Tablet Surface Area Research Articles

Polyethylene oxide matrix tablet swelling evolution: The impact of molecular mass and tablet composition.

This article describes the designing of matrix tablets composed of polyethylene oxides (PEOs) with relative molecular masses of 1 × 106, 2 × 106, and 4 × 106. Percolation thresholds were determined for all of the selected PEO formulations (18, 16, and 12 %, m/m), taking into consideration excipients and tablet surface area which significantly increased the percolation threshold. Moreover, the robustness of the gel layer in PEO matrix tablets was evaluated by magnetic resonance imaging under various mechanical stresses (no flow, 12 mL min-1, and 64 mL-1 of medium flow). Correlations between the percolation threshold and gel thickness (R2 = 0.86), gel thickness and the erosion coefficient (R2 = 0.96) was detected. Furthermore, small-angle X-ray scattering of the selected PEOs detected differences in polymer molecular complexity at the nanoscale. Finally, the ratio of the heat of coalescence to the heat of fusion has confirmed the PEO molecular mass-dependent percolation threshold.

Exploring tablet design options for tailoring drug release and dose via fused deposition modeling (FDM) 3D printing.

The aim of this paper was to explore tablet design options for FDM 3D printing for simultaneous tailoring of drug release and dose. The drug, griseofulvin (GF), the polymer, hydroxypropyl cellulose (HPC), and processing temperatures were selected to avoid confounding effects arising from drug-polymer interactions. Filaments containing 0-30wt% GF were prepared using a twin-screw extruder. Five tablet designs were printed using combinations of fixed or varying drug-concentration filaments, fixed or varying tablet sizes, or placebo and drug-rich regions. Two of five options met the main objective; varying drug-concentration filaments for fixed tablet size or printing fixed size duo-tablet having internal placebo regions of varying sizes. Analysis of the drug dissolution profiles revealed that the tablet surface area to volume (SA/V) ratio was the dominant factor, a higher SA/V ratio resulted in a faster release rate, mostly independent of the drug amount or its placement within the tablet. Use of HPC led to near zero-order release for most cases. For duo-tablets, long lag times proportional to placebo shell-thickness were observed. These results suggest that design options other than varying the tablet size would be needed to achieve desired drug release from FDM-based 3D printed personalized dosages.

To Maintain Formulation Composition Similarity of Coated Tablets of Different Strengths: Should Coating be Based on Core Tablet Weight or Surface Area?

As per the Japanese or SUPAC guidance to maintain formulation composition similarity across tablet strengths, the coating should be applied based on the core tablet surface area or weight, respectively. These two coating approaches were compared by evaluating protective effects of coating on the light stability of three model compounds. Core tablets of three light sensitive drugs, nifedipine, rosuvastatin calcium, and montelukast sodium were coated either with PVA-based Opadry® II white or Opadry® II beige. The coated tablets were exposed to light up to three ICH cycles. For Opadry® II white, the surface area based coating provided consistent light protection across tablet strengths when the coating amount was more than 0.1mg/mm2 compared to that based on core tablet weights. For Opadry® II beige, both approaches gave comparable and better light protection due to presence of iron oxides. The light protection by Opadry® II white could be because of physical barrier of coating, which was uniform across the strengths when it was based on core tablet surface area. For a routine tablet formulation development with Opadry color coating, it does not matter whether the coating is applied based on the core tablet surface area or weight.

The Influence of Matrix Technology on the Subdivision of Sustained Release Matrix Tablets.

The subdivision of sustained release tablets is a controversial issue, especially concerning its impact on dissolution profiles. The purpose of this study was to elucidate the behavior upon subdivision of this class of tablets. For this, three common sustained release matrices containing different technologies were selected, e.g., a tablet comprised of a multiple-unit particulate system (MUPS), a lipid matrix tablet, and a polymeric inert matrix tablet. These tablets were studied concerning their physicochemical performance, dissolution rate, and kinetic profile before and after their subdivision. When subdivision occurred in the scoreline, mass variation and mass loss were below the mean values described in the literature. The dissolution of tablets with inert matrices and some lipid tablets that had their matrices preserved along the dissolution was influenced directly by tablet surface area, which increased after the subdivision. Such a result implies possible clinical consequences, especially in the case of drugs with a narrow therapeutic window, such as clomipramine. Conversely, the subdivision of MUPS tablets did not interfere in the dissolution profile since the drug was released from the granules that resulted from tablet disintegration. Hence, MUPS technology is the most recommended to produce sustained release matrix tablets intended for dose adjustment upon subdivision.

