Influence of Hydroxypropyl Methylcellulose Mixture,Apparent Viscosity,and Tablet Hardness on Drug Release Using a 23 Full Factorial Design

ABSTRACT

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3–6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000–19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

Influence of soluble and insoluble cyclodextrin polymers on drug release from hydroxypropyl methylcellulose tablets

Background: The influence of β-cyclodextrin (β-CD) polymers on drug release from hydroxypropyl methylcellulose (HPMC) matrices has not been reported in the literature. Aim: The influence of monomeric β-CD and both soluble and insoluble β‐CD polymers on drug release from tablets containing either 30% or 50% hydroxypropyl methylcellulose has been studied using diflunisal (DF) as model drug. Method: The DF-β-CD inclusion complex (1:1 M) was prepared by coevaporation and characterised using X-ray diffraction, differential thermal analysis, and IR spectroscopy. The dissolution assays were performed according to the USP paddle method. Results: The incorporation of β-CD in the complexed form increases drug release from hydroxypropyl methylcellulose tablets in comparison with the physical mixture because of the better solubilization of the drug. The soluble polymer promotes drug release to a higher extent than the physical mixture with monomeric β-CD, but the insoluble polymer, which is itself a hydrogel, gives rise to the most retarded release profile, probably by retention of the drug in its structure. The formulations containing physical mixtures with either β‐CD or the soluble polymer present an optimum adjustment to zero-order release kinetics, and the inclusion complex followed non-Fickian diffusion according to the Korsmeyer–Peppas model. Conclusion: The release profile of DF from a HPMC matrix can be modulated in different ways by the use of either monomeric or polymeric β-CD.     

Effects of Cellulose Derivatives and Additives in the Spray-Drying Preparation of Acetaminophen Delivery Systems

Microcrystalline cellulose (MCC), sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypro pylcellulose (HPC), and ethylcellulose (EC) were used for the production of time-controlled acetaminophen delivery systems using a spray-drying technique. The influence of factors such as polymer concentration, inlet temperature, and drug/polymer ratio were investigated. The product yields were a function of the type and concentration of the polymer, with the highest values being reached from feeds containing 1% MCC and EC. Parameters of 1% polymer concentration and an inlet temperature of 140°C gave rise to optimal processing conditions. Using these parameters, the influence of some adjuncts, such as polyethylene glycol 6000 (PEG 6000), dibutyl sebacate (DBS), polyvinylpyrrolidone (PVP), and carboxylic acids such as citric acid (CA), phthalic acid (PA), succinic acid (SA), tartaric acid (TA), and oxalic acid (OA), on the spray-drying process was evaluated. Of the additives tested, PVP (with MCC), DBS (with EC), and PEG 6000 (with NaCMC) induced yield decreases from 70% to 49%, 66% to 39%, and 37% to 17%, respectively. As for carboxylic acids (with NaCMC), similar or better performances of 43%, 45%, 47%, and 49% were obtained with SA, OA, PA, and TA, respectively. Dissolution studies in pH 1 dilute HCl and pH 6.8 phosphate buffer dissolution media showed that formulations consisting of 1% polymer with a drug/polymer ratio of 1/1 exhibited the slowest drug release, with the spheroids coated with NaCMC and HEC showing the longest T_50% values (with 45 and 53 min at pH 1 and 49 and 55 min at pH 6.8, respectively). Slightly better sustained drug release in pH 6.8 dissolution medium was reached, showing the following trend: HEC > NaCMC > MCC > EC > HPMC. Concerning the additives, the trends in dissolution T_50% of drug revealed TA > SA > CA > OA > PVP > PA > DBS in acidic pH 1 dissolution medium and PVP > OA > TA > SA > PA > CA > DBS in phosphate buffer at pH 6.8.     

Role of Cellulose Ether Polymers on Ibuprofen Release from Matrix Tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE_{20 h}), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.     

