Development, characterization and performance evaluation of oro-dispersible tablet containing aceclofenac hydroxypropyl-β-cyclodextrin binary system

The purpose of this research was to mask the intensely bitter taste of aceclofenac (ACF) and to formulate oro dispersible tablet (ODT) of the taste-masked drug. Taste masking was done by complexing aceclofenac with Hydroxypropyl-β-Cyclodextrin (HPβCD) by different methods. Phase solubility studies indicated complex with possible stoichiometry of 1:1 and a stability constant of 221.11 M^?1. The complexes were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry studies. The characterization studies confirmed inclusion of the ACF within the nonpolar cavity of HPβCD in the neutralization method (NM). Remarkable improvement in the in vitro drug release profiles in pH 6.8 phosphate buffer was observed with all complexes, especially the neutralization. The complexes of ACF–HPβCD (1:1) was compressed into tablet and properties of tablets such as tensile strength, wetting time, in vitro disintegration time, and disintegration in the oral cavity were investigated to elucidate the wetting and disintegration characteristics of tablets. Polyplasdone XL-10 7% wt/wt gave the minimum disintegration time. Tablets of batch F4 containing Avicel 200 and 7% wt/wt Polyplasdone XL-10 showed faster disintegration, within 12 s, than the marketed tablet (128 s). Good correlation between in vitro disintegration with in-house developed method and in the oral cavity was recognized. Taste evaluation of ODT in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value. Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity.     

Improvement of HPMC tablet disintegration by the addition of inorganic salts

Effects of inorganic salts on disintegration of hydroxypropylmethylcellulose (HPMC) matrix tablets have been studied. Adding disintegrants, such as Ac-di-sol, Primojel, Kolidon-CL, or low substituted hydroxypropylcellulose (L-HPC) to HPMC matrix tablets had no effect on disintegration property. Disintegration time was improved by adding NaHCO(3), KH(2)PO(4), K(2)SO(4), KCl, or NaCl to the HPMC tablets as tablet components. On the other hand, addition of Na(2)CO(3), or Na(2)SO(4) to the tablets showed no improvement of disintegration. The heat of dissolution of inorganic salts that improved disintegration of tablets was endothermic, while that of inorganic salts that did not improve disintegration of tablets was exothermic. These results suggested that the thermal environment and ionic strength inside the tablet might affect the disintegration of HPMC matrix tablets.     

Properties of gastroretentive sustained release tablets prepared by combination of melt/sublimation actions of L-menthol and penetration of molten polymers into tablets

A novel floating sustained release tablet having a cavity in the center was developed by utilizing the physicochemical properties of L-menthol and the penetration of molten hydrophobic polymer into tablets. A dry-coated tablet containing famotidine as a model drug in outer layer was prepared with a L-menthol core by direct compression. The tablet was placed in an oven at 80°C to remove the L-menthol core from tablet. The resulting tablet was then immersed in the molten hydrophobic polymers at 90°C. The buoyancy and drug release properties of tablets were investigated using United States Pharmacopeia (USP) 32 Apparatus 2 (paddle 100 rpm) and 900 ml of 0.01 N HCl. The L-menthol core in tablets disappeared completely through pathways in the outer layer with no drug outflows when placed in an oven for 90 min, resulting in a formation of a hollow tablet. The hollow tablets floated on the dissolution media for a short time and the drug release was rapid due to the disintegration of tablet. When the hollow tablets were immersed in molten hydrophobic polymers for 1 min, the rapid drug release was drastically retarded due to a formation of wax matrices within the shell of tablets and the tablets floated on the media for at least 6 h. When Lubri wax? was used as a polymer, the tablets showed the slowest sustained release. On the other hand, faster sustained release properties were obtained by using glyceryl monostearate (GMS) due to its low hydrophobic nature. The results obtained in this study suggested that the drug release rate from floating tablets could be controlled by both the choice of hydrophobic polymer and the combined use of hydrophobic polymers.     

A novel method for predicting disintegration time in the mouth of rapidly disintegrating tablet by compaction analysis using TabAll

A tableting process analyzer (TabAll) was used to predict disintegration time in the mouth of rapidly disintegrating tablet. Analyzer profiles recorded upper punch displacement and die wall force encountered during tablet processing. Changes in the mixing ratio of spherical sugar granules and microcrystalline cellulose or lactose affected upper punch displacement and die wall force profiles. Analysis of the compaction process revealed a strong association between disintegration time in the mouth and stationary time, relaxation time of upper punch displacement, and relaxation time of die wall force; disintegration time in the mouth decreased as the three parameters increased. Thus, analysis of the compaction process is useful for predicting disintegration time in the mouth of rapidly disintegrating tablet, which can assist the formulation of new rapidly disintegrating tablets.     