Color change in Perlodel® tablets induced by LED lighting - photolysis of bromocriptine mesylate.

Various types of fluorescent lights are found in the dispensing rooms of medical facilities, such as hospitals and pharmacies, in Japan. However, to reduce electric power consumption, it was necessary to evaluate the substitution of fluorescent lighting with light emitting diode (LED) lighting, which has become widespread in recent years. We subjectively evaluated several types of medicines stored under various light sources and found that different color changes were induced in tablets. In this study, we focused on Perlodel ® tablets, containing 2.5 mg bromocriptine mesylate, as an example for the objective evaluation of the differences in the color change of tablets when stored under LED lighting and fluorescent lighting. High-performance liquid chromatography (HPLC) analysis of part of the tablet surface area revealed a change from white to light brown or dark brown after 28 days of irradiation, with a residual concentration of bromocriptine mesylate of 85.5 % under fluorescent lighting, 85.6 % under daylight-color LED lighting, 90.3 % under bulb-color LED lighting, and 99.2 % in the dark. In addition, the ultraviolet (UV)-visible spectral study of the absorbance of a photo-product at 400-550 nm indicated that the color change of the Perlodel® 2.5 mg tablet was caused by photochemical degradation of bromocriptine mesylate. Thus, this analysis of the photochemical changes in drugs stored under different light sources demonstrated the potency of LED lights. Through the objective evaluation of the color change, the cause of the color change was determined; this will allow us to develop a strategy that minimizes possible disadvantages to patients, such as a decrease in treatment efficacy owing to decomposition of the main component or adverse caused by decomposed matter.

Development of Novel Functional Formulations Based on Pharmaceutical Technologies

After 32 years as a researcher in a pharmaceutical company, the author has served as a professor in the Development of Pharmaceutical Engineering and Drug Delivery Science at University of Shizuoka for the past 11 years. The research I was involved in can be categorized into four main items. First, the crystal transformation of clarithromycin (CAM) was focused on to develop the CAM high-loaded sustained release and gastro-floating formulations. Furthermore, the stabilization mechanism of CAM in the gastro-intestinal tract was clarified to elucidate gel formation under conditions of low pH. Second, the development of novel dosage regimens and optimization of formulation design were carried out using powder technology. In this category, a wax matrix formulation for taste masking, highly drug-loaded fine globular granules using a multi-functional rotor processor, and orally disintegrating tablets treated with microwave or high-pressure carbon dioxide were our targets. The third category was the manufacture of dispersion systems including lipid nanoparticles and cubosomes in order to improve the bioavailability and stability of poorly water-soluble drugs. The fourth category was the development and application of novel physical testing methods including investigation of the internal structure of fine granules using microtomography with synchrotron X-ray radiation, dissolution of spherical granules under non-sink conditions, mathematical models to analyze the dissolution behavior of metastable crystals or amorphous drugs and prediction of the available surface area of tablets during dissolution process.

Computational hydrodynamic comparison of a mini vessel and a USP 2 dissolution testing system to predict the dynamic operating conditions for similarity of dissolution performance

The hydrodynamic characteristics of a mini vessel and a USP 2 dissolution testing system were obtained and compared to predict the tablet-liquid mass transfer coefficient from velocity distributions near the tablet and establish the dynamic operating conditions under which dissolution in mini vessels could be conducted to generate concentration profiles similar to those in the USP 2. Velocity profiles were obtained experimentally using Particle Image Velocimetry (PIV). Computational Fluid Dynamics (CFD) was used to predict the velocity distribution and strain rate around a model tablet. A CFD-based mass transfer model was also developed. When plotted against strain rate, the predicted tablet-liquid mass transfer coefficient was found to be independent of the system where it was obtained, implying that a tablet would dissolve at the same rate in both systems provided that the concentration gradient between the tablet surface and the bulk is the same, the tablet surface area per unit liquid volume is identical, and the two systems are operated at the appropriate agitation speeds specified in this work. The results of this work will help dissolution scientists operate mini vessels so as to predict the dissolution profiles in the USP 2, especially during the early stages of drug development.

