Performance Of Tablets Research Articles

Understanding the relationship between crystal structure, plasticity and compaction behaviour of theophylline, methyl gallate, and their 1 : 1 co-crystal

Theophylline and methyl gallate can form a 1 : 1 co-crystal. Their tableting performance follows the order of theophylline > co-crystal ≫ methyl gallate. While co-crystallization profoundly improves the tabletability of methyl gallate, it significantly deteriorates that of theophylline. This difference in bulk compaction behaviour originates from the dissimilar crystal plasticity and elasticity, which results from unique molecular packing features in the respective crystal lattices. The presence of a three-dimensional hydrogen bonded network gives rise to very low plasticity in the methyl gallate crystal, which leads to its poor tabletability. In contrast, the layers of two-dimensional rigid, hydrogen bonded molecules in the co-crystal improve the crystal plasticity, by facilitating slip with shear that, in turn, enhances tabletability. However, theophylline undergoes plastic deformation more readily when compared to the co-crystal, because the slip layers in theophylline are composed of hydrogen bonded columns, which provide additional flexibility for slip. As a consequence, theophylline crystals have significantly enhanced tabletability.

Dissolution parameters for sodium diclofenac-containing hypromellose matrix tablet

Sodium diclofenac (SD) release from dosage forms has been studied under different conditions. However, no dissolution method that is discriminatory enough to reflect slight changes in formulation or manufacturing process, and which could be effectively correlated with the biological properties of the dosage form, has been reported. This study sought to develop three different formulae of SD-containing matrix tablets and to determine the effect of agitation speed in its dissolution profiles. F1, F2 and F3 formulations were developed using hypromellose (10, 20 and 30%, respectively for F1, F2 and F3) and other conventional excipients. Dissolution tests were carried out in phosphate buffer pH 6.8 at 37 °C using apparatus II at 50, 75 or 100 rpm. Dissolution efficiency (DE), T 50 and T 90 were determined and plotted as functions of the variables agitation speed and hypromellose concentration. Regarding DE, F2 showed more sensitivity to variations in agitation speed than F1 and F3. Increasing hypromellose concentration reduced DE values, independent of agitation speed. Analysis of T 50 and T 90 suggests that F1 is less sensitive to variations in agitation speed than F2 and F3. Most discriminatory dissolution conditions were observed at 50 rpm. Results suggest that the comparison of dissolution performance of SD matrix tablets should take into account polymer concentration and agitation conditions.

Measuring the hydrophobicity of lubricated blends of pharmaceutical excipients

Abstract This paper discusses how the hydrophobicity of lubricated pharmaceutical formulations is affected by process variables such as shear rate and strain. Hydrophobicity is a critical property that affects the dissolution of powder formulations, tablets and capsules as well as the performance of tablet coating and granulation operations. In this paper, hydrophobicity is measured using a modified Washburn method. Results show that, in the absence of lubricant, the hydrophobicity of powders does not change substantially as a function of shear rate or strain. However, when magnesium stearate is present (concentrations studied here range between 0.5% and 2%), hydrophobicity increases as a function of strain, shear rate and lubricant concentration. Observed changes range over several orders of magnitude, readily explaining common “overlubrication” observations of delayed drug dissolution.

Chitosan–polycarbophil interpolyelectrolyte complex as a matrix former for controlled release of poorly water-soluble drugs I: in vitro evaluation

Purpose: It was previously shown in our laboratories that the interpolyelectrolyte complex between chitosan and polycarbophil has promise as a matrix former to control the release of water-soluble drugs. This study further investigates the applications of this polymeric complex to produce controlled release matrices for poorly water-soluble drugs. Methods: The swelling, erosion, and drug release performance of matrix-type tablets containing the chitosan–polycarbophil complex as matrix former was compared to those consisting of hydroxypropylmethylcellulose and a simple mixture of chitosan and polycarbophil powders. Results: The chitosan–polycarbophil complex matrices showed good swelling with relatively low erosion and slower drug release compared to those prepared from other polymeric materials. They also exhibited release exponent (n) values closer to unity and therefore to zero-order release compared to the other matrices. Conclusions: The chitosan–polycarbophil complex formed matrix-type tablets that controlled the release of poorly water-soluble drugs approaching zero-order kinetics. The mechanism of drug release was mainly diffusion from swollen systems.