Evaluation of the disintegration time of rapidly disintegrating tablets via a novel method utilizing a CCD camera

Many kinds of rapidly disintegrating or oral disintegrating tablets (RDT) have been developed to improve the ease of tablet administration, especially for elderly and pediatric patients. In these cases, knowledge regarding disintegration behavior appears important with respect to the development of such a novel tablet. Ordinary disintegration testing, such as the Japanese Pharmacopoeia (JP) method, faces limitations with respect to the evaluation of rapid disintegration due to strong agitation. Therefore, we have developed a novel apparatus and method to determine the dissolution of the RDT. The novel device consists of a disintegrating bath and CCD camera interfaced with a personal computer equipped with motion capture and image analysis software. A newly developed RDT containing various types of binder was evaluated with this protocol. In this method, disintegration occurs in a mildly agitated medium, which allows differentiation of minor distinctions among RDTs of different formulations. Simultaneously, we were also able to detect qualitative information, i.e., morphological changes in the tablet during disintegration. This method is useful for the evaluation of the disintegration of RDT during pharmaceutical development, and also for quality control during production.     

Effect of formulated ingredients on rapidly disintegrating oral tablets prepared by the crystalline transition method

The aim of this article was to determine the optimal ingredients for the rapidly disintegrating oral tablets prepared by the crystalline transition method (CT method). The effect of ingredients (diluent, active drug substance and amorphous sugar) on the characteristics of the tablets was investigated. The ingredients were compressed and the resultant tablets were stored under various conditions. The oral disintegration time of the tablet significantly depended on diluents, due to differences in the penetration of a small amount of water in the mouth and the viscous area formed inside the tablet. The oral disintegration time was 10-30 s for tablets with a tensile strength of approximately 1 MPa, when erythritol, mannitol or xylitol was used as the diluent. The increase in the tensile strength of tablets containing highly water-soluble active drug substances during storage was as large as that of tablets without active drug substances, while the increase in the tensile strength of tablets containing low water-soluble active drug substances was small. It was therefore found that highly water-soluble active drug substances were more suitable for the formulation prepared by the CT method than low water-soluble active drug substances. Irrespective of the type of amorphous sugar (amorphous sucrose, lactose or maltose) used, the porosity of tablets with 1 MPa of tensile strength was 30-40%, and their oral disintegration time was 10-20 s. The optimal ingredients for rapidly disintegrating oral tablets with reasonable tensile strength and disintegration time were therefore determined from these results.     

A new method for disintegration studies of rapid disintegrating tablet

The aim of this study was to develop a simple and suitable disintegration method specific for rapid disintegrating tablets (RDTs). The new disintegration method that we propose employs a rotary shaft to exert mechanical pressure on the RDT. To assess our method, we manufactured several placebo RDTs and exposed them to severe storage conditions (60 degrees C/75%RH for 1 week) in order to obtain RDTs with a wide range of disintegration times. These placebo RDTs were utilized to compare the disintegration times obtained by several methods, including the proposed method. As expected, the disintegration time of the placebo RDTs in human sensory test varied widely. The disintegration times determined by the conventional disintegration test were in good correlation to those in human sensory test, but the slope was far from 1 (0.241). There was no correlation between the disintegration time of RDTs in human sensory test and those determined by the conventional dissolution test. In contrast, we acquired good correlation between the disintegration times obtained with the new method and those in human sensory test, and the slope was very close to 1 (0.858). We attribute this to the use of mechanical stress in the new method, similar to that the RDT is subject to in the oral cavity. We therefore concluded that the proposed method was suitable for the measurement of the disintegration time of RDTs. This new method might provide a valuable approach for the establishment of the official disintegration test for RDTs in the future.     

Preparation and evaluation of tablets rapidly disintegrating in saliva containing bitter-taste-masked granules by the compression method.