Relationseips Between Drug Dissolution Profile and Gelling Agent Viscosity in Tablets Prepared with Hydroxypropylmethylcellulose (HPMC) and Sodium Carboxymethylcellulose (NaCMC) Mixtures

Abstract

Two varieties of HPMC, two varieties of NaCMC and various HPMC/NaCMC mixtures were characterized with the aim of providing a sound basis for the selection of appropriate mixtures to use as gelling agents in controlled-release tablets for hydrosoluble drugs. For both HPMC and NaCMC, one variety was of high and the other of low nominal viscosity. We also investigated possible relationships between the rheological properties of HPMC/NaCMC mixtures and atenolol release from tablets prepared with such mixtures. The mean molecular weights of each polymer variety were estimated on the basis of determination of their intrinsic viscosities in aqueous dispersions. Rotational viscosimetry of 2% aqueous dispersions of the polymers and polymer mixtures revealed rheological synergism in some mixtures. Drug dissolution trials were carried out in water and 0.1 N HCl. Dissolution medium, gelling agent composition and proportion of gelling agent in the tablet all affected dissolution profiles. Fitting of Korsmeyer et al.'s equation to the data for dissolution in water indicated zero-order dissolution kinetics for all formulations. For tablets prepared with the most viscous HPMC variety, %hour dissolution efficiency was closely correlated with the apparent viscosity (shear rate 0.5 s^?1) of the aqueous dispersion of the polymer mixture used as gelling agent. Assays of tablet erosion rates indicated that the erosion mechanism may contribute to the observed zero-order dissolution kinetics, but that other factors are probably also involved.     

Effect of polymer hydration on the kinetic release of drugs: a study of ibuprofen and ketoprofen in HPMC matrices

Samples of drug/hydroxypropylmethylcellulose (HPMC) mixtures and matrices (drug/HPMC mixtures plus excipients) were allowed to equilibrate in closed chambers with defined relative humidities (RHs). Their water uptake and drug release were evaluated by differential scanning calorimetry/thermogravimetric analysis and dissolution studies, respectively. Analysis of the thermal behaviors of the drug/HPMC mixtures and of the polymer alone, as functions of RH, leads to the conclusion that most of the hydration water is retained by the polymer, and points to the occurrence of different types of hydration water, from the strongly polymer-bound water molecules at RH values up to 81%, to the almost “free water” for RH values close to 100%. In addition, application of the Korsmeyer model to the dissolution results leads to the conclusion that the rate determining dissolution processes are predominantly of the fickian type.     

Role of cellulose ether polymers on ibuprofen release from matrix tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE_{20 h}), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.     

Development of a HPMC-based controlled release formulation with hot melt extrusion (HME)

The objective of this study was to develop hydroxypropyl methylcellulose (HPMC) based controlled release (CR) formulations via hot melt extrusion (HME) with a highly soluble crystalline active pharmaceutical ingredient (API) embedded In the polymer phase. HPMC is considered a challenging CR polymer for extrusion due to its high glass transition temperature (T_g), low degradation temperature, and high viscosity. These problems were partially overcome by plasticizing the HPMC with up to 40% propylene glycol (PG). Theophylline was selected as the model API. By using differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), dynamic mechanical analysis (DMA), and X-ray powder diffraction (XRPD), the physical properties of the formulations were systematically characterized. Five grades of HPMC (Methocel^®) – E6, K100LV, K4M, K15M, and K100M – were tested. The extrusion trials were conducted on a 16?mm twIn screw extruder with HPMC/PG placebo and formulations containing theophylline/HPMC/PG (30:42:28, w/w/w). The dissolution results showed sustained release profiles without burst release for the HPMC K4M, K15M, and K100M formulations. The extrudates have good dissolution stability after being stressed for 2 weeks under 40°C/75% RH open dish conditions and the crystalline API form did not change upon storage. Overall, the processing windows were established for the HPMC based HME-CR formulations.     

New sustained release of Zidovudine Matrix tablets − cytotoxicity toward Caco-2 cells

Objective: The aim of this study was to adjust the zidovudine (AZT) release from solid tablets to an ideal profile, by developing matrices comprising swellable polymers with nonswellable ones.

Methods: Directly compressed matrices comprised different ratios of hydroxypropylmethylcellulose K15M and K100M, ethylcellulose, and methacrylic acid (Eudragit^® RS PO and Eudragit^® RL PO) were prepared. Technological characterization and evaluation of the in vitro release behavior were carried out. Cell density and viability following drug exposure were evaluated by the SRB method, for the Caco-2 line, while cell morphology was assessed upon Trypan blue staining.

