Formulation and pharmacokinetics of multi-layered matrix tablets: Biphasic delivery of diclofenac.

The rapid availability of the drug at the site of action followed by maintaining its effect for a long period of time is of great clinical importance. Thus, the purpose of the present study was to prepare and evaluate multi-layered matrix tablets of diclofenac using Eudragit RL/RS blend to achieve both immediate and sustained therapeutic effects. Diclofenac potassium (25 mg) was incorporated in an outer immediate release layer to provide immediate pain relief whereas diclofenac sodium (75 mg) was incorporated in the inner core to provide extended drug release. Wet granulation was employed to prepare the inner core of the tablets that were further layered with an immediate release drug layer in the perforated pan coater. The in-vitro and in-vivo performance of the developed formulation was compared with the marketed products Voltaren® SR 75 mg and Cataflam® 25 mg. The in-vitro drug release of the prepared formulation showed similarity (f2 = 66.19) to the marketed product. The pharmacokinetic study showed no significant difference (p > 0.05) in AUC0-24 and Cmax between the test and reference formulations. The AUC0-24 values were 105.36 ± 83.3 and 92.87 ± 55.53 µg h/ml whereas the Cmax values were 11.25 ± 6.87 and 12.97 ± 8.45 µg/ml, for the test and reference, respectively. The multi-layered tablets were proved to be bioequivalent with the commercially available tablets and were in agreement with the observed in-vitro drug release results. Stable physical characteristics and drug release profiles were observed in both long term and accelerated conditions stability studies.

Multiple response optimization of processing and formulation parameters of Eudragit RL/RS-based matrix tablets for sustained delivery of diclofenac.

CONTEXT: Multiple response optimization is an efficient technique to develop sustained release formulation while decreasing the number of experiments based on trial and error approach. OBJECTIVE: Diclofenac matrix tablets were optimized to achieve a release profile conforming to USP monograph, matching Voltaren®SR and withstand formulation variables. The percent of drug released at predetermined multiple time points were the response variables in the design. Statistical models were obtained with relative contour diagrams being overlaid to predict process and formulation parameters expected to produce the target release profile. MATERIALS AND METHODS: Tablets were prepared by wet granulation using mixture of equivalent quantities of Eudragit RL/RS at overall polymer concentration of 10-30%w/w and compressed at 5-15KN. RESULTS AND DISCUSSION: Drug release from the optimized formulation E4 (15%w/w, 15KN) was similar to Voltaren, conformed to USP monograph and found to be stable. Substituting lactose with mannitol, reversing the ratio between lactose and microcrystalline cellulose or increasing drug load showed no significant difference in drug release. Using dextromethorphan hydrobromide as a model soluble drug showed burst release due to higher solubility and formation of micro cavities. CONCLUSION: A numerical optimization technique was employed to develop a stable consistent promising formulation for sustained delivery of diclofenac.

STUDYING THE IMPACT OF FORMULATION AND PROCESSING PARAMETERS ON THE RELEASE CHARACTERISTICS FROM HYDROXYPROPYL METHYLCELLULOSE MATRIX TABLETS OF DICLOFENAC.

Hydrophilic matrices, especially HPMC based, are widely used to provide sustained delivery where drug release occurs mainly by diffusion. A 3(2) full factorial design was used to develop and evaluate HPMC matrix tablet for sustained delivery of diclofenac. The influences of polymer concentration/viscosity, diluent type/ratio, drug load/solubility, compression force and pH change on drug release were investigated. Ten tablet formulations were prepared using wet granulation. HPMC K15M (10-30% w/w) was used as the polymer forming matrix. The release kinetics, compatibility studies, lot reproducibility and effect on storage were discussed. Increasing polymer concentration and compression force showed antagonistic effect on release rate. Mannitol tends to increase release rate more than lactose. Reversing diluent ratio between lactose and MCC did not affect drug release. Changing pH resulted in burst release whereas drug solubility is pH independent. F1 showed similar release to Voltaren SR and followed Higuchi model. Drug and polymer were compatible to each other. The formulation is stable at long and intermediate conditions with a significant increase in release rate at accelerated conditions due to water uptake and polymer swelling. The developed formulation was successful for a sustained delivery of diclofenac.

