Dissolution kinetics evaluation of controlled-release tablets containing propranolol hydrochloride

In the present research, controlled-release propranolol hydrochloride tablets were prepared for twice-daily administration, allowing more uniform plasmatic levels of the drug. Pharmaceutical formulations were prepared with hydrophobic Eudragit® RSPO. The physical properties of the tablets were determined. Dissolution tests were performed in capsules containing the raw material using the following dissolution media: (A) distilled water, (B) simulated gastric juice without enzymes, and (C) simulated enteric juice without enzymes. A dissolution test was also performed for simulated samples (tablets) using distilled water as the dissolution medium.     

Formulation optimization of controlled-release pellets of metoclopramide hydrochloride using dissolution fit factor approach

The purpose of this study was to optimize the formulation variables for the preparation of ethyl cellulose-coated nonpareils loaded with metoclopramide hydrochloride (MCL). The approach to evaluate the effectiveness of formulation parameters was monitored by release rate testing using dissolution fit factors as a tool. The content of ethyl cellulose used in the formulation was based on the drug-loaded weight. The interrelationship of each developed formulation and the reference formulation Gastro-Timelets and their respective dissolution curves were evaluated using Moore's equation: [equation: see text]. The relationship between the ethyl cellulose content in the formulation and the dissolution fit factor f2 can be described as the following regression equation: Y = -0.054X2 + 3.347X - 1.915 (r2 = 0.99). The optimum ethyl cellulose content obtained from the equation was 30.8%. The type and content of plasticizer used in the formulation to achieve the greatest f2 were determined to be Myvacet 9-40 at the concentration of 25%. Results indicated that using the release rate testing approach with the dissolution fit factor as a tool could provide valuable information for formulation optimization.     

Evaluation of performance of co crystals of mefloquine hydrochloride in tablet dosage form

Objective: The objective of present investigation was to evaluate performance of cocrystals of Mefloquine Hydrochloride (MFL) in tablet dosage form. Our previous investigation showed significant effect of cocrystal formers on improving the solubility and dissolution rate of Mefloquine hydrochloride by cocrystallization method when prepared by solution cocrystallization method.

Materials and methods: Prepared cocrystals of MFL with different ratio of cocrystal formers were incorporated in tablet dosage form and evaluated for micrometric properties, drug content, hardness, disintegration test, vitro dissolution studies and stability studies. Performance was compared with laboratory prepared tablet of MFL 250 mg.

Results: The considerable improvement in the dissolution rate was observed in case of cocrystals based tablets than pure MFL tablets.

Discussion and conclusion: So we can incorporate cocrystals in tablet dosage form to enhance in vitro and in vivo performance. To the best of our knowledge, this is the first report, cocrystals has been evaluated in tablet dosage form.     

Mucoadhesive dosage form of lidocaine hydrochloride: I. Mucoadhesive and physicochemical characterization

The aim of this study was to characterize a buccal mucoadhesive film using lidocaine and its hydrochloride salt (LDHCL) as a model drug. Buccal films were developed using carbopol 971P as a mucoadhesive polymer, and glycerol as a plasticizer. Scanning Electron Microscope, Differential Scanning Calorimetry, X-ray powder diffraction, and Fourier Transform Infra Red techniques were used to characterize the mucoadhesive films. Bioadhesive properties were evaluated using the Universal Instron Instrument with chicken pouch as a model tissue.

LDHCL and its base were present in carbopol 971P films in a molecular dispersion state without exerting any effect on the glass transition of these films. The mucoadhesive force between the chicken pouches and the film containing glycerol did not change by time during the tested period (1-20 min), while increased with increasing the amount of glycerol (10-40% w/w of polymer content). Furthermore, a linear increase in the mucoadhesive force was accompanied by the increase in the film thickness, while a linear decrease followed by plateau was obtained when loading the patch with LDHCL at concentration above 1 mg/cm².

Loading carbopol film with lidocaine base, in a concentration up to 6 mg/cm² decreased linearly the mucoadhesive properties, which could be attributed to salt formation between the acidic carboxylic moiety of carbopol and basic lidocaine.     

