.8 and water based on the guidelines for bioequivalence studies of generic products. The dissolution profiles of OTCs differed significantly from ED showing a similarity factor (f2) value ranging from 8.9 to 42.9. Time until 85% dissolution ranged from 23 to 95 min and from 17 to 174 min at pH 1.2 and pH 6.8, respectively. Then JP XV disintegration tests were conducted to investigate differences in the disintegration process. The disintegration time of preparations showing delayed dissolution was prolonged compared to that of others, suggesting that the disintegration of the tablet or capsule is one of the important factors affecting the drug dissolution. These differences in the disintegration and drug dissolution might cause differences in the bioavailability of the drug. For patient safety, more detailed product information of OTCs should be supplied by the manufacturer, and not be assumed from that of corresponding ED.

Mathematical modeling of variables involved in dissolution testing

Dissolution testing is an important technique used for development and quality control of solid oral dosage forms of pharmaceutical products. However, the variability associated with this technique, especially with USP apparatuses 1 and 2, is a concern for both the US Food and Drug Administration and pharmaceutical companies. Dissolution testing involves a number of variables, which can be divided into four main categories: (1) analyst, (2) dissolution apparatus, (3) testing environment, and (4) sample. Both linear and nonlinear models have been used to study dissolution profiles, and various mathematical functions have been used to model the observed data. In this study, several variables, including dissolved gases in the dissolution medium, off-center placement of the test tablet, environmental vibration, and various agitation speeds, were modeled. Mathematical models including Higuchi, Korsmeyer-Peppas, Weibull, and the Noyes-Whitney equation were employed to study the dissolution profile of 10 mg prednisone tablets (NCDA #2) using the USP paddle method. The results showed that the nonlinear models (Korsmeyer-Peppas and Weibull) accurately described the entire dissolution profile. The results also showed that dissolution variables affected dissolution rate constants differently, depending on whether the tablets disintegrated or dissolved.

Dissolution of a poorly water-soluble drug dry coated with magnesium and sodium stearate

The purpose of this research was to investigate the influence of dry coating micronized cohesive powders of a poorly water-soluble drug, indomethacin with force control agents, on its dissolution performance. A dry mechanical fusion method (mechanofusion) was used to coat indomethacin powders with magnesium stearate (0.25%,1%,5%) and sodium stearate (5%). After mechanofusion, significantly increased bulk and tapped densities and decreased intrinsic cohesion were observed for all samples. X-ray photoelectron spectroscopy analysis confirmed that a thicker magnesium stearate surface coating was achieved with increasing concentrations of the material. Dissolution was studied using the USP paddle method in buffer pH 5.0; several modelling approaches were used to explore the dissolution mechanisms. Whilst the bi-exponential equation represented dissolution of mechanofused indomethacin powders occurring from dispersed and agglomerated particles, it provided unrealistic parameter estimates for the two coating materials of contrasting properties. Initial increases in indomethacin dissolution were dependent on the concentration of magnesium stearate mechanofused onto the drug powders. The dissolution enhancing effect of indomethacin powders mechanofused with 5% sodium stearate was attributed to its surfactant properties that increased dispersion of indomethacin agglomerates. Initial drug release from the coated powders was described by a matrix-diffusion system according to the Higuchi model.

Understanding improved dissolution of indomethacin through the use of cohesive poorly water‐soluble aluminium hydroxide: Effects of concentration and particle size distribution