The aim of this study was to prepare, using taste-masked granules, tablets which can rapidly disintegrate in saliva (rapidly disintegrating tablet), of drugs with bitter taste (pirenzepine HCl or oxybutynin HCl). The taste-masked granules were prepared using aminoalkyl methacrylate copolymers (Eudragit E-100) by the extrusion method. None of the drugs dissolved from the granules (% of dissolved, < 5%) even at 480 min at pH 6.8 in the dissolution test. However, the drugs dissolved rapidly in the medium at pH 1.2 in the dissolution test. Rapidly disintegrating tablets were prepared using the prepared taste-masked granules, and a mixture of excipients consisting of crystalline cellulose (Avicel PH-102) and low-substituted hydroxypropylcellulose (L-HPC, LH-11). The granules and excipients were mixed well (mixing ratio by weight, crystalline cellulose: L-HPC = 8:2) with 1% magnesium stearate, and subsequently compressed at 500-1500 kgf in a single-punch tableting machine. The prepared tablets (compressed at 500 kgf) containing the taste-masked granules have sufficient strength (the crushing strength: oxybutynin tablet, 3.5 kg; pirenzepine tablet, 2.2 kg), and a rapid disintegration time (within 20 s) was observed in the saliva of healthy volunteers. None of the volunteers felt any bitter taste after the disintegration of the tablet which contained the taste-masked granules. We confirmed that the rapidly disintegrating tablets can be prepared using these taste-masked granules and excipients which are commonly used in tablet preparation.     

Glycine and L-Lysine Ionization in a Mixed Aqueous Solution

In mixed aqueous solution of glycine and L-lysine the ionization of both amino acids increases due to the proton transfer from glycine zwitterion to lysine zwitterion. This is manifested by a considerable nonlinear (pairwise interaction of amino acids) increase in the mixed solution electroconductivity at high amino acid concentrations. The solution pH varies negligibly, as the amino acids in aqueous solutions demonstrate buffering. The refraction coefficient additively depends on glycine and L-lysine concentrations.     

Evaluation of the disintegration properties of commercial famotidine 20 mg orally disintegrating tablets using a simple new test and human sensory test

The purpose of this study was to demonstrate the usefulness and broad-applicability of a simple disintegration test method for orally disintegrating tablets (ODT). Eight types of commercial famotidine 20 mg orally disintegrating tablets with different physical properties (formulation, manufacturing method, tablet weight, shape, diameter, thickness, etc.), were used. Disintegration times of these tablets were evaluated employing human sensory test, conventional disintegration test, and the new proposed disintegration test. The human sensory test was performed in 5 healthy volunteers. In the conventional disintegration test, the disintegration apparatus described in the Japanese Pharmacopeia (JP 1(st)) was used. Our proposed new test which is characterized by a rotating shaft with a low weight (10, 15 g) and rotation speed (10, 25, 50 rpm) was evaluated using tablets with and without storage under severe conditions (60 degrees C/75%RH for 1 week). The disintegration times of famotidine 20 mg orally disintegrating tablets in human sensory test varied from 9 to 32 s. In contrast, disintegration times in the conventional test were prolonged to over 300 s. Disintegration times in the new proposed test were close to those in human sensory test. Especially, when the new test was conducted with 15 or 10 g weight and 25 rpm, the slope (human sensory test vs. new proposed test) was almost 1. We were able to demonstrate that the new proposed test was useful to estimate the actual human disintegration time.     

Supported absorption of CO2 by tetrabutylphosphonium amino acid ionic liquids

A new type of "task specific ionic liquid", tetrabutylphosphonium amino acid [P(C4)4][AA], was synthesized by the reaction of tetrabutylphosphonium hydroxide [P(C4)4][OH] with amino acids, including glycine, L-alanine, L-beta-alanine, L-serine, and L-lysine. The liquids produced were characterized by NMR, IR spectroscopies, and elemental analysis, and their thermal decomposition temperature, glass transition temperature, electrical conductivity, density, and viscosity were recorded in detail. The [P(C4)4][AA] supported on porous silica gel effected fast and reversible CO2 absorption when compared with bubbling CO2 into the bulk of the ionic liquid. No changes in absorption capacity and kinetics were found after four cycles of absorption/desorption. The CO2 absorption capacity at equilibrium was 50 mol % of the ionic liquids. In the presence of water (1 wt %), the ionic liquids could absorb equimolar amounts of CO2. The CO2 absorption mechanisms of the ionic liquids with and without water were different.     

An SFG study of interfacial amino acids at the hydrophilic SiO2 and hydrophobic deuterated polystyrene surfaces

Sum frequency generation (SFG) vibrational spectroscopy was employed to characterize the interfacial structure of eight individual amino acids--L-phenylalanine, L-leucine, glycine, L-lysine, L-arginine, L-cysteine, L-alanine, and L-proline--in aqueous solution adsorbed at model hydrophilic and hydrophobic surfaces. Specifically, SFG vibrational spectra were obtained for the amino acids at the solid-liquid interface between both hydrophobic d(8)-polystyrene (d(8)-PS) and SiO(2) model surfaces and phosphate buffered saline (PBS) at pH 7.4. At the hydrophobic d(8)-PS surface, seven of the amino acids solutions investigated showed clear and identifiable C-H vibrational modes, with the exception being l-alanine. In the SFG spectra obtained at the hydrophilic SiO(2) surface, no C-H vibrational modes were observed from any of the amino acids studied. However, it was confirmed by quartz crystal microbalance that amino acids do adsorb to the SiO(2) interface, and the amino acid solutions were found to have a detectable and widely varying influence on the magnitude of SFG signal from water at the SiO(2)/PBS interface. This study provides the first known SFG spectra of several individual amino acids in aqueous solution at the solid-liquid interface and under physiological conditions.     

