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.     

Disintegration test to measure lot-to-lot variations of vaginal tablets

Attempts were made to investigate the disintegration test for vaginal tablets. Disintegration tests were done for four different commercial vaginal tablets (three lots each) by the watch glass method and Japanese Pharmacopoeia (JP) disintegration method, and the resulting profiles were compared to those by the modified British Pharmacopoeia (BP) method on a point of lot-to-lot variation of the disintegration times. The disintegration time of every tablet by the modified BP method was longest, followed by the watch glass method, and finally by the JP disintegration method. The results for lot-to-lot differences in disintegration times by the modified BP method were similar to those by the watch glass method. However, such lot-to-lot differences as found by the modified BP method and watch glass method were not always observed by the JP disintegration method. It was concluded from these results that the modified BP method was most suitable for investigating lot-to-lot differences in the disintegration of vaginal tablets.     

The quantitative prediction of bitterness-suppressing effect of sweeteners on the bitterness of famotidine by sweetness-responsive sensor

The purpose of the present study was the quantitative prediction of the bitterness-suppressing effect of sweeteners (sucrose or sugar alcohols) on the bitterness of famotidine (or quinine sulfate as control) solutions using an artificial taste sensor. Firstly, we examined the response characteristics of the sensor response to sweetness. The sensor membrane is charged negatively in the presence of sweeteners, which tend to receive protons from one of the components of the sensor membrane. The magnitude of the sensor response was shown to increase in direct proportion to the concentration of the sweetener. Secondly, we used direct or indirect methods to evaluate and predict the bitterness-suppressing effect of sweeteners on 1 mg/ml famotidine and 81.4 microM quinine sulfate solutions. In direct method, a regression between the sensor output of the sweetness-responsive sensor and the bitterness intensity obtained in human gustatory tests of famotidine solutions containing sweeteners at various concentrations, was performed. As a result, we were able to predict directly the bitterness intensity of the mixed solution. Finally, we also evaluated the bitterness intensity of the dissolution media of commercially available, orally disintegrating tablets containing famotidine by the combined usage of bitterness- and sweetness-responsive sensor. We found that the sugar alcohols in the tablet seem to be effective in the bitterness-suppression of famotidine from these tablets, especially in the initial phase (within 30 s) of the disintegration process.     

Pharmacokinetics of acetaminophen from rapidly disintegrating compressed tablet prepared using microcrystalline cellulose (PH-M-06) and spherical sugar granules

The aim of the present study was to evaluate the bioavailability of a drug from rapidly disintegrating tablets prepared using fine spherical crystalline cellulose (PH-M-06) and spherical sugar granules (Nonpareil, NP). Rapidly disintegrating tablets containing acetaminophen as the model drug in combination with a mixture of NP-108 (purified n-mannitol) and PH-M-06 were prepared. Plasma concentration profiles and pharmacokinetic parameters of acetaminophen in rabbits were investigated after oral administration of the prepared tablets. No significant difference in Cmax and AUC(0-infinity) of acetaminophen between rapidly disintegrating tablets and conventional tablets was observed after direct administration of these tablets into the stomach of rabbits. However, tmax (15 min) of acetaminophen from rapidly disintegrating tablets was significantly (p<0.05) shorter than that from conventional tablets (130 min). The same tmax was observed for rapidly disintegrating tablets and solution. When suitable excipients such as fine spherical microcrystalline cellulose (PH-M series) and spherical sugar granules (NP series) were used, rapidly disintegrating tablets could be prepared by the conventional direct compression method. According to the results of moment analysis, the mean residence time (MRT) obtained between both rapidly disintegrating and conventional tablets indicates that the mean absorption time (MAT) from these tablets is approximately 60 and 90 min, respectively. This difference in MAT between the two tablets may be caused by the difference in the sum of the mean dissolution time (MDT) and the mean disintegration time (MDIT) of these tablets. Rapidly disintegrating tablets allow rapid absorption of the drug compared with conventional tablets.     

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.     

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?.     

Preparation and evaluation of orally rapidly disintegrating tablets containing taste-masked particles using one-step dry-coated tablets technology

In this study, in order to address the problems with manufacturing orally rapidly disintegrating tablets (ODT) containing functional (taste masking or controlled release) coated particles, such as the low compactability of coated particles and the rupture of coated membrane during compression, a novel ODT containing taste-masked coated particles (TMP) in the center of the tablets were prepared using one-step dry-coated tablets (OSDrC) technology. As a reference, physical-mixture tablets (PM) were prepared by a conventional tableting method, and the properties of the tablets and the effect of compression on the characteristics of TMP were evaluated. OSDrC was found to have higher tensile strength and far lower friability than PM, but the oral disintegration time of OSDrC is slightly longer than that of PM following high compression pressure. Consequently, OSDrC approaches the target tablet properties of ODT, whereas PM does not. The deformation of TMP in OSDrC due to compression is slight, and the release rate of acetaminophen (AAP) from OSDrC is the same as from TMP. However, TMP on the surface of PM are considerably deformed, and the release rate of AAP from PM is faster than from TMP. These findings suggest that OSDrC technology is a useful approach for preparing ODT containing functional coated particles. Furthermore, we demonstrate that the elastic recovery of tablets can affect differences in the properties of OSDrC, PM and placebo tablets (PC).     