Results: A specific formulation containing 5% of each excipient ? HPMC K15M, HPMC K100M, Eudragit^® RS PO, and Eudragit^® RL PO ? was found to yield the best release profile. Application of the Korsmeyer–Peppas model to the dissolution profile evidenced that a non-Fickian (anomalous) transport is involved in the drug release. Regarding the influence of the tablets’ composition on the drug’s cytotoxic effect toward the Caco-2 cell line, a reduction of cell biomass (0–15%) was verified for the distinct AZT formulations tested, F19 having displayed the highest cytotoxicity, after 24 and 48?h of incubation. Additionally, a high reversibility of the AZT effect was observed.

Conclusions: The results showed that the simultaneous application of both hydrophilic and hydrophobic polymers can modulate the drug release process, leading to an improved efficacy and patient compliance. All AZT formulations studied were found to be cytotoxic against Caco-2 cells, F19 being the most effective one.     

Relationseips Between Drug Dissolution Profile and Gelling Agent Viscosity in Tablets Prepared with Hydroxypropylmethylcellulose (HPMC) and Sodium Carboxymethylcellulose (NaCMC) Mixtures

Two varieties of HPMC, two varieties of NaCMC and various HPMC/NaCMC mixtures were characterized with the aim of providing a sound basis for the selection of appropriate mixtures to use as gelling agents in controlled-release tablets for hydrosoluble drugs. For both HPMC and NaCMC, one variety was of high and the other of low nominal viscosity. We also investigated possible relationships between the rheological properties of HPMC/NaCMC mixtures and atenolol release from tablets prepared with such mixtures. The mean molecular weights of each polymer variety were estimated on the basis of determination of their intrinsic viscosities in aqueous dispersions. Rotational viscosimetry of 2% aqueous dispersions of the polymers and polymer mixtures revealed rheological synergism in some mixtures. Drug dissolution trials were carried out in water and 0.1 N HCl. Dissolution medium, gelling agent composition and proportion of gelling agent in the tablet all affected dissolution profiles. Fitting of Korsmeyer et al.'s equation to the data for dissolution in water indicated zero-order dissolution kinetics for all formulations. For tablets prepared with the most viscous HPMC variety, %hour dissolution efficiency was closely correlated with the apparent viscosity (shear rate 0.5 s^-1) of the aqueous dispersion of the polymer mixture used as gelling agent. Assays of tablet erosion rates indicated that the erosion mechanism may contribute to the observed zero-order dissolution kinetics, but that other factors are probably also involved.     

Vitamin B12 buccoadhesive tablets: auspicious non-invasive substitute for intra muscular injection: formulation,in vitro and in vivo appraisal

Attempting to prepare a convenient bioavailable formulation of vitamin B₁₂ (cyanocobalamin), 17 tablet formulations were prepared by direct compression. Different concentrations of hydroxypropyl methyl cellulose (HPMC), carbopol 971p (CP971p), and chitosan (Cs) were used. The tablets were characterized for thickness, weight, drug content, hardness, friability, surface pH, in vitro drug release, and mucoadhesion. Kinetic analysis of the release data was conducted. Vitamin B₁₂ bioavailability from the optimized formulations was studied on rabbits by the aid of enzyme-linked immunosorbent assay. Neurotone^® I.M. injection was used for comparison. HPMC (F1-F4), CP971p (F5-F8), and HPMC/CP971p (F12-F15)-based formulations showed acceptable mechanical properties. The formulated tablets showed maximum swelling indices of 232?±?0.13. The surface pH values ranged from 5.3?±?0.03 to 6.6?±?0.02. Bioadhesive force ranged from 66?±?0.6 to 150?±?0.5?mN. Results showed that CP971p-based tablets had superior in vitro drug release, mechanical, and mucoadhesive properties. In vitro release date of selected formulations were fitted well to Peppas model. HPMC/CP971p-based formulations showed bioavailability up to 2.7-folds that of Neurotone^® I.M. injection.     