Potential mucoadhesive dosage form of lidocaine hydrochloride: II. In vitro and in vivo evaluation

The aim of this study was to develop a controlled release buccal mucoadhesive delivery system for systemic delivery of lidocaine hydrochloride as a model drug. In vitro release and buccal permeation as well as in vivo permeation of LDHCL patches were evaluated. The drug release and the permeability of the drug through porcine buccal mucosa were evaluated using Franz diffusion cell. In vivo evaluation of patches was carried out on rabbits as an animal model. Patches were designed in two fashions, bi-layer (BLP; LDHCL, carbopol, glycerin, pentration enhancer, and Tween 20 as the first layer; and EVA as the second layer) and triple layer (TLP; LDHCL, carbopol and glycerin as the first layer; carbopol, glycerin, pentration enhancer and pluronic F-127 as the middle layer; and EVA as the third layer) patches, respectively. Presence of oleic acid as PE in the formulation significantly enhanced the in vitro permeability of LDHCL (p<0.05), while propylene glycol monolaurate as PE suppressed it (p<0.05). The in vivo evaluation in rabbits showed that TLP had significantly higher Cmax and AUC0-8 (p<0.05) than BLP. Furthermore, TLP showed a well-controlled drug plasma concentration over 6 hr which was significantly longer than BLP (p<0.05). Patches were well adhered to buccal mucosa of the rabbits over the 8-hr study period. It was postulated that the hypothetical release mechanism of the drug and oleic acid from TLP was controlled by their diffusion through the swollen polymer network and micelled gel.     

Advances in solid dosage form manufacturing technology

Currently, the pharmaceutical and healthcare industries are moving through a period of unparalleled change. Major multinational pharmaceutical companies are restructuring, consolidating, merging and more importantly critically assessing their competitiveness to ensure constant growth in an ever-more demanding market where the cost of developing novel products is continuously increasing. The pharmaceutical manufacturing processes currently in existence for the production of solid oral dosage forms are associated with significant disadvantages and in many instances provide many processing problems. Therefore, it is well accepted that there is an increasing need for alternative processes to dramatically improve powder processing, and more importantly to ensure that acceptable, reproducible solid dosage forms can be manufactured. Consequently, pharmaceutical companies are beginning to invest in innovative processes capable of producing solid dosage forms that better meet the needs of the patient while providing efficient manufacturing operations. This article discusses two emerging solid dosage form manufacturing technologies, namely hot-melt extrusion and fluidized hot-melt granulation.     

Development of a tamsulosin hydrochloride controlled-release capsule consisting of two different coated pellets

Tamsulosin hydrochloride (TSH) controlled-release capsule (pellets) was successfully prepared using a novel, simple, and flexible multiunit drug delivery system, which consisted of two different coated pellets. The TSH-loaded core pellets consisting of microcrystalline cellulose (MCC), lactose, Carbopol(R) 974P, and the active agent, were prepared by extrusion/spheronization method. Eudragit NE30D and Eudragit L30D-55 were used as the coating materials to prepare sustained-release (SR) pellets and enteric-release (ER) pellets. The coated pellets were prepared using two different equipments: centrifugal coater and fluidized-bed coater. By adjusting the ratio of SR and ER pellets, more than one blend ratios, which meet the in vitro release criterion were obtained. A similarity factor (f(2)) was employed to choose the optimum proportion compared with the commercial product (Harnal capsule). The morphology of the pellet surfaces was examined by scanning electron microscopy (SEM) before and after dissolution. The release profiles were significantly affected by changing the proportions of SR and ER. The optimum ratio is SR:ER = 2:1 using a centrifugal coater (f(2) = 61.93) and SR:ER = 3:1 using a fluidized coater (f(2) = 66.42). This result suggests that blending these two-part pellets (SR and ER) can provide an alternative to preparing a controlled-release dosage form, instead of blending of the coating polymer.     