Development and optimization of dextromethorphan hydrobromide oral disintegrating tablets: effect of formulation and process variables.

Orally disintegrating tablets (ODTs), which disintegrate rapidly (<1 min) in the mouth and do not require water for administration, have become a very popular dosage form. The study aims to develop a simple and inexpensive method of manufacturing ODTs of a sparingly water-soluble drug, Dextromethorphan hydrobromide. Two factors, three levels (3(2)) full factorial design was used to optimize the diluent, microcrystalline cellulose (X(1)) and superdisintegrant, croscarmellose sodium (X(2)) concentrations. Disintegration time, hardness and T(50) values for all the formulations varied from 12.5 to 152.6 s, 3.58 to 4.92 kp and 0.8 to 2.8 min, respectively. The results indicated that the selected variables have a strong influence on disintegration time, hardness and T(50) of the ODTs. The manufactured ODTs formula composed of 30% microcrystalline cellulose in combination with 3% croscarmellose sodium was chosen as optimized formula, as it showed the lowest disintegration time (12.5 ± 1.22 s), low T(50) (0.8 min.) and hard tablets (4.92 ± 0.28 kp) amongst other tested ODTs formulations. Hardness of DM ODTs was not affected by changing the type of superdisintegrant and lubricant. The disintegration time was significantly (p < 0.05) increased by using sodium starch glycolate instead of croscarmellose sodium.

Content uniformity testing: suitability of different approaches for marketed low dose tablets.

CONTEXT: Content uniformity (CU) testing was developed and improved to control the effectiveness and safety of dosage units. Many modifications of compendial CU test have been introduced and several alternatives have been suggested. OBJECTIVES: This study aims to evaluate the degree of suitability of current USP CU test for low dose tablets and to compare the performance of the current test with that of the former USP27-NF22 and other alternatives for different sample sizes. METHODS: All locally marketed risperidone (RSP) tablets were analyzed using newly developed and validated isocratic UPLC method. The CU results were statistically analyzed in groups with sample sizes comparable to the USP sampling plans. RESULTS: Seven out of eleven products failed the different requirements of the former and current USP <905>chapters as well as of several alternative CU tests with several substantial deviations. CONCLUSION: The current USP <905> chapter was found to have some deficiencies that allowed such failed products to exist in the market. The dependence of compendial CU test on two-staged sampling plan and the use of arithmetic mean to calculate the reference and acceptance values were obvious shortcomings.

Influence of Carbopol 71G-NF on the release of dextromethorphan hydrobromide from extended-release matrix tablets.

The objective of this study was to evaluate the potential of Carbopol(®) 71G-NF on the release of dextromethorphan hydrobromide (DM) from matrix tablets in comparison with hydroxypropyl methylcellulose (HPMC(®) K15M) and Eudragit(®) L100-55 polymers. Controlled release DM matrix tablets were prepared using Carbopol 71G-NF, HPMC K15M, and Eudragit L100-55 at different drug to polymer ratios by direct compression technique. The mechanical properties of the tablets as tested by crushing strength and friability tests were improved as the concentration of Carbopol, HPMC, and Eudragit increased. However, Carbopol-based tablets showed a significantly (P<0.05) higher crushing strength and a lower friability than HPMC and Eudragit tablets. No significant differences in weight uniformity and thickness values were observed between the different formulations. It was also found that Carbopol significantly (P<0.05) delayed the release of DM in comparison with HPMC K15M and Eudragit L100-55. A combination of HPMC K15M and Eudragit L100-55 in a 1:1 ratio at 20 and 30% significantly (P<0.05) delayed the release of DM than Eudragit L100-55 alone. Moreover, blends of Carbopol and HPMC at a 1:1 ratio at the 10, 20, and 30% total polymer concentration were investigated. The blend of Carbopol and HPMC at 10% level significantly (P<0.05) slowed the release of DM than Carbopol or HPMC alone, whereas blends at 20 and 30% level significantly (P<0.05) delayed the release of DM compared with HPMC or Carbopol alone. The results with these polymer blends showed that it was possible to reduce the total amount of polymers when used as a combination in formulation.