The objective of this study was to explore the effects of concentration and particle size distribution of an added poorly water‐soluble inorganic salt, aluminium hydroxide, on the dissolution of a poorly water‐soluble drug, indomethacin (IMC), from lactose interactive mixtures. Dissolution was studied using the United States Pharmacopeia paddle method in buffer pH 5.0 and the data most aptly fitted a bi‐exponential dissolution model which represented dissolution occurring from dispersed and agglomerated particles. The dispersion of IMC mixtures was measured in dissolution media under non‐sink conditions by laser diffraction. The dissolution of IMC increased as a function of the concentration of aluminium hydroxide (5–20%) added to the mixtures. Increasing the proportion of larger particles of the cohesive aluminium hydroxide increased the dissolution rate of IMC. The enhanced dissolution was attributed to increases in both the dissolution rate constant and initial concentration of dispersed particles. Mechanistically, the aluminium hydroxide was found to facilitate the detachment of IMC particles from the carrier surface, forming a complex interactive mixture that more readily deagglomerated than the cohesive drug agglomerates. The outcomes of this work would therefore allow more careful control and selection of the excipient specifications in producing solid dosage formulations with improved dissolution of poorly water‐soluble drugs. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4269–4280, 2011

Gel formulations containing catanionic vesicles composed of alprenolol and SDS: Effects of drug release and skin penetration on aggregate structure

To fully utilize the extended contact time of gel formulations a novel formulation with drug containing catanionic aggregates offering prolonged drug release and skin penetration were investigated. This study aimed to further explore the drug release process from catanionic vesicles in gels.Catanionic vesicles were formed from alprenolol and sodium dodecyl sulphate. Physical gels composed of catanionic vesicles and a SoftCAT polymer were used as well as covalent Carbopol gels. Drug release was measured in vitro using a modified USP paddle method and the skin penetration was studied using dermatomized pig ear skin mounted in horizontal Ussing chambers. The aggregate structure was visualized with cryo-TEM during the drug release and skin penetration process.The study results show that catanionic vesicles are present in the formulations throughout the drug release process and during the clinically relevant skin application time. Hence, the decreased skin penetration rate stems from the prolonged release of drug substance from the gels. The rheological investigation shows that the gel structure of the physically cross-linked gels is maintained even as the drug substance is released and the gel volume is decreased. These findings indicate that the applicability of formulations like these is a future possibility.

Solvent shift method for anti-precipitant screening of poorly soluble drugs using biorelevant medium and dimethyl sulfoxide

96-well plate based anti-precipitant screening using bio-relevant medium FaSSIF (fasted-state simulated small intestinal fluid) is a useful technique for discovering anti-precipitants that maintain supersaturation of poorly soluble drugs. In a previous report, two disadvantages of the solvent evaporation method (solvent casting method) were mentioned: precipitation during the evaporation process and the use of volatile solvents to dissolve compounds. In this report, we propose a solvent shift method using DMSO (dimethyl sulfoxide). Initially, the drug substance was dissolved in DMSO at a high concentration and diluted with FaSSIF that contained anti-precipitants. To evaluate the validity of the method, itraconazole (ITZ) was used as the poorly soluble model drug. The solvent shift method resolved the disadvantages of the evaporation method, and AQOAT (HPMC-AS) was found as the most appropriate anti-precipitant for ITZ in a facile and expeditious manner when compared with the solvent evaporation method. In the large scale JP paddle method, AQOAT-based solid dispersion maintained a higher concentration than Tc-5Ew (HPMC)-based formulation; this result corresponded well with the small scale of the solvent shift method.

Acceleration of in vitro dissolution studies of sustained release dosage form of theophylline and in vitro–in vivo evaluations in terms of correlations