Release and permeation studies of propranolol hydrochloride from hydrophilic polymeric matrices

Abstract

In-vitro release of propranolol hydrochloride, from various hydrophilic polymeric bases was studied. These included: methocel®, avicel® CL-611/ methylcellulose, polyvinyl alcohol/gelatin based systems. Several additives, such as, ethyl alcohol, dimethylsulfoxide (DMSO) and polyethylene glycol-400 were included in the formulations for possible enhancement of the drug release. The release studies were carried out using the cellulose membrane and the hairless mouse skin as the diffusion barriers. The general rank order for the drug release through these membranes was observed to be: the methocel® matrix > the avicel® CL-611 matrix > the polyvinyl alcohol/gelatin matrix > and the emulsion base. The additives in the formulations had little or no effect in enhancing the drug release. However, when the hairless mouse skin was soaked in (DMSO) for one hour prior to its use in the diffusion studies, the drug release was found to increase by 40% from the methocel® matrix formulation.

The drug release data were treated with various kinetic principles to assess the relevant parameters, such as the diffusion, partition and permeability coefficients. Using these information, the formulations were screened for their suitability to deliver propranolol hydrochloride via the diadermatic dosage form.     

Process and dosage form controlts: Formulation factors

Abstract

During the last decades, there have been considerable developments in the field of pharmaceutics, pharmaceutical technology and product manufacture.

The trend of the pharmaceutical industry is, like in most of the sophisticated industries, to produce, day after day, a better product, and as final goal, to manufacture continueously a perfect drug dosage form.

A few years ago, the defaults were counted in “percent”. After that, it was in per “thousand”. Now it is often expressed in “per million”, or even for very high series (for example empty hard gelatine capsules) the trend is “per billion”. Such an evaluation can only be achieved with a complete control of the whole manufacturing process.

The requirement for pharmaceutical dosage form are numerous (1): adequate biopharmaceutical profile, ease of manufacture, quality assurance (the dosage form must contain the correct quantity of the correct drug, and liberate it at the correct place, at the correct time, and in the correct quantity, with the correct speed), stability, …

These requirements can only be fulfilled with a perfect knowledge of the drug and the dosage form, from the beginning of the development of the dosage form (formulation) to the end of the manufacturing process (production and final product control).

It is the aim of the present lecture to show how important are the formulation factors and what is their influence on the processing and the dosage form control.     

Development of a mucoadhesive dosage form for vaginal administration

The antimycotic imidazole derivative clotrimazole is employed locally for the treatment of genitourinary tract mycotic infections and is formulated as creams, foams, tablets, gels, irrigations, or pessaries. In this study, a new dosage form was developed by including bioadhesive polymers (polycarbophyl, hydroxypropylmethylcellulose, and hyaluronic sodium salt) into pessaries made of semisynthetic solid triglycerides. These polymers hold the delivery systems in the vaginal tract for a few days without any toxic effects or important physiological modifications, prolonging the permanence of the drug on the vaginal mucosa. Technological controls (compatibility with differential scanning calorimetry [DSC] studies, particle size analysis, and liquefaction time test) and biopharmaceutics studies for the evaluation of the release of the drug from the dosage form and of the bioadhesive properties were carried out. Moreover, a new test for the evaluation of the permanence of the drug in a simulated application site was developed from a modification of the Satnikar and Fantelli method for the evaluation of the liquefaction time of rectal suppositories. This test simulates the physiological vaginal condition and verifies the efficiency of the polymers in prolonging the permanence of the dosage form in the location where it is applied. The technological controls demonstrated that the presence of the polymers did not have an influence on the characteristics of the pessaries. On the other hand, there was an improvement in adhesivity of the pessaries in the in vitro adhesion test and prolonging of the liquefaction time in the liquefaction time test in the presence of mucoadhesive polymers, which increased with increasing polymer concentration. The presence of the mucoadhesive had a large influence on the permanence of the drug in the simulated application site because it modified the distribution of the drug along the simulated application site. In conclusion, the developed new formulations showed good technological and adhesion properties and the capacity of hold the dosage form in the target site. Among the employed bioadhesive polymers, the best behavior in the performed test was by polycarbophyl at its maximum concentration.     