Fabrication of Triple-Layer Matrix Tablets of Venlafaxine Hydrochloride Using Xanthan Gum

The objective of present investigation was to develop venlafaxine hydrochloride-layered tablets for obtaining sustained drug release. The tablets containing venlafaxine hydrochloride 150 mg were prepared by wet granulation technique using xanthan gum in the middle layer and barrier layers. The granules and tablets were characterized. The in vitro drug dissolution study was conducted in distilled water. The tablets containing two lower strengths were also developed using the same percentage composition of the middle layer. Kinetics of drug release was studied. The optimized batches were tested for water uptake study. Radar diagrams are provided to compare the performance of formulated tablets with the reference products, Effexor XR capsules. The granules ready for compression exhibited good flow and compressibility when xanthan gum was used in the intragranular and extragranular fractions. Monolayer tablets failed to give the release pattern similar to that of the reference product. The drug release was best explained by Weibull model. A unified Weibull equation was evolved to express drug release from the formulated tablets. Lactose facilitated drug release from barrier layers. Substantial water uptake and gelling of xanthan gum appears to be responsible for sustained drug release. The present study underlines the importance of formulation factors in achieving same drug release pattern from three strengths of venlafaxine hydrochloride tablets.

Multifunctional coprocessed excipients for improved tabletting performance

With the advancement of tablet manufacturing process, the demand of excipients with improved functionalities, mainly in terms of flow and compression properties, has increased. Coprocessed excipients are a mixture of two or more existing excipients at subparticle level, offer substantial benefits of the incorporated excipients and minimize their drawbacks. These multipurpose excipients have dramatically reduced the number of incorporating excipients in the tablet. The present review discusses the potential advantages of coprocessing and coprocessed excipients, material characteristics required for coprocessing, methods of coprocessing and various coprocessed excipients for direct compression available in the market.

Crystal Morphology Engineering of Pharmaceutical Solids: Tabletting Performance Enhancement

Crystal morphology engineering of a macrolide antibiotic, erythromycin A dihydrate, was investigated as a tool for tailoring tabletting performance of pharmaceutical solids. Crystal habit modification was induced by using a common pharmaceutical excipient, hydroxypropyl cellulose, as an additive during crystallization from solution. Observed morphology of the crystals was compared with the predicted Bravais-Friedel-Donnay-Harker morphology. An analysis of the molecular arrangements along the three dominant crystal faces [(002), (011), and (101)] was carried out using molecular simulation and thus the nature of the host-additive interactions was deduced. The crystals with modified habit showed improved compaction properties as compared with those of unmodified crystals. Overall, the results of this study proved that crystal morphology engineering is a valuable tool for enhancing tabletting properties of active pharmaceutical ingredients and thus of utmost practical value.

Evaluating particle hardness of pharmaceutical solids using AFM nanoindentation

Understanding mechanical properties of pharmaceutical solids at the submicron scale can be very important to pharmaceutical research & development. In this paper, the hardness of individual particles of various pharmaceutical solids including sucrose, lactose, ascorbic acid, and ibuprofen was quantified using the atomic force microscopy (AFM) nanoindentation. Effects of data variation and indentation size or peak load on hardness are evaluated. The results show acceptable reproducibility and indicate that data variation may be primarily from the inhomogeneous nature of the samples. Different extents of indentation size or peak load effect on hardness were observed for the samples. With consideration of both data variation and indentation size effects, the hardness values of different samples were compared at similar contact depths or peak loads. The hardness ranked as: ascorbic acid > sucrose > lactose ≈ ibuprofen, at contact depths from ∼40 to 400 nm or peak loads ranging from ∼16 to 70 μN. Additionally, the potential implication of particle hardness to compact hardness and tableting performance was discussed.

Development of a drug release methodology for carbamazepine CR tablets based on bioequivalence evaluation

The aim of this study was to investigate the influence of experimental conditions on carbamazepine (CBZ) release from the two controlled-release (CR) tablet formulations with proven bioequivalence and to propose the universal release method which would be biorelevant. In vitro data were obtained in various release media using the USP apparatus II in order to assess their influence on CBZ release from CR tablets. An empirical correlation between in vivo plasma concentration data expressed as a fraction drug absorbed and the cumulative amount of in vitro release was established. The most complete release and highest level A correlation was observed by using the half change method (HCM) compared to other release methodologies tested. The results obtained indicate that the release test developed offers a promising in vitro tool for predicting the in vivo performance of CBZ CR tablets, ensuring batch to batch bioequivalence and verification of certain postapproval changes without the need for additional in vivo studies.