The aim of the study was to accelerate the dissolution of the sustained release dosage forms using both elevated temperature and high rpm rates. Teokap(®) SR 200 mg pellets were tested by in vitro sustained and accelerated dissolution studies using USP XXIII rotating paddle method. Sustained dissolution studies were carried out for 12 h in phosphate buffer at 37 ± 0.5°C and 50 rpm. Accelerated dissolution studies were performed for 48 min in distilled water at 90 ± 1°C and 250 rpm. The results obtained from accelerated and sustained dissolution studies were correlated using both linear and linear kinetic correlation methods by a computer program. While r (2) and maximum error between calculated and observed drug release rates were found to be 0.9129 and 15.9%, respectively, in linear correlation method, these values were observed as 0.9938 and 3.6%, respectively, in linear kinetic correlation method. In vivo plasma concentration data were obtained from six New Zealand rabbits after administration of a single dose of Teokap(®) SR 200 mg pellet. Then, the results of in vivo study were evaluated with in vitro accelerated and sustained dissolution results by applying them to in vitro-in vivo linear correlations. As a result of these correlations, it was shown that the in vitro correlation plots were very similar to the plot which was obtained by the in vivo study (f (2) = 73.81-77.11). This study suggested a way to prevent the loss of time for routine dissolution studies of sustained release preparations for quality control procedures using in vitro accelerated dissolution tests. The storage and quarantine periods of the product in process and process controls in the manufactories could be shortened by this method. Calculation of the in vivo performance of sustained release dosage forms using the results of the accelerated dissolution studies may be counted as another advantage of the method.

Counter-intuitive enhancement in the dissolution of indomethacin with the incorporation of cohesive poorly water-soluble inorganic salt additives

The objective of this work was to investigate the influence of various micronized poorly water-soluble inorganic materials on the dissolution and de-agglomeration behaviour of a micronized, poorly water-soluble model drug, indomethacin, from lactose interactive mixtures. Dissolution of indomethacin was studied using the USP paddle method and the data were modelled with multi-exponential equations using a nonlinear least squares algorithm in order to obtain key parameter estimates. The dispersion of indomethacin mixtures was measured by laser diffraction. The addition of aluminium hydroxide and calcium phosphate to binary mixtures of indomethacin counter-intuitively improved the dissolution rate of indomethacin due to significant increases in both the estimated initial concentration and dissolution rate constant of dispersed particles of indomethacin. While some enhancement was due to pH changes in the dissolution medium, the presence of these poorly water-soluble inorganic salts caused de-agglomeration. Average particle size distributions indicated that the presence of aluminium hydroxide within the matrix of indomethacin had reduced the agglomerate concentration whilst increasing the dispersed particle concentration. These findings provide the first evidence of the ability of poorly water-soluble inorganic salts to enhance the de-agglomeration and dissolution of micronized powders, potentially translating to improved bioavailability of poorly water-soluble drugs.

Concentration Dependence of 5-Aminosalicylic Acid Pharmacological Actions in Intestinal Mucosa after Oral Administration of a pH-Dependent Formulation

Asacol, a medication that delivers delayed release 5-aminosalicylic acid (5-ASA), is a useful therapeutic agent for inflammatory bowel disease (IBD), but the relationship between its pharmacological actions and intestinal concentrations has not been studied in detail. Therefore, our aim was to assess 5-ASA's pharmacological actions as a function of its concentration at its target site. We first evaluated 5-ASA's release profiles in vitro by the paddle method and found that Asacol starts to release 5-ASA at pH ≥ 7. Orally administered Asacol pharmacokinetic parameters were evaluated in dogs. Asacol's T(max) was much longer than that of the time-dependent release 5-ASA formulation. We also determined 5-ASA's distribution in the intestinal mucosa and found that it is effectively delivered there by Asacol. These results indicated that Asacol released 5-ASA in a pH-dependent manner, resulting in efficient delivery to the large intestine. We also compared the mucosal 5-ASA concentrations with the IC(50) values for scavenging free radicals or suppressing LTB(4) production. The 5-ASA concentration in the large intestine was higher than IC(50) values necessary to suppress inflammatory processes. We also report the release characteristics of Asacol and the targeted delivery of 5-ASA to affected sites in IBD patients.

