Behavior Of Tablets Research Articles

Swelling and hydrolytic degradation of poly( d, l-lactic acid) in aqueous solutions

Low molecular weight poly(lactic acid) was synthesized by direct polycondensation of lactic acid. The oligomers were characterized by viscometry, light scattering, and gel permeation chromatography (GPC). The swelling behaviour of tablets made of the above polymer immersed in buffer solutions at 37 °C was studied. In the same experiments, the hydrolytic stability of d, l-PLA was assessed by measuring the weight loss after drying the tablets. In order to inhibit any degradation due to bacteria, formaldehyde was added in the solution as biostatic factor. The effect of an incorporated drug on the swelling behaviour of d, l-PLA tablets was also considered. It was found that the incorporation of drug in d, l-PLA tablets increases their swelling index, probably due to the creation of additional porosity in the specimens or other interaction between drug and polymeric matrix.

A level A in vitro/in vivo correlation in fasted and fed states using different methods: Applied to solid immediate release oral dosage form

The first purpose of this study was to simulate the impact of food intake on drug release and absorption in vivo using a novel in vitro system which mimics the gastro-intestinal (GI) tract in man. The drug studied was acetaminophen in the form of immediate release (IR) tablets. The second purpose was to establish a level A in vitro/in vivo correlation that could predict the bioavailability of a drug instead of using difficult, time-consuming and expensive in vivo bioequivalence studies. The artificial digestive system was used to estimate the availability of acetaminophen IR tablets for absorption in fasted and fed states. The same study was performed in vivo under similar conditions. A comparison study was carried out between the classical and the novel methods to estimate the efficacy of the new in vitro system to simulate the influence of food on drug release and absorption in vivo. A level A in vitro/in vivo correlation was established with a correlation coefficient of 0.9128 and 0.9984 in the fasted and fed states, respectively. Compared to USP II method, the novel in vitro model demonstrated a high level of efficacy in mimicking the behaviour of acetaminophen IR tablets in vivo in fasted and fed states.

Comparison of the Granulation Behavior of Three Different Excipients in a Laboratory Fluidized Bed Granulator Using Statistical Methods

The granulation process and, subsequently, the tableting behavior of the resulting granules of α-lactose-monohydrate, dicalcium phosphate anhydrous, and potato starch were investigated using statistical designs. The three substances were chosen due to their differences in granulation and tableting behavior, such as water solubility, swelling, and compressional properties. Granulation process variables, namely the inlet air temperature, spray rate, binder concentration of granulating solution, and inlet air flow rate were investigated. A central composite design was applied to study the granulation of α-lactose-monohydrate. Granulations of dicalcium phosphate and potato starch were investigated using a 23 factorial design, in which the effects of the inlet air temperature, spray rate, and binder concentration were considered. To compare the granulation behavior of theses substances the particle size distribution, angle of repose, and yield of the granules were used as responses for the statistical designs. The granules were compressed into tablets and the tensile strength was used as an additional statistical response. Based on the process parameters, models were developed using multiple regression modeling for each examined response. These models were then used to optimize the granulation process that provides granules with a Sauter mean diameter of D32 between 300 and 500 µm, an angle of repose smaller than 36° and a granule yield above 90%. Moreover, the values of the tensile strength of the tablets should be between 1.6 and 2.5 N/mm2. The intersections of the response surfaces of each examined substance were compared using contour plots. To achieve the largest “satisfactory zone,” the granulations of milled α-lactose-monohydrate, dicalcium phosphate, or potato starch should be performed at low inlet air temperatures.

Quantitative evaluation of polymer concentration profile during swelling of hydrophilic matrix tablets using 1H NMR and MRI methods

Many pharmaceutical tablets are based on hydrophilic polymers, which, after exposure to water, form a gel layer around the tablet that limits the dissolution and diffusion of the drug and provides a mechanism for controlled drug release. Our aim was to determine the thickness of the swollen gel layer of matrix tablets and to develop a method for calculating the polymer concentration profile across the gel layer. MR imaging has been used to investigate the in situ swelling behaviour of cellulose ether matrix tablets and NMR spectroscopy experiments were performed on homogeneous hydrogels with known polymer concentration. The MRI results show that the thickest gel layer was observed for hydroxyethylcellulose tablets, followed by definitely thinner but almost equal gel layer for hydroxypropylcellulose and hydroxypropylmethylcellulose of both molecular weights. The water proton NMR relaxation parameters were combined with the MRI data to obtain a quantitative description of the swelling process on the basis of the concentrations and mobilities of water and polymer as functions of time and distance. The different concentration profiles observed after the same swelling time are the consequence of the different polymer characteristics. The procedure developed here could be used as a general method for calculating polymer concentration profiles on other similar polymeric systems.