Upgrading wet granulation monitoring from hand squeeze test to mixing torque rheometry.

With over 50 years of research in granulation technology, however more research is required to elucidate this widely applicable technology. Wetting phenomena could influence redistribution of individual ingredients within a granule according their solubility and also could affect the drying processes. Binder selection for a particular system is quite often empirical and dependent on the skills and experience of the formulator. Hand squeeze test was and still the main way for determination of wet granulation end point, but it is subjected to individual variation. It depends mainly on operator experience, so it is not possible to be validated. Literature reveals a variety of advanced monitoring techniques following up different wet massing stages. Torque measurement has been proved to be the most reliable control method as its tight relation to mass resistance. Many reports showed successful applications of mixing torque rheometer (MTR) for monitoring the wet massing procedure and scale up in addition to some preformulation applications. MTR as a new approach allows formulators to select a liquid addition range where the granule growth behavior is more predictable.

Assessment of the pharmaceutical quality of marketed enteric coated pantoprazole sodium sesquihydrate products.

Pantoprazole sodium sesquihydrate (PSS) is a proton pump inhibitor, used in acid-related disorders, like peptic ulcer and gastroesophageal reflux. Increasing the number of pantoprazole containing products in the market, raises questions of its efficacy and generic substitution. The pharmaceutical quality of 6 generic PSS enteric coated tablets in 2 local markets was assessed relative to the innovator product (pantozol®). Uniformity of dosage unit, disintegration and in vitro drug release were determined using United States pharmacopeia for delayed release tablets. The similarity factor (f2) was assessed using the FDA recommended approach (f2 similarity factor). The content uniformity of the innovator product was 98.39% of the labeled claim with RSD value of 1.08%, while the content of generic products ranged from 96.98% to 98.80% with RSD values of 1.24-2.19%. All the products showed no disintegration, cracks or swelling in 0.1 N HCl, except product 1, which showed complete disintegration after 20 min. However, the disintegration of all the products in phosphate buffer met USP requirements. Dissolution of tablets in 0.1 N HCl showed no drug release after 2 h except product 1 in which one tablet showed a drug release more than 10% at acid stage level A1. In addition, three tablets of this product showed dissolution of 45%, 48% and 69% at acid stage level A2. The similarity factor f2 of the products was between 71 and 74 indicating the similarity in dissolution profiles of all the products in accordance to FDA requirements, except product 1 in which f2 value was 18.67.

Effect of Kollidon® SR on the release of Albuterol Sulphate from matrix tablets.

The objective of this study was to evaluate Kollidon SR for the development of extended release Albuterol Sulphate matrix tablets in comparison with other polymers as Hydroxypropylmethylcellulose K15M, Carbopol 71G NF, and Eudragit L100-55. The mechanical properties of the tablets were improved as concentration of Kollidon SR or other polymers increased. It was found that Kollidon SR 30% (w/w) and HPMC 30% (w/w) tablets have f 2 similarity factor of 83.5 in their Albuterol Sulphate dissolution profile. The marketed product was found to release 99.7% of drug content within 8 h, while Kollidon SR and HPMC tablets with 30% (w/w) polymer concentration level released 92.7% and 92.9% respectively of drug content within 8 h. Kollidon SR has a unique character of maintaining tablets geometric shape until the end of dissolution test, this is mainly due to the water insoluble content, polyvinyl acetate, forming 80% (w/w) of Kollidon SR, while the remaining content 20% (w/w) is the water soluble, polyvinylpyrrolidone, responsible for pore formation causing a diffusion controlled release. Drug release from all previous formulations is best described to be controlled by more than one kinetic mechanism of release. In conclusion, Kollidon SR and HPMC and Carbopol were found to be potential candidates for the development of extended release of Albuterol Sulphate tablets.

