In-die evaluation of capping tendency of pharmaceutical tablets using force-displacement curve and stress relaxation parameter

A novel in-die evaluation method of tablet capping tendency was proposed based on a force-displacement curve and stress relaxation parameter in a tableting process. In our previous study (Chem. Pharm. Bull., 59, 2011, Nakamura et al.), the phase diagram consisting of elastic recovery energy (E(e)) and plastic deformation energy (E(p)) of compressed powder, named as the E(e)-E(p) diagram, was proposed. However, it was found that capping tendency of tablets prepared by double-compression with multi-component powder formulations cannot be discriminated using the E(e)-E(p) diagram. To improve the capping discrimination ability, we here proposed a novel corrected phase diagram consisting of the E(e) and an interparticle bonding parameter E(b)(t), named as the E(e)-E(b)(t) diagram. The E(b)(t) was proposed as a new parameter expressing strength of the interparticle bonding formed by the stress relaxation inside compressed powder. The E(b)(t) was defined as a product of the E(p) and the stress relaxation parameter Y(t), estimated from the force-displacement curve and the stress relaxation test. The capping discrimination ability of the diagrams was evaluated using a hierarchical-clustering analysis. The results exhibited that the capping tendency could be clearly discriminated using the proposed E(e)-E(b)(t) diagram at the double-compression and the multi-component powder formulations, as compared to the E(e)-E(p) diagram. This proposed diagram can be used for screening of the powder formulations to avoid the capping.     

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.     

Sodium mefenamate as a solution for the formulation and dissolution problems of mefenamic acid

Sodium salt formation of mefenamic acid (MA) was studied as a way to solve the formulation and dissolution problems of MA. For this purpose, sodium salt of mefenamic acid (Na-MA) was prepared by reacting MA powder with equimolar sodium hydroxide in an aqueous phase, and consequently, Na-MA solution was obtained. The resultant solution was lyophilized and Na-MA powder was collected. The salt formation was confirmed by the results of fourier transformation-infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) studies on Na-MA powder in comparison to MA powder. Na-MA powder was assessed for direct compressibility, in comparison to MA powder, when formulated as a mixture with minimum amount of Avicel((R)) pH 101 and then compressed into tablets using a hydraulic tablet press. Na-MA tablets exhibited satisfactory hardness and friability, and did not show capping or lamination. On the other hand, some MA tablets showed capping or lamination upon compression and all the tested MA tablets for friability capped. Na-MA tablets were also studied for drug dissolution, in comparison to MA tablets, in water, a pH 7.4 phosphate buffer, and a pH 7.4 phosphate buffer after soaking in 0.1 m HCl. Under these different dissolution conditions, Na-MA tablets showed much higher dissolution rate and extent than MA tablets. The results of the study suggested that Na-MA can be considered as a solution form for the formulation and dissolution problems of MA.     

Influence of compression pressure and velocity on tablet sticking

A rotary tablet machine fitted with 8-mm diameter flat-faced punches was used to measure scraper pressure (SCR), a type of shear stress, to evaluate sticking behavior. The shear stress between the surfaces of the tablet and lower punch was determined using an SCR detection system. Mean surface roughness (R(a)) of tablets, measured by a scanning laser-microscope, was used to estimate the magnitude of sticking. Tablet tensile strength tended to increase with compression pressure at either of the tablet production velocities tested, which was consistent with previous reports. SCR decreased with increasing compression pressure for samples at all compression velocities, and showed a tendency to increase with binder concentration. SCR also tended to increase with compression velocity for samples at all compression pressures, suggesting that the frequency of tablet sticking increased as compression velocity increased. R(a) associated with sticking increased with SCR, indicating that the adhesive force between the particles of the tablet surface and the lower punch surface plays an important role in sticking.     

Evaluation of the compaction properties of a solid dispersion of indomethacin with crospovidone by tableting process analyzer

A powder solid dispersion system (SD) of indomethacin (IM) with crospovidone (CrosPVP) possesses good fluidity and can be used for tablet formulation. Tablets of SD can be prepared by direct compression and have adequate hardness and a small variation in weight. Forces during the tableting process were measured with a tableting process analyzer (TabAll) equipped with a single-punch. The pressure transmission ratio (PTR) from the upper to the lower punch and the die wall force (DWF) were examined during the tableting process. Ejection force (EF) and scraper pressure (SP) were measured for determining the capping and sticking properties during the tableting process. Adding 1% magnesium stearate (MS) to the SD resulted in high PTR and DWF values and a low EF value. PTR and DWF values increased and EF value decreased when MS and microcrystalline cellulose (MCC) were added to the SD. A thousand tablets could be manufactured without problems such as sticking or capping when 1% MS and 50% MCC were added to the SD containing 25% IM.     