Hydroxypropyl methylcellulose based cephalexin extended release tablets: influence of tablet formulation,hardness and storage on in vitro release kinetics

The object of this study was to develop hydroxypropyl methylcellulose (HPMC) based cephalexin extended release tablet, which can release the drug for six hours in predetermined rate. Twenty-one batches of cephalexin tablets were prepared by changing various physical and chemical parameters, in order to get required theoretical release profile. The influences of HPMC, microcrystalline cellulose powder (MCCP), granulation technique, wetting agent and tablet hardness on cephalexin release from HPMC based extended release tablets were studied. The formulated tablets were also characterized by physical and chemical parameters. The dissolution results showed that a higher amount of HPMC in tablet composition resulted in reduced drug release. Addition of MCCP resulted in faster drug release. Tablets prepared by dry granulation was released the drug slowly than the same prepared with a wet granulation technique. Addition of wetting agent in the tablets prepared with dry granulation technique showed slower release. An increase in tablet hardness resulted in faster drug release. Tablets prepared with a wet granulation technique and having a composition of 9.3% w/w HPMC with a hardness of 10-12 kg/cm(2) gave predicted release for 6 h. The in vitro release data was well fit in to Higuchi and Korsmeyer-Peppas model. Physical and chemical parameters of all formulated tablets were within acceptable limits. One batch among formulated twenty-one batches was successful and showed required theoretical release. The effect of storage on in vitro release and physicochemical parameters of successful batch was studied and was found to be in acceptable limits.     

The effects of adsorbed water on tensile strength and Young's modulus of moldings determined by means of a three-point bending method

Young's moduli (E) of three representative tableting excipients and their mix powders were measured for compressed rectangular beam specimens over a range of porosities using a three-point bending technique. We also examined the effects of the amount of water adsorbed on the tensile strength of these specimens. The maximal tensile strength (sigma(max)) decreased with increasing water vapor adsorption for microcrystalline cellulose (MCC) and mixed powders of lactose and MCC. Sigma(max) increased with increasing compression stress and specimen weight for all samples. Sigma(max) of an alpha-lactose and cornstarch mixture with a ratio of 7:3 showed a large value. Young's modulus (E) and the crushing energy (CE) of MCC were larger than those of the other samples. Young's modulus of specimens decreased as the proportion of alpha-lactose increased. Disintegration time (DT) of tablets comprised of lactose and MCC mixture was much faster than those of tablets comprised of individual powders. This appeared to demonstrate the effect of MCC swelling on the disintegration time of the tablet. The disintegration time of the lactose/cornstarch series increased only when Young's modulus increased sharply.     

Formulation and optimization of orally disintegrating tablets of sumatriptan succinate

The aims of the present research were to mask the intensely bitter taste of sumatriptan succinate and to formulate orally disintegrating tablets (ODTs) of the taste masked drug. Taste masking was performed by coating sumatriptan succinate with Eudragit EPO using spray drying technique. The resultant microspheres were evaluated for thermal analysis, yield, particle size, entrapment efficiency and in vitro taste masking. The tablets were formulated by mixing the taste masked microspheres with different types and concentrations of superdisintegrants and compressed using direct compression method followed by sublimation technique. The prepared tablets were evaluated for weight variation, thickness, hardness, friability, drug content, water content, in vitro disintegration time and in vitro drug release. All the tablet formulations disintegrated in vitro within 37-410 s. The optimized formulation containing 5% Kollidon CL-SF released more than 90% of the drug within 15 min and the release was comparable to that of commercial product (Suminat?). In human volunteers, the optimized formulation was found to have a pleasant taste and mouth feel and disintegrated in the oral cavity within 41 s. The optimized formulation was found to be stable and bioequivalent with Suminat?.     

Solvation thermodynamics of L-cystine,L-tyrosine,and L-leucine in aqueous-electrolyte media

Solubilities of L-cystine, L-tyrosine, and L-leucine in aqueous NaCl media at 298.15 K have been studied. Indispensable and related solvent parameters such as molar mass, molar volume, etc., were also determined. The results are used to evaluate the standard transfer Gibbs free energy, cavity forming enthalpy of transfer, cavity forming transfer Gibbs free energy and dipole-dipole interaction effects during the course of solvation. Various weak interactions involving solute–solvent or solvent–solvent molecules were characterized in order to find their role on the solvation of these amino acids.     