Influence of crystal structure on the tableting properties of n‐alkyl 4‐hydroxybenzoate esters (parabens)

Certain crystallographic features, such as the existence of slip planes, can greatly facilitate the ability of crystals to deform plastically. An investigation of the relationship between the slip planes and the tableting performance of the crystals of methyl, ethyl, n-propyl, and n-butyl 4-hydroxybenzoate (parabens) was conducted. The absence of slip planes in methyl paraben crystal structure results in significantly poorer tableting performance than the other three parabens. While slip planes are present in the crystal structures of ethyl, propyl, and butyl parabens, they exhibited different plasticity as confirmed by crystal free volume analysis, crystal nano-indentation hardness, and Heckel analysis. Sieved fraction, 150-250 microm, of each paraben powder was compressed into tablets under different conditions. Tablet tensile strength, porosity, and Indices of tableting performance (ITP) were obtained. Under the same compaction pressure, tablet tensile strength was higher for crystals with higher plasticity. Tableting performance, assessed using the ITP, also improved with increasing crystal plasticity. The results confirm that high levels of plasticity, which can result from the presence of slip planes in crystal lattice, plays a critical role in the formation of strong and intact tablets by means of powder compaction.

Evaluation of the compaction of sulfathiazole polymorphs

The aim of this study was to relate the tableting performance assessed by an instrumented tableting machine to the mechanical properties measured by nanoindentation. Three different polymorphic forms of sulfathiazole were prepared by recrystallization, and the density and X-ray powder diffraction patterns were measured and compared with theoretical density and simulated powder patterns, respectively. Tablets were prepared using a series of applied pressures, and the results were subjected to energy analysis, three dimensional (3D) modeling, and the traditional Heckel analysis. With these approaches, form I was found to be consistently the most brittle material, but the subtle differences between forms II and III were only revealed by 3D modeling. The rank order of the crushing force was found to be I is congruent to II < III. From nanoindentation, form III was found to be much harder than forms I and II, and III also had a much higher Young's modulus. The energy calculations of the nanoindentation curves showed that form III was distinct from forms I and II, which is consistent with the presence of slip planes that are only present in form III. However, in this system, there was little correspondence between the macroscopic and microscopic measurements, and thus particle-particle interactions may to be of paramount importance.

In-vitro/in-vivo correlation of pulsatile drug release from press-coated tablet formulations: A pharmacoscintigraphic study in the beagle dog

The aim of the current study was to investigate the in-vitro and in-vivo performance of a press-coated tablet (PCT) intended for time delayed drug release, consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and low-substituted hydroxypropylcellulose (L-HPC). The PCTs showed pulsatile release with a lag time dependent upon the GB and L-HPC composition of the barrier layer. In-vivo γ-scintigraphic studies were carried out for PCTs containing GB:L-HPC at 65:35 w/w and 75:25 w/w in the barrier layer in four beagle dogs, in either the fed or fasted state. The in-vivo lag time in both the fed and fasted states did not differ significantly ( p > 0.05) from the in-vitro lag time. Additionally, no significant difference ( p < 0.05) between in-vivo fed and fasted disintegration times was observed, demonstrating that in-vivo performance of the PCT was not influenced by the presence or absence of food in the gastrointestinal tract. A distinct lag time was obtained prior to the appearance of drug in plasma and correlated ( R 2 = 0.98) with disintegration time observed from scintigraphic images. However, following disintegration, no difference in pharmacokinetic parameters (AUC 0–6 dis, K el, C max) was observed. The current study highlighted the potential use of these formulations for chronopharmaceutical drug delivery.

Matrices containing NaCMC and HPMC: 1. Dissolution performance characterization

In this study hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) were used as polymeric carriers to improve controlled release performances of matrix tablets containing a soluble drug. The drug release behaviour of the systems containing these two polymers mixture and each material separately was investigated. To evaluate the effect of the dissolution medium pH, on the drug release performance, release tests were conducted at pH 1, 4.5 and 6.8. In vitro release studies demonstrated that the mixture of the two cellulose derivatives enables a better control of the drug release profiles at pH 4.5 and at 6.8 both in term of rate and mechanism. Texture analysis on the swollen tablets helps to understand drug release kinetic and mechanism. In fact, the results obtained confirm that a gel, which is characterized by high strength and consistence is less susceptible to erosion and chains disentanglement and the drug release mechanism is mainly governed by diffusion. On the contrary, gels, which show a low strength and texture, have low resistance to the fluid erosion action and the release of the active molecule is manly due to polymer relaxation and chains disentanglement moving the drug delivery kinetic towards an erosion/relaxation mechanism.