Influence of Dissolution Medium Agitation on Release Profiles of Sustained-Release Tablets

Reaching nearly perfect sink conditions is very important in the determination of drug dissolution rates. Many times, the only factor that is taken into consideration in achieving sink conditions is the relation between the drug concentration and its solubility. The analytical conditions of the dissolution assay, as well as the dissolution apparatus, stirring speed, and nature and volume of the dissolution fluid may also influence the dissolution results. The main objective of this work was to study the influence of the stirring rate conditions and of the dissolution apparatus in the diltiazem hydrochloride release from tablets. Diltiazem hydrochloride sustained-release (SR) tablets were tested and the following dissolution parameters were evaluated: t_10%, t_25%, t_50%, dissolution time, mean dissolution time (MDT), and dissolution efficiency (DE) at t₁₂₀, and at t₃₆₀. To analyze the release mechanism, several release models were tested, such as Higuchi, zero order, first order, Baker-Lonsdale, Hixson-Crowell, Weibull, and Korsmeyer-Peppas. The similarities between two in vitro dissolution profiles were assessed by the similarity factor f₂. The in vitro release kinetics of diltiazem hydrochloride sustained-release tablets were evaluated using the USP 2 (paddle) and USP 4 (flow-through) apparatus.     

Novel Use of Similarity Factors f2 and Sd for the Development of Diltiazem HCl Modified-Release Tablets Using a 32 Factorial Design

ABSTRACT

The objective of this study was to develop modified-release tablets of diltiazem HCl using a direct compression technique. A 3² factorial design was employed using the amount of alkali-treated guar gum and cetyl alcohol as independent variables. This article proposes the use of a novel approach—f₂and S_d values as dependent variables—to evaluate the effect of selected independent variables along with other dependent variables (i.e., percentage drug released in x min, Y_x; time required for z% drug release, t_z; and mean dissolution time (MDT)). It is concluded that when a decision is to be made for the selection of a best batch, it is perhaps more realistic to use the f₂ or S_d value which takes into account the dissolution profile as a whole, as opposed to Y_x and t_z values which use just one point from the dissolution plot. The batch showing the f₂ value nearest to 100 or the S_d value nearest to zero is ranked as the best batch (diltiazem HCl 90 mg, alkali-treated guar gum 80 mg and cetyl alcohol 15 mg). The gel strength and matrix erosion of the formulated tablets were dependent on the type and amount of the adjuvants. The drug release rate is well correlated with matrix erosion. The kinetics of drug release fitted best to the Korsmeyer and Peppas model. It is concluded that by using a proper combination of the hydrophilic polymer and cetyl alcohol one can achieve a desirable drug release pattern.     

Film Coated Pellets Containing Verapamil Hydrochloride: Enhanced Dissolution into Neutral Medium

Abstract

Weakly basic drugs, such as verapamil hydrochloride, that are poorly soluble in neutral/alkaline medium may have poor oral bioavailability due to reduced solubility in the small intestine and colon. Film coated pellets were prepared using two strategies to enhance drug release at high pH values. Firstly, pellets were coated with Eudragit® RS/hydroxypropyl methylcellulose acetate succinate (HMAS) mixtures in proportions of 10:1 and 10:3, respectively. The enteric polymer, HMAS, would dissolve in medium at pH>6 creating pores through the insoluble Eudragit RS membrane to increase drug release. Secondly, an acidic environment was created within the core by the inclusion of fumaric acid at concentrations of 5 and 10% in order to increase drug solubility. Both strategies enhanced drug release into neutral medium in dissolution studies using the pH change method to simulate GIT transit. Dissolution profiles of samples tested in pH 1.2 for 12 hr were compared with those using the pH change method (pH 1.2 for first 1.5 hr, pH raised to 6.8 for remaining 10.5 hr) using the area under the dissolution curve (AUC), the dissolution half-life (t_50%), and the amount of drug released in 3 hr (A_{3 hr}) values. Both strategies enhanced drug release into neutral medium although the strategy using HMAS in the film was more effective. The formulation least affected by pH change was a combination of the two strategies, i.e., pellets containing 5% fumaric acid coated with Eudragit RS 12% w/w and HMAS 1.2% w/w.     