Application of on-line Raman spectroscopy for characterizing relationships between drug hydration state and tablet physical stability.

Experiments were conducted to elucidate the relationship between risedronate sodium (RS) hydration state and the physical stability of tablets containing RS. The RS crystal lattice contains channels occupied by water, which is removed by drying processes at temperatures below the boiling point of water, causing a reversible contraction of the crystal lattice. In this study, risedronate sodium was wet granulated followed by fluid bed drying to final granulation moisture contents between 1 and 7%, and then compressed into tablets. During drying, the RS solid-state form was continuously monitored using on-line Raman spectroscopy. Raman spectra acquired in these experiments enabled direct monitoring of changes in the RS crystal lattice, due to dehydration, which provided key information relating RS solid-state form characteristics to final granulation moisture content. Final granulation moisture was found to have a significant effect on the change in RS hydration state measured by Raman spectroscopy. As the final granulation moisture decreased, the amount of RS dehydrated form increased. The largest Raman spectral changes were in the CH stretching region and the region including the 3-picoline ring and PO2- stretches. These changes are indicative of substantial changes in the RS solid-state structure. Final granulation moisture also had a significant effect on the change in tablet thickness over time. Lower final granulation moisture caused a greater increase in tablet thickness as the RS rehydrated. In addition, the change in RS hydration state during fluid bed drying, measured by on-line Raman, was correlated to the increase in tablet thickness and subsequent loss of tablet integrity. Raman spectroscopy allowed direct RS hydration state monitoring, rather than inference from a bulk moisture measurement. Development of a Process Analytical Technology (PAT), specifically Raman, to monitor RS solid-state during drying enabled establishment of relationships between fundamental hydration dynamics associated with RS and final product performance attributes.

Application of Raman spectroscopy for on-line monitoring of low dose blend uniformity.

On-line Raman spectroscopy was used to evaluate the effect of blending time on low dose, 1%, blend uniformity of azimilide dihydrochloride. An 8 qt blender was used for the experiments and instrumented with a Raman probe through the I-bar port. The blender was slowed to 6.75 rpm to better illustrate the blending process (normal speed is 25 rpm). Uniformity was reached after 20 min of blending at 6.75 rpm (135 revolutions or 5.4 min at 25 rpm). On-line Raman analysis of blend uniformity provided more benefits than traditional thief sampling and off-line analysis. On-line Raman spectroscopy enabled generating data rich blend profiles, due to the ability to collect a large number of samples during the blending process (sampling every 20s). In addition, the Raman blend profile was rapidly generated, compared to the lengthy time to complete a blend profile with thief sampling and off-line analysis. The on-line Raman blend uniformity results were also significantly correlated (p-value < 0.05) to the HPLC uniformity results of thief samples.

Development and evaluation of extended release bioadhesive sodium fluoride tablets.