The release behavior and kinetic evaluation of tramadol HCl from chemically cross linked Ter polymeric hydrogels.

Background and the purpose of the studyHydrogels, being stimuli responsive are considered to be effective for targeted and sustained drug delivery. The main purpose for this work was to study the release behavior and kinetic evaluation of Tramadol HCl from chemically cross linked ter polymeric hydrogels.MethodsTer-polymers of methacrylate, vinyl acetate and acrylic acid cross linked with ethylene glycol dimethacrylate (EGDMA) were prepared by free radical polymerization. The drug release rates, dynamic swelling behavior and pH sensitivity of hydrogels ranging in composition from 1-10 mol% EGDMA were studied. Tramadol HCl was used as model drug substance. The release behavior was investigated at pH 8 where all formulations exhibited non-Fickian diffusion mechanism.Results and major conclusionAbsorbency was found to be more than 99% indicating good drug loading capability of these hydrogels towards the selected drug substance. Formulations designed with increasing amounts of EGDMA had a decreased equilibrium media content as well as media penetrating velocity and thus exhibited a slower drug release rate. Fitting of release data to different kinetic models indicate that the kinetic order shifts from the first to zero order as the concentration of drug was increased in the medium, showing gradual independency of drug release towards its concentration. Formulations with low drug content showed best fitness with Higuchi model whereas those with higher concentration of drug followed Hixson-Crowell model with better correlation values indicating that the drug release from these formulations depends more on change in surface area and diameter of tablets than that on concentration of the drug. Release exponent (n) derived from Korse-Meyer Peppas equation implied that the release of Tramadol HCl from these formulations was generally non-Fickian (n > 0.5 > 1) showing swelling controlled mechanism. The mechanical strength and controlled release capability of the systems indicate that these co-polymeric hydrogels have a great potential to be used as colon drug delivery device through oral administration.

Changes in the specific surface area of tablets composed of pharmaceutical materials with various deformation behaviors

Objective: The aim of this work is to study the effect of compaction on the specific surface area of tablets composed of various pharmaceutical materials (microcrystalline cellulose, lactose, and anhydrous calcium phosphate) compacted under seven degrees of compaction pressure. Methods: In a first part, the influence of the deformation behavior of the compacted materials on the evolution of the specific surface area is observed. In a second part, the brittle and ductile abilities of the materials are calculated using the specific surface area values. The experimental results are used to calculate the number and the force of interparticulate bonds inside the tablet.Results and Discussion: Tablets made of microcrystalline cellulose, which deform plastically, have specific surface areas that fall under pressure. In the case of lactose, the tablet specific surface area first increases to reach a maximum value at a pressure of 150 MPa. At higher pressure, however, the specific surface area decreases. The specific surface area of tablets composed of anhydrous calcium phosphate consistently increases, whatever the compaction pressure applied. Moreover, the evolution of the specific surface area is correlated with the tensile strength of the corresponding tablets. The number and the force of interparticulate bonds make it possible to classify the materials according to their deformation behavior and to quantify their ability to form cohesive tablets.

Effect of Tablet Surface Area and Surface Area/Volume on Drug Release from Lamivudine Extended Release Matrix Tablets

The purpose of this study was to investigate the influence of tablet surface area/ volume (SA/Vol) on drug release from extended-release matrix tablets of lamivudine prepared with hydroxy propyl methylcellulose (HPMC). Highly soluble drug such as lamivudine was utilized in this study to give predominantly diffusion-controlled release. Drug release from HPMC matrix tablets with similar values of SA/Vol was comparable within the same tablet shaped tablet. Tablets having the same surface area but different SA/Vol values did not result in similar drug release, tablets with larger SA/Vol values had faster release profiles. Utility of SA/Vol to affect drug release was demonstrated by changing drug doses, and altering tablet shape to adjust SA/Vol. When SA/Vol was held constant, similar release profiles were obtained. Thus, surface area/volume is one of the key variables in controlling drug release from HPMC matrix tablets. Proper use of this variable has practical application by formulators who may need to duplicate drug release profiles from tablets of different sizes and different shapes.