An Investigation into the In Vivo Performance Variability of pH Responsive Polymers for Ileo-Colonic Drug Delivery Using Gamma Scintigraphy in Humans

Gastrointestinal performance of tablets coated with pH responsive acrylic polymers (Eudragit) was investigated in human volunteers. Tablet cores were coated with Eudragit S dissolved in ethanol (organic), Eudragit S aqueous dispersion (aqueous), or Eudragit FS aqueous dispersion. Eight fasted volunteers received the tablets in a two-way crossover design—treatment 1: Eudragit S (organic) and Eudragit FS coated tablets; treatment 2: Eudragit S (aqueous) and Eudragit FS coated tablets. Eudragit FS coated tablets were included in both treatments to assess its intra-subject performance. Tablets were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. Tablets coated with Eudragit S (aqueous) disintegrated in all volunteers mainly in the proximal to mid small intestine. Eudragit S (organic) tablets failed to disintegrate in three out of eight volunteers, while disintegration was in the ileo-caecal junction and ascending colon in all others. Eudragit FS coated tablets disintegrated in 14 out of the 16 administrations. The Eudragit FS coated tablets that did disintegrate exhibited consistent intra- and inter-subject performance, with the site of disintegration focused on the ileo-caecal junction and ascending colon. These in vivo results correlate better with our published in vitro dissolution data in physiological bicarbonate buffers compared to phosphate buffers.

Influence of Crystal Structure on the Compaction Properties of n-Alkyl 4-Hydroxybenzoate Esters (Parabens)

The aim of the study is to examine the influence of slip planes on the nanoindentation hardness and compaction properties of methyl, ethyl, n-propyl, and n-butyl 4-hydroxybenzoate (parabens). Molecular modeling calculations, embodying the attachment energy concept, were performed to predict the slip planes in the crystal lattices, whereas the nanoindentation hardness of the crystals and the tensile strength of directly compressed compacts were measured. Unlike the other three parabens, methyl paraben has no slip planes in its crystal lattice, and its crystals showed greater nanoindentation hardness, corresponding to lower plasticity, whereas its tablets exhibited substantially lower tensile strength than those of ethyl, propyl, or butyl paraben. The nanoindentation hardness of the crystals and the tensile strength of directly compressed tablets were each found to correlate directly with the absence or presence of slip planes in the crystal structures of the parabens because slip planes confer greater plasticity. This work presents a molecular insight into the influence of crystal structural features on the tableting performance of molecular crystals in general and of crystalline pharmaceuticals in particular.

Compression Physics in the Formulation Development of Tablets

The advantages of high-precision dosing, manufacturing efficiency, and patient compliance make tablets the most popular dosage forms. Compaction, an essential manufacturing step in the manufacture of tablets, includes compression (i.e., volume reduction and particle rearrangement), and consolidation (i.e., interparticulate bond formation). The success of the compaction process depends not only on the physico-technical properties of drugs and excipients, especially their deformation behavior, but also on the choice of instrument settings with respect to rate and magnitude of force transfer. This review discusses various properties of drugs and excipients, such as moisture content, particle size and distribution, polymorphism, amorphism, crystal habit, hydration state, and lubricant and binder level of the blend that have an influence on compaction. Tableting speed and pre/main compression force profile, also have a bearing on the quality of the final tablet. Mechanistic aspects of tableting can be studied using, instrumented punches/dies, instrumented tableting machines, and compaction simulators. These have potential application in pharmaceutical research and development, such as studying basic compaction mechanism, process variables, scale-up parameters, trouble shooting problem batches, creating compaction data bank, and fingerprinting of new active pharmaceutical ingredients (APIs) or excipients. Also, the mathematical equations used to describe compaction events have been covered. These equations describe density-pressure relationships that predict the pressures required for achieving an optimum density. This understanding has found active application in solving the analytical problems related to tableting such as capping, lamination, picking, sticking, etc. Mathematical models, force-time, force-distance, and die-wall force parameters of tableting are used to describe work of compaction, elasticity' plasticity, and time dependent deformation behavior of pharmaceuticals. Various indices of tableting performance such as the bonding index, brittle fracture index, and strain index can be used to predict compaction related problems. Compaction related physico-technical properties of commonly used tableting excipients have been reviewed with emphasis on selecting suitable combination to minimize tableting problems. Specialized tools such as co-processing of API and excipients can be used to improve their functionality.