Anomalous dissolution behaviour of tablets prepared from sugar glass-based solid dispersions

Anomalous dissolution behaviour of tablets prepared from sugar glass-based solid dispersions

Anomalous dissolution behaviour of tablets prepared from sugar glass-based solid dispersions

In this study, anomalous dissolution behaviour of tablets consisting of sugar glass dispersions was investigated. The poorly aqueous soluble diazepam was used as a lipophilic model drug. The release of diazepam and sugar carrier was determined to study the mechanisms governing dissolution behaviour. The effect of carrier dissolution rate and drug load was tested with four different sugars, in the order of decreasing dissolution rates: sucrose, trehalose and two oligo-fructoses; inulinDP11 and inulinDP23 having a number average degree of polymerization (DP) of 11 and 23, respectively. Diazepam was incorporated in these sugar glasses in the amorphous state by means of freeze drying using water and tertiary butyl alcohol (TBA) as solvents. None of the tablets disintegrated during dissolution. Dissolution of 80% of the lipophilic drug within 20 min was found when diazepam and sugar dissolution profiles coincided. The sugar carrier and diazepam dissolved at the same rate, which was constant in time and fast. This condition was met for relatively slow dissolving carriers like the inulins or for low drug loads. For relatively fast dissolving carriers like sucrose or trehalose with high drug loads, release profiles of diazepam and sugar did not coincide: diazepam dissolved much more slowly than the sugars. In case of non-coinciding release profiles, diazepam release was split into three phases. During the first phase non-steady-state dissolution was observed: diazepam release accelerated and a drug rich layer consisting of crystalline diazepam was gradually formed. This first phase determined the further release of diazepam. During the second phase a steady-state release rate was reached: zero-order release was observed for both drug and carrier. During this phase, the remaining (non-crystallised) solid dispersion is dissolved without the further occurrence of crystallisation. The third phase, starting when all carrier is dissolved, involved the very slow dissolution of crystallised diazepam, which was present either as the skeleton of a tablet resulting in a zero-order release profile or as separate particles dispersed in the dissolution medium resulting in a first-order release. To understand the anomalous dissolution behaviour, a model is proposed. It describes the phenomena during dissolution of amorphous solid dispersion tablets and explains that fast dissolution is observed for low drug loads or slow dissolving carriers like inulin.

How do roll compaction/dry granulation affect the tableting behaviour of inorganic materials? Microhardness of ribbons and mercury porosimetry measurements of tablets.

The effect of roll compaction/dry granulation on the ribbon and tablet properties produced using different magnesium carbonates was evaluated. The ribbon microhardness and the pore size distribution of tablets were used as evaluation factors. Increasing the specific compaction force resulted in higher microhardness for ribbons prepared with all four magnesium carbonates accompanied with decreased part of fine. Consequently, the corresponding produced tablets displayed a lower tensile strength. A possible correlation between the particle shape, surface area and the resulting pore structure of tablets produced with the four different types of magnesium carbonate was observed. The tensile strength of tablets prepared using granules was lower than tensile strength of tablets produced using starting materials. The partial loss of compactibility resulted in a demand of low loads during roll compaction. However, the impact of changes in the material properties during the roll compaction depended greatly on the type of magnesium carbonate, the specific compaction force and the tableting pressure applied.

A new wet conductivimetric method to estimate the drug percolation threshold.

The main objectives of this work are to study the behavior of fluid imbibition into a consolidated matrix through a wet invasive conductivimetric technique, to investigate if the changes in the behavior observed can be related to the drug percolation threshold, and to use this technique for its estimation. Matrix tablets were prepared using five sieving fractions of KCl and Eudragit RS-PM. In vitro release assays were carried out on 45 batches. The drug percolation thresholds were estimated following the method of Leuenberger and Bonny, and the results were compared to the obtained employing the conductivimetric technique described in this paper. The wet conductivimetric technique and the standard method provided similar results for the estimation of the percolation threshold. The presented technique also provides quantitative information about the consolidated matrix. A new apparatus has been developed for the study of the conductivimetric behavior of matrix tablets during water uptake. This technique provides measurable parameters of fluid penetration and can be used to estimate the drug percolation threshold, providing similar results to the Leuenberger and Bonny method and being clearly faster.