Optimization of propranolol hydrochloride sustained-release pellets using box-behnken design and desirability function

The objective of the present study was to evaluate three process parameters for the application of ethylcellulose films from organic solutions to obtain multi-particulate controlled drug delivery of propranolol hydrochloride. The coating process was developed in a classical coating pan. A Box-Behnken central composite design was used to evaluate the effect of the film thickness (expressed as the amount of lacquer applied on pellets' surface unit), concentration of lacquer in the coating dispersion, and the plasticizer concentration on the independent variables. Those were t85, the degree of sticking in the coating pan, and the duration of the coating process. Contour and response surface plots were depicted based on the equation given by the model. Because the results were competitive, i.e., improving one response had an opposite effect on another one, an overall desirability function was described to ameliorate the interpretation of the results. The optimization procedure generated the maximum overall desirability value. A formulation was prepared under the optimized conditions yielding response values which were close to the predicted values. To understand the mechanism of drug release from the optimized pellets various models were used to fit the dissolution data. The Higuchi model appears to provide the best correlation.     

Application of near-infrared spectroscopy in the pharmaceutical solid dosage form

Near-infrared (NIR) spectroscopy, one of the most rapidly growing methodologies in pharmaceutical analysis, has been used to analyze the pharmaceutical solid dosage form. The objective of this study was to examine the information that can be gathered from NIR spectroscopy and demonstrate the potential utility of the technique as an alternative to current methods of tablet performance testing. The tablet formulation included active drug (acetaminophen or theophylline), binder (hydroxyethylcellulose), filler (lactose, calcium sulfate, dibasic calcium phosphate dihydrate, or microcrystalline cellulose), and lubricant (magnesium stearate). The compression forces were varied from 5 to 25 kN. A Foss/NIRSystems scanning near-infrared spectrometer was used to measure the diffuse reflectance from the tablet surface. Each tablet was scanned on opposite sides to reduce the effects of positioning. First derivative and multiplicative scatter correction data treatments were explored. A calibration for compression force, independent of the filler, was developed. In addition, the spectra were able to distinguish among the fillers used. A comparison of these spectra with data collected earlier suggests that the technique could differentiate among drugs as well. Near-infrared diffuse reflection spectroscopy, when properly calibrated, can determine the compression force used to prepare a tablet. This measurement may be independent of the different active drugs or fillers used in the tablet formulations.     

Characterization of the absorption of theophylline from immediate- and controlled-release dosage forms with a numerical approach using the in vitro dissolution-permeation process using caco-2 cells

After oral administration, drug absorption rate is recognized to be dependent on two major factors: dissolution and intestinal cells permeability. Caco-2 monolayer cells have been largely used as a permeation study model. In this study, a numerical approach funded on an exponential first-order time relationship was tested to compare immediate- and controlled-release tablets of theophylline using a dissolution-permeation system. The dissolution performance using USP II paddle apparatus was coupled to the permeability studies investigated in Caco-2 cell monolayers. The dissolved samples were taken at different times; their pH and osmolarity were adjusted to render them suitable to Caco-2 permeability studies (osmolarity = 300 mosm, pH = 7.4). The experimental data show that the dissolution fits the exponential first-order relationship rate. The permeability values were in a range of 4.45 10(- 6)-5.28 10(- 6) cm/s, and percentages of absorbed drug dose were dependent on the fraction initially present in the donor compartment, indicating that absorption of theophylline was dissolution rate limited. Plotting experimental absorbed fractions (F(a)) against experimental dissolved fractions (F(d)) show that permeation is the rate-limiting step in drug absorption process in the extended release form of theophylline. Our results demonstrate a general agreement between observed F(a)/F(d) relationships and theoretical F(a)/F(d) relationships obtained with our approach funded on dissolution and permeation behavior. We concluded that the couple dissolution-caco-2 system could be a useful tool to characterize intestinal permeation for a new formulation of a drug compared with the conventional one.     