Enhanced Dissolution Rate of Glipizide by a Liquisolid Technique

This study aims to prepare immediate release glipizide liquisolid tablets using Avicel PH-102 and Aerosil 200 as the carrier and coating material respectively to increase dissolution rate of poorly soluble glipizide. This study also aims to evaluate treated Gellan gum as disintegrant in the preparation of liquisolid tablets. The solubility of glipizide was increased by use of liquisolid technique. The glipizide liquisolid tablets were evaluated for characteristics like drug content, friability, hardness, disintegration time, thermal analysis, X-ray diffraction (XRD) study and dissolution rates. The dissolution patterns of glipizide liquisolid tablets, carried out according to USP paddle method, and were compared with their commercial counterparts. The results obtained shows that all glipizide liquisolid tablets exhibits higher dissolution rates than those of marketed glipizide tablets. Dissolution rates increases with increasing concentration of liquid vehicles and maximum drug release achieved by formulations containing Polyethylene glycol 400 (PEG 400) as a liquid vehicle. The results of XRD and thermal analysis did not show any changes in crystallinity of drug and interaction between glipizide and excipients during the formulation process.

Enhancement of dissolution profile for oral delivery of Fexofenadine Hydrochloride by solid dispersion (solvent evaporation) technique

The objective of present work is to investigate the enhancement of dissolution profile for oral delivery of Fexofenadine Hydrochloride (FH) through solid dispersion (SD) technique by the method of solvent evaporation. The SD was prepared by using ethanol as a solvent. Tablets were formulated containing solid dispersion of FH and compared with tablets of same formula without solid dispersion of FH. The using of ethanol to prepare solid dispersion found a significant effect on the dissolution of FH. Dissolution studies using the USP-33 paddle method were performed for tablets formulated with and without solid dispersions of FH. Dissolution of FH improved significantly in tablets formulated with SD (85% in 10 minutes) exhibited better dissolution profile than tablets formulated without SD. Infrared (IR) spectroscopy was also performed to identify the physicochemical interaction between drug and solvent, hence its effect on dissolution.

Inclusion complexes of ketoconazole with beta-cyclodextrin: physicochemical characterization and in vitro dissolution behaviour of its vaginal suppositories

Ketoconazole (KZ) is an imidazole antifungal agent which is administered topically and also orally. KZ is practically insoluble in water. Vaginal candidiasis is a common condition and up to 75% of all women have at least one episode of this infection during their lifetime. The aim of study was to prepare KZ/β-cyclodextrin (β-CD) complex to improve the physicochemical properties of KZ and to investigate the possibility of preparing vaginal suppositories with the complexes. A linear increase in KZ solubility as a function of β-CD concentration was verified using the phase-solubility diagram. The resulting diagram was classified as AL-type, is generally related to the formation of a soluble complex. Complexes were prepared in a 1:1 molar ratio by different methods, namely freeze-drying, spray-drying, co-evaporation and kneading. Characterization of the complexes prepared was performed by practical yield %, aqueous solubility, active agent amount analyses, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffractometry (PXRD) and 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. Characterization studies provided additional evidences of complexation. The paddle method defined in USP31 was used in in vitro dissolution experiments on the prepared vaginal suppositories. It was found that solubility enhancement by preparing KZ/β-CD complexes depends on the type of the preparation method. Dissolution of KZ from complexes was found to be faster than the active agent and the commercial suppositories. This result may be attributed to the interactions between β-CD and active agent, high energetic amorphous state and decrease in the interfacial tension between insoluble active agent and dissolution media.

Formulation and Evaluation of Sustained Release Matrix Tablets of Metformin Hydrochloride Using pH Dependent and pH Independent Methacrylate Polymers