Approach to design push–pull osmotic pumps

Despite more than 30 years of clinical use, only few studies have been published reporting on the release mechanism underlying the drug delivery from push–pull osmotic pumps (PPOP). The aim of this study is to understand which factors have an effect on the drug delivery for modelling the drug release and to develop a mathematical model predictive of the drug release kinetics. The influence of the drug property was tested on two model drugs, isradipine (ISR) and chlorpheniramine (CPA) which are respectively practically insoluble and freely soluble. Results show that, regardless of the drug properties which do not significantly affect the drug delivery, the release kinetics is mainly controlled by four factors, (i) the PEG proportion in the membrane, (ii) the tablet surface area, (iii) the osmotic agent proportion and (iv) the drug layer polymer grade. The influence of each key formulation factors on the release mechanism was investigated defining their applicability range. A mathematical approach was developed to predict the drug delivery kinetics varying the PPOP controlling factors and helps to more efficiently design PPOP.

NIR chemical imaging to guide/support BMS-561389 tablet formulation development

The objective of this study was to determine whether the particle size of extra-granular tartaric acid affects the uniformity of its distribution within BMS-561389 tablets. A near-infrared imaging technique was used to assess the distribution of tartaric acid near the surface of tablet tops and bottoms. Three batches of BMS-561389 tablets were manufactured using three lots of granular tartaric acid having different particle size distributions. Near-Infrared chemical images were acquired on the tops and bottoms of 15 tablets from each lot. Spectra were collected from 1350 to 1600 nm in 10 nm increments and 16 co-added scans at each wavelength. Data were analyzed using ISys™ 3.1 (Spectral Dimensions, Inc.) Chemical Imaging Software. Data analysis consisted of preprocessing, principal component analysis, and image analysis of the principal component scores image. It was feasible to map tartaric acid particles near the surface of BMS-561389 tablets using near infrared chemical imaging. The tartaric acid particle size statistics based on image analysis results correlated well with pre-compaction measurements using a laser-light scattering method. The image analysis results indicate that segregation of tartaric acid between tablet tops and bottoms was apparent in tablets lots containing both the largest and intermediate-size tartaric acid particles. For tablets made with the smallest tartaric acid particles, differences between tablet tops and bottoms in either the number of tartaric acid particles or the percent tablet surface area covered by tartaric acid were not statistically different at the 95% confidence level.

An Investigation into the Factors Influencing Drug Release from Hydrophilic Matrix Tablets Based on Novel Carbomer Polymers

Drug release from hydrophilic matrix tablets can be strongly influenced by the proportion of matrix forming polymer and the dimensions and geometry of the tablets. A complete two-factor, three-level factorial design, followed by multiple regression analysis and response surface methodology, was applied to investigate the influence of polymer level and tablet size on drug release kinetics from hydrophilic matrix tablets prepared with Carbopol 971P and Carbopol 71G. Tablet diameter, radius-to-height ratio, tablet surface area, and surface-area-to-volume ratio were evaluated as independent variables in terms of their applicability to characterize tablet size and geometry. The results indicate that it may be possible to control the rate of drug release by modifying the proportion of carbomer in tablets and tablet dimensions. The practical benefit of these simulations is to optimize the geometry and dimensions of a controlled release device and reduce the number of experiments involved in the development of new controlled release dosage forms.