Assay of amoxicillin sustained release from matrix tablets containing different proportions of Carbopol 971P NF

The sustained release of amoxicillin is desired because of its short biological half-life. Particularly to treat Helicobacter pylori infections, the sustained release is desired to be confined to the upper gastrointestinal tract. In vitro dissolution of amoxicillin has been evaluated utilizing a direct UV-absorption method. However, UV-absorption has been reported as not useful to determine amoxicillin in acidic dissolution test medium. To clarify the suitability of the assay method, the stability and dissolution behavior of amoxicillin sustained release tablets was determined by HPLC, iodometric titration and UV-absorption. Stability of amoxicillin studied under dissolution test conditions of pH 1.2, 37 °C and 50 rpm and determined by HPLC and titration showed considerable degradation of amoxicillin. On the other hand, the UV-absorption increased progressively as amoxicillin degradation proceeded. Amoxicillin release curves determined by different analytical methods show different release profiles, which can be corrected for amoxicillin degradation and change in the UV-absorption to produce similar dissolution results. Release curves determined by UV-absorption and obtained from tablets containing 1017 mg amoxicillin trihydrate and Carbopol 971P NF in a range from 180 to 680 mg showed increasing values of the exponent indicative of the release mechanism ( n) and decreasing release constant values ( k) as the matrix polymer content increased. The release constant ( k) and the exponent ( n) were found to be logarithmically related.

Effect of Formulation and Process Variables on the Release Behavior of Amoxicillin Matrix Tablets

The sustained release of amoxicillin is desired to be confined to the upper gastrointestinal tract to treat certain kind of infections. In vitro dissolution, at pH 1.2, of amoxicillin sustained release tablets has been studied varying the proportion of Carbopol 971P NF and sodium alginate as well as the ethanol/water proportion in the granulation fluid. Mt, the amount of drug released at time (t) and defined in terms of the total drug released over a long time period (Minf), was described by Mt/Minf = ktn. Matrices with increasing proportions of sodium alginate showed increasing values of the exponent indicative of the release mechanism (n) and increasing release constant values (k). This is attributed to a drop in the coherence of the polymeric matrix with increasing alginate proportions that produces an increasing polymer relaxation and erosion. Decreasing Carbopol 971P NF proportions reduce the amount of dissolved polymer during granulation, producing a lesser obstruction of amoxicillin dissolution. Alginate proportions of 80% produce near zero order release profiles. Granules obtained with increasing ethanol proportions showed increasing release constant values and a minor change in the exponent (n) values. This is considered a result of lower polymer dissolution during granulation that allows a lesser matrix coherence and a greater amoxicillin dissolution. Alginate matrices granulated with different ethanol/water proportions showed no significant changes in the amoxicillin release profile. There is a trend toward increasing floating times with increasing Carbopol 971P NF proportions.

Comparison Studies on the Percolation Thresholds of Binary Mixture Tablets Containing Excipients of Plastic/Brittle and Plastic/Plastic Deformation Properties

Percolation theory has been used with great interest in understanding the design and characterization of dosage forms. In this study, work has been carried out to investigate the behavior of binary mixture tablets containing excipients of similar and different deformation properties. The binary mixture tablets were prepared by direct compression using lactose, polyvinyl chloride (PVC), Eudragit RS 100, and microcrystalline cellulose (MCC). The application of percolation theory on the relationships between compactibility, Pmax, or compression susceptibility (compressibility), γ, and mixture compositions reveals the presence of percolation thresholds even for mixtures of similar deformation properties. The results showed that all mixture compositions exhibited at least one discreet change in the slope, which was referred to as the percolation threshold. The PVC/Eudragit RS100 mixture compositions showed significant percolation threshold at 80% (w/w) PVC loading. Two percolation thresholds were observed from a series of binary mixtures containing similar plastic deformation materials (PVC/MCC). The percolation thresholds were determined at 20% (w/w) and 80% (w/w) PVC loading. These are areas where one of the components percolates throughout the system and the properties of the tablets are expected to experience a sudden change. Experimental results, however, showed that total disruption of the tablet physical properties at the specified percolation thresholds can be observed for PVC/lactose mixtures at 20–30% (w/w) loading while only minor changes in the tablets' strength for PVC/MCC or PVC/Eudragit RS 100 mixtures were observed.