Metformin hydrochloride is recommended globally as first line therapy due to its favorable profile on morbidity and mortality associated with type-2 diabetes mellitus. However, limitations of multiple dosing and risk of triggering gastrointestinal symptoms make its dose optimization difficult. Extended-release metformin matrix tablets were prepared by direct compression of drug and different pH-dependent (Eudragit L-100 and S-100) and pH-independent (Eudragit RLPO and RSPO) polymer combinations. The influence of varying the polymer/polymer (w/w) ratio was evaluated. Among the different examined polymer blends, matrix tablets based on S-100/RLPO and S-100/RSPO mixtures gave the more sustained release pattern. The excipients used in this study did not alter physicochemical properties of the drug, as tested by Fourier transform Infrared Spectroscopy and the thermal analysis using differential scanning calorimetry. All the batches were evaluated for thickness, weight variation, hardness, and drug content uniformity. The in vitro drug dissolution study was carried out using USP 22 apparatus II, paddle method and the release mechanisms were explored. Mean dissolution time is used to characterize drug release rate from a dosage form and indicates the drug release retarding efficiency of polymer. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled to anomalous type. Fitting the data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release. Research Article

Formulation and evaluation of a sustained-release tablets of metformin hydrochloride using hydrophilic synthetic and hydrophobic natural polymers.

Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study was to develop an oral sustained release metformin hydrochloride tablet by using hydrophilic Eudragit RSPO alone or its combination with hydrophobic natural polymers Gum copal and gum damar as rate controlling factor. The tablets were prepared by wet granulation method. The in vitro dissolution study was carried out using USP 22 apparatus I, paddle method and the data was analysed using zero order, first order, Higuchi, Korsmeyer and Hixson-Crowell equations. The drug release study revealed that Eudragit RSPO alone was unable to sustain the drug release. Combining Eudragit with gum Copal and gum Damar sustained the drug release for more than 12 h. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.

Interchangeability evaluation of multisource Ibuprofen drug products using biowaiver procedure.

The WHO biowaiver procedure for BCS Class II weak acids was evaluated by running two multisource IR ibuprofen drug products (Ibuprofen, 200 mg tablets, Tatchempharmpreparaty, Russia and Ibuprofen, 200 mg tablets, Biosintez, Russia) with current Marketing Authorizations (i.e. in vivo bioequivalent) through that procedure. Risks associated with excipients interaction and therapeutic index were considered to be not critical. In vitro dissolution kinetic studies were carried out according WHO Guidance (WHO Technical Report Series, No. 937, Annexes 7 and 8) using USP Apparatus II (paddle method) at 75 rpm. Dissolution profiles of test and reference ibuprofen tablets were considered equivalent in pH 4.5 using factors f1 (13) and f2 (72) and not equivalent in pH 6.8 (factor f1 was 26 and f2 was 24). Drug release of ibuprofen at pH 1.2 was negligible due to its weak acid properties. Therefore, two in vivo bioequivalent tablets were declared bioinequivalent by this procedure, indicating that procedure seems to be over-discriminatory.

Formulation and Evaluation of Hydroxypropyl Methylcellulose-based Controlled Release Matrix Tablets for Theophylline.

The objectives of the study were to formulate hydroxypropyl methyl cellulose-based controlled release matrix tablets for theophylline with varying drug:polymer ratios (1:1 and 1:2) and differing tablet hardness (5, 6 and 7 kg/cm2), and to evaluate the tablet's physico-chemical properties such as hardness, uniformity of weight, friability, drug content and in vitro drug release. Initially, granules were made by wet granulation technique and evaluated for angle of repose, bulk density, tapped density, bulkiness, compressibility index and hausner ratio. The results indicate good flow property of the granules and thus, the evaluated tablet physical properties were within the acceptable limits. The FT-IR study for the F-6 formulation showed that there was no interaction between the drug and the polymer. In vitro release studies were performed using Disso-2000 (paddle method) in 900 ml of pH 7.4 at 50 rpm. The result indicated that at high drug:polymer ratio (1:2) and hardness value 7 kg/cm2, prolonged drug release was observed than the low drug: polymer ratio (1:1) and hardness values (5 and 6 kg/cm2). The release kinetics was found to follow korsmeyers-peppas model and the mechanism of drug release was by non-fickian or anomalous diffusion. The F-6 formulation was chosen for stability studies. F-6 formulation was stable when it was kept at different temperatures for a period of 6 months.