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.     

Formulation study for orally disintegrating tablet using partly pregelatinized starch binder

In this study, we aimed to design orally disintegrating tablets by employing a formulation design approach that enables the production of such tablets in the same facilities used for the production of solid dosage forms on an industrial scale. First, we examined the relationships between the types of binders used in the tablets and the properties of orally disintegrating tablets prepared by the wet granulation method. Results revealed that partly pregelatinized starch is a relatively suitable binder for orally disintegrating tablets as it also serves as a disintegrant. Next, we employed a central composite design for 2 factors, namely, corn starch and partly pregelatinized starch, in order to design granules suited for orally disintegrating tablets composed of D-mannitol, corn starch or partly pregelatinized starch. The effects of these 2 factors on 3 types of responses, namely, 50% granule size, compressing index and disintegrating index, were analyzed with a software package, and responses to changes in the factors were predicted. This study investigated the effects of binder type and binder content in orally disintegrating tablets, and provided evidence that the binder exerts a strong influence on tablet properties, and is therefore an important component of orally disintegrating tablets.     

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.     

Development and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen granules prepared by hot melt extrusion

In the current study Ibuprofen was embedded in a methacrylate copolymer (Eudragit^® EPO) matrix to produce solid dispersions by hot-melt extrusion (HME) processing. The obtained granules were incorporated in orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and crosslinked polyvinylpyrrolidone grades while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets which included porosity, hardness, friability and dissolution profiles were further evaluated and compared with Nurofen^® Meltlet ODTs. The taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and improved tablet palatability.     

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.     

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.     

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.     

Development of fast disintegrating compressed tablets using amino acid as disintegration accelerator: evaluation of wetting and disintegration of tablet on the basis of surface free energy

A fast disintegrating compressed tablet was formulated using amino acids, such as L-lysine HCl, L-alanine, glycine and L-tyrosine as disintegration accelerator. The tablets having the hardness of about 4 kgf were prepared and the effect of amino acids on the wetting time and disintegration time in the oral cavity of tablets was examined on the basis of surface free energy of amino acids. The wetting time of the tablets increased in the order of L-lysine HCl, L-alanine, glycine and L-tyrosine, whereas the disintegration time in the oral cavity of the tablets increased in the order of L-alanine, glycine, L-lysine HCl and L-tyrosine. These behaviors were well analyzed by the introduction of surface free energy. When the polar component of amino acid was large value or the dispersion component was small value, faster wetting of tablet was observed. When the dispersion component of amino acid was large value or the dispersion component was small value, faster disintegration of tablet was observed, expect of L-tyrosine tablet. The fast disintegration of tablets was explained by the theory presented by Matsumaru.     

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.     

Spray dried excipient base: a novel technique for the formulation of orally disintegrating tablets

Orally disintegrating tablets (ODT) are gaining popularity over conventional tablets due to their convenience in administration and suitability for patients having dysphagia. Moreover no water is required for swallowing the tablets and hence suitable for geriatric, pediatric and traveling patients. The purpose of this study is to assess the suitability of spray dried excipient base in the formulation of ODTs of Valdecoxib (low aqueous solubility) and Metoclopramide (high aqueous solubility). Spray dried excipient base was prepared using Scientech spray drier. Super disintegrants (such as Ac-Di-Sol, Kollidon CL, sodium starch glycolate), diluent (mannitol) alongwith sweetening agent (aspartame) were used in the formulation of tablets. The tablets were evaluated for hardness, friability, water absorption ratio, disintegration time (DT) and in vitro drug release. Using the same excipients, the tablets were prepared by direct compression and were evaluated in the similar way. Maximum drug release and minimum DT were observed with Kollidon CL excipient base as compared to tablets prepared by direct compression, showing the superiority of the spray dried excipient base technique over direct compression technique.     