Temperature/Humidity Sensitivity of Sustained‐Release Formulations Containing Kollidon® SR

The effects of temperature and humidity on tablets containing Kollidon® SR have been evaluated using diphenhydramine HCl as a model drug. Exposure of tablets to ICH accelerated stability condition (40°C/75%RH) in an open dish resulted in rapid increases in tablet hardness, accompanied by step‐wise decreases in dissolution rate. Such a change can be observed as fast as an hour upon exposure. The tablet matrix appears to rapidly absorb atmospheric moisture, as demonstrated by tablet weight gain and moisture adsorption isotherms. Exposure to 25°C/60%RH similarly resulted in increases in tablet hardness, although with minimal impact on dissolution. Potential implications of such rapid moisture uptake during aqueous film‐coating were further evaluated by spraying either water or an Opadry solution in a coating pan. Exposure of Kollidon SR tablets to the aqueous coating process indeed resulted in noticeable changes in both hardness and dissolution. Application of the Opadry solution appears to affect tablet behavior to a lesser degree, compared to water, most likely due to protection via formed barrier film. Attention needs to be paid to the extreme sensitivity of Kollidon SR matrix tablets to temperature and moisture during product development.

Swelling and drug release behavior of tablets coated with aqueous hydroxypropyl methylcellulose phthalate (HPMCP) nanoparticles

Organic solvent-based enteric coating technology using hydroxypropyl methyl cellulose phthalate (HPMCP) has been developed for many years due to low water solubility of HPMCP. In this work, aqueous HPMCP nanoparticles (HPMCP-NPs) were prepared by neutralization emulsification method using HPMCP powder and ammonium hydroxide (NH 4OH) in the absence of any organic solvent and emulsifier. Tablets for enteric use were coated with HPMCP-NP dispersions having different degree of neutralization that was manipulated by ion-exchange process. Disintegration and dissolution behavior of coated tablets were investigated using UV-visible spectrophotometer based on USP method (pH 1.2 and at 37 °C) and simulated intestinal fluid (pH 6.8 and at 37 °C for 60 min), respectively. The ion-exchange process, which was directly achieved by the protonation of dissociated carboxylic acid group of the aqueous HPMCP-NPs, was introduced as a useful way to control the release rate of drug and hydrophobic nature of HPMCP coating layer with a view for pharmaceutical application. The drug release and swelling were increased with increase in conductivity of aqueous HPMCP-NPs. On the other hand, particle size and polydispersity were decreased with increase in degree of neutralization.

Chemical structure and glass transition temperature of non-ionic cellulose ethers

Glass transitions of several non-ionic cellulose ethers differing in molecular mass and nature and amount of substituents were analyzed (as compressed probes) by differential scanning calorimetry (DSC), modulated temperature differential scanning calorimetry (TMDSC@®), and oscillatory rheometry. In general, the low energy transitions accompanying the Tg of methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), and hydroxypropylcelluloses of low (L-HPC) or medium-high (HPC) degree of substitution were difficult to characterize using DSC. Non-reversing heat flow signals obtained in TMDSC experiments were more sensitive. However, the best resolution was obtained using oscillatory rheometry since these cellulose ethers undergo considerable changes in their storage and loss moduli when reaching the Tg. Oscillatory rheometry also appears as a useful technique to characterize the viscoelastic behavior and thermal stability of pharmaceutical tablets. Tg values followed the order HPC (105°C)<HPMC (170-198°C)<MC (184-197°C)<L-HPC (220°C). For HPMCs, the Tg increases as the methoxyl/hydroxypropoxyl content ratio decreases. The results indicate that Tg depends strongly on the structure of the cellulose ethers. In general, increasing the degree of substitution of cellulosic hydroxyls, the hydrogen bonding network of cellulose decreases (especially when the substituents cannot form hydrogen bonds) and, in consequence, Tg also decreases.

The relevance of glass transition temperature for the process of tablet formation

The aim was to determine the relevance of the glass transition temperature (Tg) on the compressibility and compactibility of different excipients as celluloses, cellulose derivatives, lactoses, starch, maltodextrin and carrageenan. Their Tg was determined, they were tableted on an instrumented eccentric tableting machine and crushing force was analyzed. Using force, time and displacement tableting behavior was analyzed by 3D modeling. The parameters obtained, d (time plasticity), e (pressure plasticity) and w (fast elastic decompression), show different deformation mechanisms for the materials in relation to their Tg. Further, if the Tg can be reversibly exceeded during tableting, crushing force is high, otherwise crushing force is lower.