Application of a sensorial response model to the design of an oral liquid pharmaceutical dosage form

In this paper, we discuss the application of a compartmental model to study the sensorial response, in terms of taste intensity versus time, in an oral solution for pharmaceutical use. The numerical model was developed from sensorial response curves obtained by a panel of three trained individuals. Parameter identification was carried out by means of a least-squares procedure that obtained the linear coefficients in the model by solving an exact linear least-squares problem conditional on the values of the nonlinear parameters for each iteration. Thus, nonlinear estimation was done in terms of the first-order kinetic parameters only, and ill-conditioning of the Hessian matrix present in these models was solved. Results of modeling for a set of formulations were used to determine the effects of various ingredients (sweeteners and an essence) on a baseline unflavored formulation of acetaminophen in a mixture of cosolvents. The first moment of the area under the curve of taste intensity versus time was found to be the best global indicator of taste for the purpose of product design. It was found that a mixture of sweeteners and an essence was the most efficient way of masking the bitter taste of this active ingredient.     

pH-responsive dual pulse multiparticulate dosage form for treatment of rheumatoid arthritis

Background: Dual pulse multiparticulate systems may provide relief from circadian disorder rheumatoid arthritis. Aim: The aim of this study was to develop a pH-responsive dual pulse multiparticulate dosage form containing a model drug ketoprofen, a nonsteroidal anti-inflammatory drug used for rheumatoid arthritis. Method: The pellets were prepared by using extrusion–spheronization method and the core pellets were coated with a pH-sensitive poly(methyl) acrylate copolymer (Eudragit® L100-55, Eudragit® S100) to achieve site-specific drug release with a lag time. The formulated pellets were characterized for shape and size uniformity, friability, surface morphology studies, coating uniformity, and drug–excipient compatibility studies. In vitro dissolution test was used for comparison of drug release profiles of various coated pellets. Results: The particle size of core and polymer-coated pellets was found to be in the range of 0.95–1.3 and 1.42–1.61 mm, respectively. The pellets were spherical in shape with smooth texture and uniformity in size. The dual pulse was aimed at release after a lag time of 2 and 5 hours. In vitro dissolution tests were carried out for the first and second dose pellets in a USP type II dissolution apparatus in media-simulating pH conditions of the gastrointestinal tract. The first dose release of the ketoprofen from the formulated pellets was established in pH 1.2 for a period of 2 hours, followed by pH 6.8. The second dose pellets were passed through pH 1.2, pH 6.8 followed by pH 7.5 for the rest of the study. Conclusion: The study concluded that the formulated multiparticulate dosage form of ketoprofen was able to relieve circadian symptoms of rheumatoid arthritis during midnight and early morning.     

Coated pelletized dosage form: Effect of compaction on drug release

The goal of this study was to investigate the effect of compaction of a coated pelletized dosage form on drug release. Three sizes of microcrystalline cellulose and hydrous lactose pellets containing 4% chlorpheniramine maleate (CPM) were manufactured using a rotogranulator (Glatt GPCG-1). Pellets having mesh cuts of: 590-840 μm (20/30 mesh); 420-590 μm (30/40 mesh); and 250-420 μm (40/60 mesh) were then coated with an aqueous ethylcellulose pseudolatex dispersion plasticized with 24% dibutyl sebacate (DBS). Percent weight gains were 25, 30 and 35% for the 20/30, 30/40 and 40/60 mesh pellets, respectively. Coated pellets were blended with 39.3% by weight excipients, then mixtures lubricated and compacted using a Korsch PH106 instrumented rotary press set at 5 kN and 20 rpm (0.30 s contact time). Magnesium stearate was used as the lubricant at a 0.7% level. Excipients used were microcrystalline cellulose, spray dried lactose, pregelatinized starch, dicalcium phosphate, spray dried sorbitol, polyethylene glycol 8000 powder and compressible sugar. Results indicated this coating to be suitable for the controlled release of CPM from small pellets (250-840 μm). However, films did not have the appropriate mechanical properties to withstand compaction stress without rupturing, regardless of the pellets particle size and excipients used. After compaction, depending on pellet size, between 65-100% CPM was released after one hour as opposed to 10-30% for the non-compacted material. The controlled release properties of the pellets were therefore lost during the process.     