Effect of Hydrodynamic Environment on Tablets Dissolution Rate

The main objective of this research was to develop an experimental method to apply well‐defined flow fields to solid dosage forms, to study the rate process underlying tablet dissolution, and to better understand the role of external hydrodynamic condition on mass transfer rate and film thickness during dissolution. Two drugs models, Theophylline (class 1) and Naproxen (class 2), were selected and formulated into conventional tablets containing 105 mg Theophylline or 300 mg Naproxen using the wet granulation method. Tablets were tested for dissolution using both the basket and paddle methods at different rotational speed of 25, 50, 75, and 100 rpm. In general, the paddle method gave higher dissolution rates than the basket method and as the velocity of rotation was increased, drug release was also increased. Six different paddles and a tablet holder were designed and used to test dissolution rate. The rate of dissolution was dependent on the tablet surface area exposed to the dissolution medium, and on the shape, diameter, and area of the paddles used. Theophylline tablets showed increased mass transfer rate and decreased film thickness as basket rotation speed was increased. At 25 rpm, the mass transfer coefficient was 0.684 × 10− 4 cm/sec and film thickness was 12.003 × 10− 2 cm; at 100 rpm, the mass transfer coefficient was 3.884 × 10− 4 cm/sec and film thickness was 2.114 × 10− 2 cm. Paddle values tested at the same speed showed higher mass transfer coefficient and lower film thickness for Theophylline and Naproxen tablets. P values obtained by modification of the Stokes‐Einstein equation showed that diffusion is the rate‐limiting step to drug release and not mass transfer. This study demonstrated that hydrodynamic condition, type of dissolution testing used, and design of the paddles have an effect on dissolution rate, mass transfer rate, and the film thickness underlying the dissolution process.

Microcrystalline cellulose and its microstructure in pharmaceutical processing

Mercury porosimetry and nitrogen adsorption methods were used in pore structure and pore surface area characterisation of microcrystalline cellulose powder, granules and tablets. The effect of compression on pore structure and surface area of tablets compressed with three different compression pressures of powder and granules was determined. Densification of MCC in wet granulation led to decreased compactibility in tableting. Effects of granulation on the microstructure of microcrystalline cellulose and plastic deformation of powder during compression were detected with nitrogen adsorption, at the diameter range 3–200 nm. Structure of granules was destroyed during tableting when compression pressures of 196 MPa were used. Fragmentation and deformation of granules were observed from the results determined using both methods. Due to different measurement ranges, different theoretical basis of the methods and behaviour of the samples during analysis, results obtained with mercury porosimetry and nitrogen adsorption methods are not strictly comparable. Results obtained with mercury porosimetry give information on the behaviour of powder and granule particles in granulation or compression, whereas nitrogen adsorption brings out the changes in intraparticular structure of particles. The results obtained using these methods together can be used in the characterisation of behaviour of materials in granulation and tableting.

Use of Tablet Tensile Strength Adjusted for Surface Area and Mean Interparticulate Distance to Evaluate Dominating Bonding Mechanisms

In this study, tablet tensile strength has been adjusted for tablet surface area and the average distance between particles in compacts of different materials. The aim of the study was to evaluate the feasibility of using this concept to assess the dominating interparticulate bonding mechanisms. Adjustment of the tensile strength for both tablet surface area and mean pore radius gave similar bonding strength values for materials bonding mainly by weak distance forces (crystalline lactose, sucrose, and microcrystalline cellulose) almost independently of compaction pressure. However, particle size and other factors may still affect the compensated strength values. The bond strength was much higher and more varied for materials bonding also with solid bridges (potassium chloride, sodium chloride, and possibly also sodium bicarbonate and amorphous lactose). For these materials, particle size and compaction pressure had a substantial effect on the bond strength. It is probably the formation of continuous bridges between adjacent particles that is important in these materials rather than the surface properties and the average distance between particles positioned at some distance from each other. Hence, adjusting the tensile strength of compacts does not necessarily reflect all the dominating factors responsible for interparticulate bonding. Nonetheless, adjustment for tablet surface area and mean pore radius allowed discrimination between different dominating interparticulate bonding mechanisms in these compacted materials.