Systematic development of pH-independent controlled release tablets of carvedilol using central composite design and artificial neural networks

The purpose of this study was to apply the optimization method incorporating artificial neural network (ANN) using pH-independent release of weakly basic drug, carvedilol from HPMC-based matrix formulation. Because of weakly basic nature of carvedilol, drug shows pH-dependent solubility. The enteric polymer EUDRAGIT L100 was added formulations to overcome pH-dependent solubility of carvedilol. Effects of the Hydroxypropylmethyl cellulose (HPMC) K4M and EUDRAGIT L100 amount on drug release were investigated. For this purpose 13 kinds of formulations were prepared at three different levels of each variables. The optimization of the formulation was evaluated by using ANN method. Two formulation parameters, the amounts of HPMC K4M and Eudragit L100 at three levels (?1, 0, 1) were selected as independent/input variables. In-vitro dissolution sampling times at twelve different time points were selected as dependent/output variables. By using experimental dissolution results and amount of HPMC K4M and EUDRAGIT L100, percentage of dissolved carvedilol was predicted by ANN. Similarity factor (f₂) between predicted and experimentally observed profile was calculated and f₂ value was found 76.33. This value showed that there was no difference between predicted and experimentally observed drug release profile. As a result of these experiments, it was found that ANNs can be successfully used to optimize controlled release drug delivery systems.     

Inlay osmotic pump tablets containing metformin and glipizide

The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose. A newly developed inlay osmotic pump tablet (IOPT) can deliver glipizide (GLZ) and metformin HCl (MET) gradually in controlled manner. The aim of present investigation was to prepare the IOPT that can deliver >75% of GLZ in 2?h, whereas MET released after 2?h and sustained up to 12?h. In the present work, HP-β-CD was used to modify the solubility of GLZ before incorporating in the osmotic system and MET was spray-dried with HPMC A15C to modify its release profile, flow property, and compressibility. Various parameters mainly G_75% (75% GLZ release), t_LMET (lag time of MET release from device), Q_{10 h} (percent of MET released within 10?h), and RSQ_ZERO (R² of release data fitted to zero-order equation) were used to compare different formulations. The effects of different formulation variables, that is, osmagents, concentration of hydrophilic polymer, diameter of drug releasing orifice, and coating composition on the drug release profile were investigated. The release rate of GLZ could be effectively modified by the addition of sodium carbonate and sodium chloride, whereas the release rate of MET was adjusted by dual-coating system and by addition of hydrophilic polymer. The developed inlay osmotic system could be effective in the multidrug therapy of diabetes by delivering both drugs in a controlled manner.     

Formulation,in vitro evaluation and study of variables on tri-layered gastro-retentive delivery system of diltiazem HCl

Context: Tri-layered floating tablets using only one grade of polyethylene oxide (PEO) would enable easy manufacturing, reproducibility and controlled release for highly soluble drugs.

Objective: To evaluate the potential of PEO as a sole polymer for the controlled release and to study the effect of formulation variables on release and gastric retention of highly soluble Diltiazem hydrochloride (DTZ).

Methods: Tablets were compressed with middle layer consisting of drug and polymer while outer layers consisted of polymer with sodium bicarbonate. Design of formulation to obtain 12?h, zero-order release and rapid floatation was done by varying the grades, quantity of PEO and sodium bicarbonate. Dissolution data were fitted in drug release models and swelling/erosion studies were undertaken to verify the drug release mechanism. Effect of formulation variables and tablet surface morphology using scanning electron microscopy were studied.

Results and discussion: The optimized formula passed the criteria of USP dissolution test I and exhibited floating lag-time of 3–4?min. Drug release was faster from low molecular weight (MW) PEO as compared to high MW. With an increase in the amount of sodium bicarbonate, faster buoyancy was achieved due to the increased CO₂ gas formation. Drug release followed zero-order and gave a good fit to the Korsmeyer–Peppas model, which suggested that drug release was due to diffusion through polymer swelling.

Conclusion: Zero-order, controlled release profile with the desired buoyancy can be achieved by using optimum formula quantities of sodium bicarbonate and polymer. The tri-layered system shows promising delivery of DTZ, and possibly other water-soluble drugs.     