Magnetic images of the disintegration process of tablets in the human stomach by ac biosusceptometry

Oral administration of solid dosage forms is usually preferred in drug therapy. Conventional imaging methods are essential tools to investigate the in vivo performance of these formulations. The non-invasive technique of ac biosusceptometry has been introduced as an alternative in studies focusing on gastrointestinal motility and, more recently, to evaluate the behaviour of magnetic tablets in vivo. The aim of this work was to employ a multisensor ac biosusceptometer system to obtain magnetic images of disintegration of tablets in vitro and in the human stomach. The results showed that the transition between the magnetic marker and the magnetic tracer characterized the onset of disintegration (t50) and occurred in a short time interval (1.1 ± 0.4 min). The multisensor ac biosusceptometer was reliable to monitor and analyse the in vivo performance of magnetic tablets showing accuracy to quantify disintegration through the magnetic images and to characterize the profile of this process.

Development of defined mixed-culture fungal fermentation starter granulate for controlled production of rice wine

As a first step in the development of defined fungal starter granules for controlled winemaking from purple glutinous rice, the interaction of moulds and yeasts isolated from Vietnamese rice wine starters and the effect of some representative oriental herbs on the growth of moulds and yeasts were examined. Amylomyces rouxii and Saccharomyces cerevisae were shown to be compatible in mixed cultures, and the herbs “Tieu Hoi” (Fennel: Foeniculum vulgare Miller) and “Dinh Huong” (Clove: Syzygium aromaticum L.) which are used as supplementary ingredients by some local starter producers, were observed to stimulate the mould and yeast growth. Based on traditional starter manufacturing methods and modified on the basis of optimization experiments, a laboratory-scale manufacturing process for defined mixed-culture starter granules was established. In accordance with the national standard method, the wine produced with new experimental starter granules was found to have superior flavour and overall acceptability, compared with local commercial rice wines. Industrial relevance One of the major problems faced by commercial brewers of rice wine in Vietnam, is the variable quality and performance of the traditional starter tablets that are commonly used. The relevance of the present paper is that a stable, granulated starter has been developed, containing a defined mixture of mould and yeast cultures. This has proven to be shelf stable for more than 3 months, producing a very well accepted quality of wine.

Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain

It is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. Eleven Caucasian patients (seven male and 4 female, aged 34-75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double-blind, cross-over trial, consisting of three 1-day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 microg, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated by noncompartment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire. The data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 microg) for dose adjusted AUC (F = 0.42, P = 0.6660), dose adjusted C(max) (F = 0.08, P = 0.9206) and Tmax (F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400-100microg) in dose adjusted AUC from the three-period crossover analysis was -0.016 min.ng/ml (t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25-40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. t(max) increased from 39.7 +/- 17.4 to 48.7 +/- 26.3 and 56.7 +/- 24.6 min for the 100, 200 and 400 microg doses, respectively. Adverse events were few and did not increase with increasing dose. With this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8-11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.

Effect of Granules Properties on the In-vitro and In-vivo Performance of Ibuprofen Sustained Release Matrix Tablets

The impact of variations in the wet granulation step during the manufacturing process on the in-vitro and in-vivo performance of ibuprofen sustained release matrix tablets was investigated. Two batches were produced under different wet granulation conditions. The granules of the first batch (T1) were characterized by having a lower bulk density (0.56 g/ml), a higher percentage of fines (56.7% w/w) and a smaller geometric mean diameter (dg), 600 µm. While the granules of batch (T2) were characterized by having a more coherent properties, a higher bulk density (0.66 g/ml), a lower percentage of fines (36.9% w/w) and a larger dg, 720 µm. Three large scale production batches (B1, B2, B3) were manufactured similarly to T2 and found to have granules possessing similar properties. In-vitro tests showed that tablets of T1 had a statistically significant higher release rate constant than tablets of either T2, B1 ,B2 or B3. In-vivo tests were done using T1 and T2 tablets. Although T1 and T2 were bioequivalent with respect to Cmax and AUC, T2 exhibited a statistically significant longer sustained release characteristics than T1 (P&lt;0.05).