Localized fluoride delivery to the oral cavity is important in caries prevention. However, no current marketed dosage forms deliver fluoride for an extended period. This work describes the effect of poly (methyl vinyl ether-co-maleic anhydride) mixed calcium/sodium salt (Gantrez MS), sodium carboxymethylcellulose (NaCMC), polyethylene glycol 8000 (PEG8000) and Carbopol 934 (C934) on the in vitro dissolution and ex vivo bioadhesion of sodium fluoride matrix tablets. Dissolution was studied using USP Apparatus 2 and a low volume (3.1 ml), low flow (0.5 ml/min) dissolution apparatus. In both apparatus, the percent drug dissolved at 2, 4 and 8 h was found to be statistically dependent on the fractions of Gantrez MS and NaCMC. The interaction term was significant at 2 and 4 h (probability > (t) of less than 0.05). Ex vivo bioadhesion was studied using excised bovine gingiva and a TA.XT2i Texture Analyzer. Peak bioadhesive force and work of bioadhesion were found to be statistically dependent on the fractions of Gantrez MS and NaCMC with no interaction (probability > (t) of less than 0.01). Results indicate that bioadhesive matrix fluoride tablets of these mixtures can be designed to exhibit both bioadhesive and extended release properties.

A study of the pharmacodynamic differences between immediate and extended release bumetanide formulations.

Optimized bumetanide extended (ER) and immediate release (IR) formulations were developed using fluid bed layering and coating techniques. We postulated that the ER bumetanide formulation would have more effective and sustained diuretic and saluretic effects than IR. The diuretic/saluretic effects of both formulations were measured in rabbits (n=8) for two days after dosing with 1mg/kg bumetanide. During the first day, both formulations produced 2-3 times more urine volume and sodium excretion than baseline. In the first 24h, despite less bumetanide excretion from the ER formulation (101+/-13.9microg/kg compared to 146+/-14.6microg/kg for the IR formulation; P<0.04); the ER formulation produced diuresis and natriuresis that was equivalent to that of the IR formulation. In contrast, urine production in the IR formulation group fell below that of placebo controls on day 2. During the second day, the ER formulation was noted to produce persistent bumetanide excretion; the diuretic and natriuretic effects were not statistically significant from baseline control. We speculate that the decrease in response to bumetanide observed especially for the IR formulation during the second day may be due to the activation of compensatory counter-regulatory homeostatic mechanism(s). We conclude that the ER formulation had similar diuretic/saluretic effects but better drug excretion to urine production efficiencies than the IR formulation in the healthy rabbit model. The ER formulation, while providing comparable diuretic/saluretic effect to the IR formulation, offers the advantage of avoiding the initial, rapid and robust diuretic effect experienced with the IR formulations. Taken together, the data provide sufficient basis to warrant further investigation and refinement of our ER bumetanide formulation in humans.

Effect of curing conditions and plasticizer level on the release of highly lipophilic drug from coated multiparticulate drug delivery system.

The study aimed to investigate the effect of triethyl citrate (TEC) plasticizer level (10, 15, and 20%), curing temperature (40, 50, and 60 degrees C) and time (0 to 168 h) on the release of a highly lipophilic drug bumetanide from pellets coated with methacrylate ester copolymer (Eudragit RS). Bumetanide was layered onto sugar pellets followed by coating with 6% Eudragit RS with and without hydroxypropyl methyl cellulose (HPMC) seal coat using Wurster Fluid Bed equipment. Coated pellets were stored for 3 months at room temperature and the release was tested in USP purified water. At 10% TEC level, increasing curing time and temperature lead to slower drug release. At 15 and 20% TEC levels, curing initially decreased drug release followed by increase in the release at longer curing time and higher temperature. Drug release from coated pellets plasticized with 15% TEC and completely cured followed zero order kinetic models. At plasticizer level of 20%, bumetanide release from the completely cured pellets was better modeled using the Higuchi's equation reflecting possible drug migration during curing. Storage led to an increase in drug release. The use of HPMC seal coat stabilized drug release after storage. It was concluded that bumetanide migration into Eudragit RS film coat was the main cause of the accelerated release after curing and storage. The drug migration during storage at room temperature was prevented by seal coating the pellets with HPMC.

The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets.