Coated pelletized dosage form: Effect of compaction on drug release

Abstract

The goal of this study was to investigate the effect of compaction of a coated pelletized dosage form on drug release. Three sizes of microcrystalline cellulose and hydrous lactose pellets containing 4% chlorpheniramine maleate (CPM) were manufactured using a rotogranulator (Glatt GPCG-1). Pellets having mesh cuts of: 590–840 μm (20/30 mesh); 420–590 μm (30/40 mesh); and 250–420 μm (40/60 mesh) were then coated with an aqueous ethylcellulose pseudolatex dispersion plasticized with 24% dibutyl sebacate (DBS). Percent weight gains were 25, 30 and 35% for the 20/30, 30/40 and 40/60 mesh pellets, respectively. Coated pellets were blended with 39.3% by weight excipients, then mixtures lubricated and compacted using a Korsch PH106 instrumented rotary press set at 5 kN and 20 rpm (0.30 s contact time). Magnesium stearate was used as the lubricant at a 0.7% level. Excipients used were microcrystalline cellulose, spray dried lactose, pregelatinized starch, dicalcium phosphate, spray dried sorbitol, polyethylene glycol 8000 powder and compressible sugar. Results indicated this coating to be suitable for the controlled release of CPM from small pellets (250–840 μm). However, films did not have the appropriate mechanical properties to withstand compaction stress without rupturing, regardless of the pellets particle size and excipients used. After compaction, depending on pellet size, between 65–100% CPM was released after one hour as opposed to 10–30% for the non-compacted material. The controlled release properties of the pellets were therefore lost during the process.     

Production and in vitro characterization of solid dosage form incorporating drug nanoparticles

The objective of this study was to develop a tablet formulation of ketoconazole incorporating drug nanoparticles to enhance saturation solubility and dissolution velocity for enhancing bioavailability and reducing variability in systemic exposure. The bioavailability of ketoconazole is dissolution limited following oral administration. To enhance bioavailability and overcome variability in systemic exposure, a nanoparticle formulation of ketoconazole was developed. Ketoconazole nanoparticles were prepared using a media-milling technique. The nanosuspension was layered onto water-soluble carriers using a fluid bed processor. The nanosuspensions were characterized for particle size before and after layering onto water-soluble carriers. The saturation solubility and dissolution characteristics were investigated and compared with commercial ketoconazole formulation to ascertain the impact of particle size on drug dissolution. The drug nanoparticles were evaluated for solid-state transitions before and after milling using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). This study demonstrated that tablet formulation incorporating ketoconazole nanoparticles showed significantly faster rate of drug dissolution in a discriminating dissolution medium as compared with commercially available tablet formulation. There was no affect on solid-state properties of ketoconazole following milling. The manufacturing process used is relatively simple and scalable indicating general applicability to enhance dissolution and bioavailability of many sparingly soluble compounds.     

Formulation, in-vitro release and therapeutic effect of hydrogels based controlled release tablets of propranolol hydrochloride

Matrix based controlled release tablets of Propranolol Hydrochloride (PHCL) were formulated using hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (sod. CMC) and their combinations. The in-vitro dissolution kinetics revealed a zero order release for selected drug, HPMC and sod. CMC combination. The selected formulation was evaluated in mongrel dog by recording the isoprenaline induced tachycardia and measuring the inhibition of tachycardia. The results showed the sustaining therapeutic effect of the formulation.     

Formulation,in-vitro release and therapeutic effect of hydrogels based controlled release tablets of propranolol hydrochloride

Abstract

Matrix based controlled release tablets of Propranolol Hydrochloride (PHCL) were formulated using hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (sod. CMC) and their combinations. The in-vitro dissolution kinetics revealed a zero order release for selected drug, HPMC and sod. CMC combination. The selected formulation was evaluated in mongrel dog by recording the isoprenaline induced tachycardia and measuring the inhibition of tachycardia. The results showed the sustaining therapeutic effect of the formulation.