Ibuprofen crystals with optimized properties

The common analgesic drug ibuprofen shows bad dissolution and tableting behavior due to its hydrophobic structure. Additionally its high cohaesivity results in low flowability. Because of the bad compaction behavior ibuprofen has to be granulated usually before tableting. Another problem in manufacturing is the high tendency for sticking to the punches. A crystal form with optimized properties of ibuprofen was prepared and characterized in this study. Crystallization was carried out using the solvent change technique in the presence of different water-soluble additives. These additives were only present during the crystallization process and removed after precipitation by a washing process. A nearly pure ibuprofen powder was received, as GC-analysis showed. Plate-shaped crystals with increased powder dissolution, increased flowability and good tableting behavior were obtained. All crystals were determined as isomorphic by DSC and X-ray analysis. Thus the improvement of the substance characteristics of ibuprofen is reached by changes in the outer appearance of the crystals and in surface modifications. Due to the fact that ibuprofen molecules can form hydrogen bonds, additives that can interact with these hydrogen bonds during the crystallization process can modify the properties of the resulting crystals.

Crystal habit and tableting behavior.

The tableting behavior of drugs can be affected by changes in the crystal habit. Different crystal habits of the common analgesic drugs ibuprofen and acetaminophen were prepared. Their tableting behavior was characterized. In the case of ibuprofen, a plate-shaped crystal was compared with the common needle-shaped form. In the case of acetaminophen, plate-shaped and prismatic crystals of two different particle sizes were prepared. The aim was to find a crystal form that is suitable for direct compression with only a low amount of excipients. This requires a substance that forms stable compacts at low punch forces, having a good flowability and only a low tendency to stick to the punches. In order to compare the tableting behavior of different substances, a comparative factor (T-factor) was calculated, based on typical parts of the punch force/displacement-profile and properties of the resulting compact. This method works with low amounts of substance and allows a rapid reproducible determination of the tableting behavior. The method was evaluated by characterizing different typical excipients normally used for the production of tablets.

Quality control of thiabendazole pre-formulation and tablets by TG and DSC coupled to the photovisual system

A stability study and thermal behavior of thiabendazole pre-formulation and tablets were investigated by TG and DSC coupled to a photovisual system. The results showed that the excipients, namely starch, PVP and magnesium stearate did not cause significant chemical interactions with the drug thiabendazole. The rate constants for the thermal decomposition reaction were determined by both an isothermal thermogravimetry and oven accelerated decomposition methods using the classical Arrhenius’ equations. Thermal stability studies showed that thiabendazole tablets presented lower stability than the drug thiabendazole. The data analysis revealed that the drug thiabendazole undergoes a thermal decomposition reaction at a temperature lower that its melting point. This fact was confirmed by DSC coupled to the photovisual system and FT-IR.

In situ, real time observation of the disintegration of paracetamol tablets in aqueous solution by magnetic resonance imaging

The disintegration behavior of paracetamol tablets was studied by magnetic resonance imaging (MRI) using the Snapshot FLASH method. The total time of the single experiment is 425 ms and allows the study of the disintegration process in real time. The study was carried out in vitro under acidic gastric pH conditions and may help to predict the behavior of paracetamol tablets in the stomach after oral administration. It was shown that in spite of identical conditions, the disintegration of the tablets under study was different. The distribution of protons of 4-( N-acetyl)aminophenol within the paracetamol tablet was shown to be homogeneous. The study was carried out in a non-destructive way by the SPI MRI method.

Plasticity and slip system of plate-shaped crystals of L-lysine monohydrochloride dihydrate.

To identify the slip system of L-lysine monohydrochloride dihydrate (LH) and to relate it to the deformation behavior under uniaxial compression. The indentation hardness of the [100] face and the indentation moduli of the [100] and [011] faces of plate-shaped single crystals of LH (LHP) were determined using Knoop and Berkovich indenters, respectively. The deformation behavior during uniaxial compression was studied by the punch-stress vs. punch-displacement profile and by electron microscopy of the deformed crystals within cracked compacts. The different indentation (elastic) moduli of the [100] and [011] faces of the crystals are consistent with the molecular packing density along these planes and suggest anisotropy. The existence of the [001] <100> slip system is proposed based on the pattern of changing indentation hardness with varying orientation of the Knoop indenter. A jagged uniaxial compression profile suggests deformation by mechanical twinning and not simple slip. The hypothesis of deformation by mechanical twinning is supported by the appearance of twin bands along the crystal faces as observed by electron microscopy of the cracked compacts. During compression, most LHP crystals have their [100] faces oriented normal to, or inclined to, the compression axis, thereby facilitating plastic deformation along the [001] <100> slip system by mechanical twinning. Due to the low attachment energy between them, the [001] planes can also act as cleavage planes. This study demonstrates that knowledge of the crystal structure and slip systems can be used to model the tableting and compaction behavior of molecular crystals, such as LH.