Levothyroxine tablets, 50 microg, have been marketed for many decades but have had numerous recalls due to degradation and failure to meet potency. These experiments were devised to study the effects of various excipients on the stability of levothyroxine sodium pentahydrate in aqueous slurries and in formulated tablets. The active alone was found to be stable in the solid state for 6 months at 40 degrees C/75% RH whether stored in open or closed containers, and was found to be non-hygroscopic under normal processing conditions (>30% RH). In aqueous slurries with an excipient, the stability of the active improved as the pH of the slurry was increased from pH 3 to 11. Tablets manufactured with lactose anhydrous, starch, or microcrystalline cellulose failed to meet USP assay requirements at 3 months at 40 degrees C/75% RH. Tablets manufactured with dibasic calcium phosphate or mannitol met USP assay requirements at 3, but not 6 months when stored at 40 degrees C/75% RH. Tablets manufactured with dibasic calcium phosphate and a basic pH modifier, such as sodium carbonate, sodium bicarbonate, or magnesium oxide, met the USP assay requirements at both 3 and 6 months. Thus, the use of basic pH modifiers is a potential technique for improving the stability of levothyroxine sodium pentahydrate tablets.

Optimization of methacrylic acid ester copolymers blends as controlled release coatings using response surface methodology.

The aim of this study was to statistically optimize the use of blends of methacrylic acid ester copolymers with different permeability properties as controlled-release coating systems for tablets to produce predictable predesigned release profiles. A full factorial design was used to study and optimize the use of methacrylic acid ester copolymers Eudragit RS 30D and Eudragit RL 30D as coating materials for controlled release. Directly compressed theophylline tablets were coated with aqueous dispersions containing different proportions of the two copolymers using a side-vented coating pan (Accela Cota). The effect of polymer loading level at 5, 7.5, and 10% weight gain and curing time at 50 degrees C for 12 and 24 hours were also evaluated. Coated tablets were tested for their drug release in water using a United States Pharmacopeia (USP) dissolution apparatus #2. The results showed that increasing the content of the lower permeability copolymer Eudragit RS 30D, increasing the polymer load, and increasing curing time at 50 degrees C resulted in slower drug release. A statistical model that describes and predicts the drug release properties of the coated tablets as a function of the copolymers ratio in the coating dispersion, polymer load, and curing time at 50 degrees C was developed. The most significant factor affecting drug release was found to be the ratio of the two copolymers in the coating dispersion followed by the curing time at 50 degrees C and the polymer loading level. Good correlations were observed between the model fitted values andthe experimental values. An optimized formula prepared by superimposing two-dimensional contour plots was prepared; its release profile was found to be in agreement with the prediction obtained from the model.

Development and validation of an in vitro-in vivo correlation for buspirone hydrochloride extended release tablets.

The aim of this study was to develop an in-vitro-in-vivo correlation (IVIVC) for two buspirone hydrochloride extended release formulations and to compare their plasma concentrations over time with the commercially available immediate release (IR) tablets. In vitro release rate data were obtained for each formulation using the USP Apparatus 2, paddle stirrer at 50 and 100 rpm in 0.1 M HCl and pH 6.8 phosphate buffer. A three-way crossover study in 18 healthy subjects studied a 30 mg "Fast" (12 h) and 30 mg "Slow" (24 h) formulation of buspirone hydrochloride given once a day, and 2x15 mg immediate release tablets dosed at a 12 h interval. The similarity factor (f(2)) was used to analyze the dissolution data. A linear correlation model was developed using percent absorbed data and percent dissolved data from the two formulations. Predicted buspirone hydrochloride concentrations were obtained by use of a curve fitting equation for the immediate release data to determine the volume of distribution and fraction absorbed constants. Prediction errors were estimated for C(max) and area under the curve (AUC) to determine the validity of the correlation. pH 6.8 at 50 rpm was found to be the most discriminating dissolution method. Linear regression analyses of the mean percentage of dose absorbed versus the mean in vitro release resulted in a significant correlation (r(2)>0.95) for the two formulations. An average percent prediction error for C(max) was -0.16%, but was 16.1%, for the AUCs of the two formulations.