Combined use of cyclodextrins and hydroxypropylmethylcellulose stearoxy ether (Sangelose®) for the preparation of orally disintegrating tablets of type-2 antidiabetes agent glimepiride

Despite recent advances in the formulation of orally disintegrating tablets (ODTs), the efforts to enhance the swallowing of the drug after disintegration have been limited. In this study, the feasibility of the combined use of cyclodextrins (CyDs) and a functional drug carrier, hydroxypropylmethylcellulose stearoxy ether (Sangelose^®) was investigated to improve usability of ODTs. Glimepiride, a potent third generation hypoglycemic agent for type 2 diabetes was used as a model drug, because it is poorly water-soluble and elimination half life is fairly short. The direct compression method was employed for the preparation of glimepiride tablets, containing CyDs and Sangelose^®, and various characteristics of the tablets were examined. In the cases of α-CyD and β-CyD, a short disintegration time with an appropriate hardness was obtained, complying with ODT criteria. On the other hand, γ-CyD, HP-β-CyD and HB-β-CyD increased in the hardness and disintegration time of the tablets. The rheological evaluation revealed that CyDs, except γ-CyD, significantly reduced the viscosity of the fluids after disintegration of the tablets, suggesting an ease of swallowing. This was ascribable to the complexation of the hydrophobic stearoyl moiety of Sangelose^® with CyDs after dissolution, leading to the inhibition of the polymer–polymer interaction of Sangelose^® and to the decrease in viscosity of the solution. The interaction of glimepiride with α- and β-CyDs was studied by the solubility method, demonstrating that glimepiride formed water-soluble complexes with these CyDs. Results obtained here suggested that α-CyD and β-CyD can be particularly useful for the Sangelose^®-based ODT formulation, compared to γ-CyD, HP-β-CyD and HB-β-CyD, because of the short disintegration time of the tablets containing α-CyD and β-CyD, their shear-thinning effect on Sangelose^® solutions and their solubility enhancing effect on the drug.     

Preparation of rapidly disintegrating tablet using new types of microcrystalline cellulose (PH-M series) and low substituted-hydroxypropylcellulose or spherical sugar granules by direct compression method

To decrease the sensation of roughness when a tablet, which is rapidly disintegrated by saliva (rapidly disintegrating tablet), is orally taken, we prepared rapidly disintegrating tablets using microcrystalline cellulose (Avicel PH-M series), a new type of pharmaceutical excipient that is spherical and has a very small particle size (particle size, 7-32 microm), instead of conventional microcrystalline cellulose (PH-102) used in the formulation of tablets containing acetaminophen or ascorbic acid as model drugs for tableting study. Tablets (200 mg) prepared using spherical microcrystalline cellulose, PH-M-06, with the smallest particle size (mean value, 7 microm) had sufficient crushing tolerance (approximately, 8 kg) and were very rapidly, disintegrated (within 15 s) when the mixing ratio of PH-M-06 to low-substituted hydroxypropylcellulose (L-HPC) was 9:1. Sensory evaluation by volunteers showed that PH-M-06 was superior to PH-102 in terms of the feeling of roughness in the mouth. Consequently, it was found that particle size is an important factor for tablet preparation using microcrystalline cellulose. It is possible to prepare drugs such as acetaminophen and ascorbic acid (concentration of approximately 50%) in the tablet form using PH-NM-06 in combination with L-HPC as a good disintegrant at a low compression force (1-6 kN). To solve the problem of poor fluidity in the preparation of these tablets, we investigated the use of spherical sugar granules (Nonpareil, NP-101 (sucrose and starch, composition ratio of 7:3), NP-103 (purified sucrose), NP-107 (purified lactose) and NP-108 (purified D-mannitol)). Rapidly disintegrating tablets can be prepared by the direct compression method when suitable excipients such as fine microcrystalline cellulose (PH-M-06) and spherical sugar granules (NP) are used.     

Evaluation of enteric coated tablet sensitive to pancreatic lipase. I. In vitro disintegration test.

We designed a new enteric coated preparation which is pH independent and functions by pancreatic lipase activity in the duodenum. Triolein (TO) and trilaurin (TL) were selected as lipase sensitive components and ethylcellulose (EC) was used as the support film for TO and TL. Tablets (330 mg, d = 10 mm) containing a model drug, sulfamethizole (SMZ), were coated with 1% each of TO, TL and EC solution by the fluidized bed coating technique. Disintegration tests were carried out in the media including JPXI 1st fluid (pH 1.2, JP-1), 2nd fluid (pH 6.8, JP-2) and JP-2 with gall powder and pancreatic lipase (JP-2-GL). The lag time of disintegration of the tablet (TOTL-Tab) coated 5-7 mg/tab with TO, TL and EC was about 10 min and all of the tablets disintegrated completely within 30 min in JP-2-GL. However, in the other media, which did not contain lipase, TOTL-Tab did not disintegrate for at least 2 h. It was confirmed that TO and TL in the coating film were digested by lipase. In addition, the tensil strength of the film decreased quickly after incubation in JP-2-GL. These results suggest that the application of TO, TL and EC to tablet coating is useful for an enteric release preparation sensitive to pancreatic lipase, even if patients have low gastric acidity or are taking antacids.