Some physical properties of tabletted seed of Garcinia kola (HECKEL)

The formulation of Garcinia kola seeds into tablet dosage form and evaluation of some physical properties of the tablets are presented. A chemical assay was conducted on the dry, powdered seeds as well as the crude aqueous extract of the seeds. The dry powdered seeds contain 0.003% of flavonoids while the crude extract contained 0.007% of flavonoids based on rutin used as the standard. The powdered material (50 mg) and crude extract (10 mg) were formulated into tablets using the wet granulation method. Named binders were evaluated in these formulations. The various tablet parameters were evaluated, namely: weight variation, thickness and diameter, hardness, friability, disintegration time, dissolution profile and content uniformity. The results indicated that the tablets had good disintegration time, dissolution and hardness/friability profiles. Tablets formulated with starch had the best disintegration properties but were consequently very friable. Tablets formulated from 10 mg of the crude extract needed a larger proportion of diluents, which affected the tablet properties.     

氨基酸从水到尿素水溶液中的迁移焓研究

用微量量热法测定甘氨酸、L-丙氨酸、L-丝氨酸在水和尿素水溶液中的溶解焓, 计算得到氨基酸从水到尿素水溶液的迁移焓, 并根据水合结构相互作用模型予以讨论. 结果表明, 氨基酸两性离子与尿素分子的静电作用以及两性离子头部与尿素分子的结构相互作用对氨基酸迁移焓有负贡献, 氨基酸侧链与尿素分子的结构相互作用依其亲水性或疏水性分别对迁移焓有负贡献或正贡献. 在实验浓度范围(0～13 mol/kg)内, 三种氨基酸的迁移焓总体上随尿素浓度的增加而下降, 其大小依次为L-丝氨酸＜甘氨酸＜L-丙氨酸, 氨基酸迁移焓的差异反映了溶质-溶剂结构相互作用的变化.     

Application of nilvadipine solid dispersion to tablet formulation and manufacturing using crospovidone and methylcellulose as dispersion carriers

Nilvadipine (NIL) solid dispersion using crospovidone (Cross-linked-N-vinyl-2-pyrolidone, cl-PVP) and methylcellulose (MC) as carriers was applied to tablet formulation. Several grades of cl-PVP and MC were used, and their influence on tablet properties such as hardness, disintegration, dissolution and chemical stability were investigated. The agitation granulation method was used for preparation of solid dispersion granules, and the granules were compressed using a rotary tableting machine, and finally the obtained tablets were coated with film. As the particle size of cl-PVP decreased, hardness and apparent solubility were increased, while dissolution rate was lowered. When a higher viscosity grade of MC was used, hardness and dissolution rate were increased, and apparent solubility did not change. All batches of tablets were chemically stable at 40 degrees C, 75% relative humidity (R.H.) for six months. Finally, tablets with enhanced dissolution properties were obtained by using Polyplasdone XL-10 and Metolose SM-25 as the grades of cl-PVP and MC, respectively. These formulation tablets showed higher solubility and dissolution rate during storage as well as initial indicating good physical stability.     

Preparation of rapidly disintegrating tablets containing itraconazole solid dispersions

The disintegratability of tablets prepared from two types of solid dispersions containing the water-soluble polymer TC-5 and the enteric polymer HP-55 as an excipient were compared. The disintegratability was better in the tablets of solid dispersions containing non-water-soluble HP-55 than those containing TC-5. In consideration of the dissolubility of solid dispersions containing HP-55, the mean diameter of the solid dispersion (coating powder) must be controlled to 120 microm or less, but as this markedly increases the adhesion/aggregation tendency of the particles (angle of repose: 47 degrees ), control of the adhesion/aggregation tendency emerged as another problem. Therefore, surface-modification was performed in a high-speed agitating granulator using 0.1% light anhydrous silicic acid as a surface modifier, and marked improvement in the flowability was observed. This made continuous tableting using a rotary tablet machine possible even with the poorly flowable solid dispersions. Also, in tableting of the solid dispersions, no recrystallization of amorphous itraconazole by the tableting pressure was observed, and the tablets maintained satisfactory dissolubility. Moreover, it was possible to obtain the rapidly disintegrating tablets with very satisfactory properties, i.e., a tablet hardness of 30 N or higher and a disintegration time of 30 s or less, by the addition of croscarmellose as a disintegrant at 2% to the surface-modified solid dispersion and selection of the tableting pressure at 4.5 kN.