Development and comparative evaluation of in vitro,in vivo properties of novel controlled release compositions of paroxetine hydrochloride hemihydrate as against Geomatrix™ platform technology

The objective of this study is to develop, in vitro and in vivo evaluation of novel approaches for controlled release of paroxetine hydrochloride hemihydrate (PHH) in comparison to patented formulation PAXIL CR^® tablets of GlaxoSmithKline (Geomatrix? technology). In one of the approaches, hydrophilic core matrix tablets containing 85% of the dose were prepared and further coated with methacrylic acid copolymer to delay the release. An immediate release coating of 15% was given as top coat. The tablets were further optionally coated using ethyl cellulose. In the second approach, hydrophobic matrix core tablets containing metharylic acid copolymer were prepared. In the third approach, PHH was granulated with enteric polymer and further hydrophobic matrix core tablets were prepared. The effect of polymer concentration, level of enteric coating on drug release was evaluated by in vitro dissolution study by varying dissolution apparatus and the rotation speeds. It was found that increase in concentration of high viscosity hydroxypropylmethylcellulose (HPMC) resulted in reduction of the release rate. The drug release was observed to be dependent on the level of enteric coating and ethyl cellulose coating, being slower at increased coating. The release mechanism of PHH followed zero-order shifting to dissolution dependent by the increase of HPMC content. The formulation was stable without change in drug release rate. In vivo study in human volunteers confirmed the similarity between test and innovator formulations. In conclusion, HPMC-based matrix tablets, which were further coated using methacrylic acid copolymer, were found to be suitable for the formulation of single layer-controlled release PHH.     

Optimization of piribedil mucoadhesive tablets for efficient therapy of Parkinson’s disease: physical characterization and ex vivo drug permeation through buccal mucosa

Objective: The aim of this study was optimization of buccal piribedil (PR) mucoadhesive tablets to improve its low bioavailability and provide controlled release for the treatment of Parkinson’s disease.

Methods: Buccal tablets were prepared by direct compression method using carbomer (CP), carboxymethyl cellulose (CMC), and hydroxypropyl methylcellulose (HPMC) as mucoadhesive polymers. Physical properties of powder mixtures and buccal tablets were evaluated. Physicochemical compatibility between ingredients was investigated with infrared spectroscopy and differential scanning calorimetry analysis. In vitro dissolution profiles and drug release kinetics of buccal tablets were investigated. Mucoadhesion and ex vivo permeation studies were performed using sheep buccal mucosa.

Results: Powder mixtures demonstrated sufficient flow properties and physical characteristics of all tablet formulations were within compendia limits. Tablet ingredients were absent of any chemical interactions. CP tablets displayed slower drug release compared to HPMC tablets with zero order release, while CMC tablets lost their integrity and released entire drug after 6?h following Higuchi model. All formulations displayed adequate mucoadhesion and steady state flux of PR through buccal mucosa were higher with HPMC compared to CP-containing tablets.

Conclusion: Overall, HPMC was found to combine desired controlled release and mucoadhesion characteristics with sufficient pharmaceutical quality for optimization of buccal tablets. Piribedil mucoadhesive buccal tablets designed for the first time may introduce a new alternative for the treatment of Parkinson’s disease.     

In-vitro evaluation of sustained-release dyphylline tablets

Dyphylline tablets were prepared by direct compression of mixtures of the drug, emcompress and different ratios of hydroxypropyl methylcellulose (HPMC) or cellulose acetate phthalate (CAP). Physical properties of the prepared tablets and the drug release in 0.1 N HC1 and phosphate buffer, pH 7.4 were investigated.

All tablets were found to satisfy the USP requirements regarding content, weight uniformity and friability. Hardness was greatly enhanced and thickness was slightly increased by increasing the polymer ratio in tablet formulations. Disintegration time of the dyphylline tablets was delayed by the presence of either HPMC or CAP and there was a direct relationship between the polymer ratio and the disintegration time. Considerable retardation in the rate and extent of drug release from the prepared tablets in both dissolution liquids was observed. As the polymer ratio increased in the tablet formulations, the drug release was significantly inhibited.