Pore structure and surface area of mannitol powder, granules and tablets determined with mercury porosimetry and nitrogen adsorption

Two methods used in pore structure characterisation, mercury porosimetry and nitrogen adsorption, were compared. Pore structure and surface area of mannitol powder, granules produced in wet granulation and tablets compressed with three compression pressures were studied. Greater surface area, more porous structure and greater number of small pores in granules, when compared with powder, increased the compactibility of mannitol granules in tableting. Plastic deformation and fragmentation of powder and granules in compression were observed in volume pore size distributions and surface areas measured with these methods. Pore volume and volume pore size distribution obtained with mercury porosimetry describe densification of mass better than those obtained with nitrogen adsorption. In spite of differences between the methods, the volume pore size distribution curves of samples in the overlapping pore size range had the same shape. The specific surface area of tablets, measured by the nitrogen gas adsorption method described well the deformation under compression. Fragmentation increased the surface area of powder, and plastic deformation decreased the surface area of granules in the pore size range determined. Surface area values measured with mercury porosimetry were larger than those determined with nitrogen adsorption.

Influence of Technological Variables on the Release of Theophylline from Hydrophilic Matrix Tablets

This study presents the results of in vitro dissolution of controlled-release theophylline tablets using hydroxypropylmethylcellulose as a rate-retarding polymer. The effects of the proportion of the polymer, the addition of diluents, and the surface area of matrix tablets on the theophylline release rate have been investigated. The results of the dissolution tests show that the drug was gradually released in all cases, and that the tablets had released 80% of their contents after 8 hr. The release rate decreased when the proportion of the polymer increased. The influence of adding diluents and effect of the surface area of matrix tablets were not observed in this study.

Porosity parameters of lactose, glucose and mannitol tablets obtained by mercury porosimetry

The effect of compression force, compression speed and the amount of granulation liquid on the porosity parameters determined from lactose, glucose and mannitol tablets by high-pressure mercury porosimetry was investigated. Compression force affected all parameters measured, except the total pore surface area of lactose tablets. The changes in tablet microstructure with increasing compression force were particularly well detected from the pore volume size distributions of tablets. Compression speed affected the total pore volume of lactose tablets, both mean and median pore diameters of lactose tablets and mannitol tablets compressed from granules produced with a low amount of liquid, and the median pore diameter of glucose tablets. The compression speed dependence of these parameters was a sign of the time-dependent deformation of materials during compression. The amount of granulation liquid affected the total pore surface area of lactose and mannitol tablets. With a high amount of liquid, the surface area of pores was greater. The mean pore size of all tablets and the median pore diameter of mannitol tablets were smaller when a high amount of granulation liquid was used. Even when compressed with a high force, the pore volume size distributions of mannitol tablets with a low amount of granulation liquid were broader and the maxima were at larger pore diameters. It was concluded that each porosity parameter measured characterised the pore structure of compressed tablets from a different aspect. Thus, the use of all porosity parameters proved to be useful.

Control of Poorly Soluble Drug Dissolution in Conditions Simulating the Gastrointestinal Tract Flow. 1. Effect of Tablet Geometry in Buffered Medium

The dissolution rate of a solid drug from the gastrointestinal (GI) tract is affected by the properties and flow dynamics of the liquid medium surrounding the tablet, as well as by the chemical nature of the drug. In this study, naproxen was used as a poorly soluble model drug. The dissolution medium was buffered with acetate, citrate, or phosphate buffer of varied concentrations and pH. GI flow conditions around a stationary tablet were simulated in a laminar flow device by anchoring the tablet on the floor of its channel having a rectangular cross section. Fresh, buffered solution was passed across the tablet and the effluent was collected for analysis and calculation of the dissolution rate. The dissolution rate was found to vary nonlinearly with the exposed tablet height, reaching a maximum at a tablet height approximately half the channel height. This maximum rate was attributed to an optimal combination of (1) eddy mixing and local turbulence generated by the flow impingement on the bluff object (tablet) and (2) the exposed tablet surface area available for dissolution. This effect was further confirmed by using dye-enhanced visual analysis of flow patterns at varied flow rates and exposed tablet heights. Elevation of the tablet to approximately the channel half-height significantly magnified the dissolution rate increase observed on exposure to buffered medium. Thus, tablet height and exposed surface area are major factors in determining dissolution rate, especially in conditions where the dissolving species reacts with the solvent. These results suggest that standard in vitro dissolution rate methods do not qualitatively indicate incremental changes in rate with altered tablet geometry or dissolution medium.