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.     

Effect of pulverization of the bulk powder on the hydration of creatine anhydrate tablets and their pharmaceutical properties

The hydration behavior and expansion properties of untreated and pulverized creatine anhydrate (CRA) tablets were studied under 60 and 75%RH at 25 degrees C by using differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). The tablet hardness of untreated and pulverized CRA tablets was significantly decreased after hydration. There was a linear relationship between the degree of hydration and the tablet hardness of untreated CRA tablets compressed at 1000 kg/cm2. In contrast, the relationship between the degree of hydration and the tablet hardness of pulverized CRA tablets was nonlinear. These results suggest that the reduction in hardness of pulverized CRA tablets does not depend solely on the hydration level of crystal water. PXRD analysis indicated that the diffraction pattern of the pulverized CRA powder was similar to that of the untreated CRA powder. However, the diffraction intensity of the pulverized CRA powder was slightly lower than that of the untreated CRA powder at high angle. The micropore radius of both untreated and pulverized CRA tablets was significantly increased after hydration, but analysis of the relationship between micropore radius and fractional hydration of crystal water showed that untreated CRA tablets were more affected than pulverized CRA tablets. Therefore, the reduction in tablet hardness depends not only on the hydration behavior but also on the crystal orientation of the CRA powder.     

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.     

Effect of surface composition on the flowability of industrial spray-dried dairy powders

The surface composition of four industrial spray-dried dairy powders (skim milk powder, whole milk powder, cream powder and whey protein concentrate) was estimated by electron spectroscopy for chemical analysis (ESCA), and its influence on powder flowability was studied. It was found that skim milk powder flows well compared to the other powders because the surface is made of lactose and protein with a small amount of fat, whereas the high surface fat composition inhibits the flow of whole milk, cream and whey protein powders. However, the poor flowability of the powders with high surface fat coverage was drastically improved by removal of fat present on the surface through a brief wash with petroleum ether. The results obtained indicate that, although there are several parameters including particle size, which influence the flowability of powders, the flowability of powders is strongly influenced by the surface composition of powders, particularly for fat-containing powders.     

Influence of physical parameters and lubricants on the compaction properties of granulated and non-granulated cross-linked high amylose starch

Cross-linked high amylose starch (CLA) is a pharmaceutical excipient used in direct compression for the preparation of controlled release tablets and implants. In this work the compression properties of CLA in bulk and granulated forms (without binder) were evaluated for the first time. Tablets were prepared on an instrumented single punch machine. The flow properties and the compression characteristics (compressibility, densification behavior, work of compression) of the materials as well as the mechanical strength of the finished compacts (compactibility) were systematically examined. Wet granulation was found to improve the flowability and the compressibility of CLA but concomitantly reduced its compactibility. It was demonstrated that CLA was a plastically deforming material with a plasticity index and a yield pressure value comparable to those of pregelatinized starch. The compactibility of granulated CLA was independent of particle size in the range of 75 to 500 microm, but slightly decreased when the percentage of the fine particles (<75 microm) in the bulk powder was increased. Water and colloidal silicone dioxide facilitated the consolidation of CLA, while magnesium stearate had an opposite effect on the tablet crushing force.     

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.     

Effect of pulverization and dehydration on the pharmaceutical properties of calcium lactate pentahydrate tablets

The effects of heat conduction and pulverization on dehydration kinetics and tablet hardness were studied by a variety of kinetic equations and physical models. The dehydration behavior of unpulverized calcium lactate pentahydrate (UCLP) and pulverized calcium lactate pentahydrate (PCLP) tablets was investigated by using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The hardness of both UCLP and PCLP tablets was significantly decreased after dehydration. The relationship between the extent of dehydration and the tablet hardness of both UCLP and PCLP tablets was linear. The results suggest that the reduction in tablet hardness is dependent on the dehydration of crystal water, and the values of the slopes indicate that the bonding energy of the UCLP was stronger than that of the PCLP. The dehydration of both UCLP and PCLP tablets at 55 °C followed a one-dimensional diffusion mechanism, whereas dehydration at storage temperatures of 60–80 °C followed a three-dimensional diffusion mechanism. UCLP and PCLP tablets contracted in thickness and diameter during dehydration, but final contraction ratios showed that PCLP tablets were more affected than UCLP tablets. In contrast, the micropore radius of both UCLP and PCLP tablets increased after dehydration. Thus, the pharmaceutical properties of calcium lactate pentahydrate (CLP) tablets are affected both by pulverization and by the extent of dehydration of the bulk powder in the tablet formulation.     

Implementation of enhanced correlation maps in near infrared chemical images: Application in pharmaceutical research

Recent developments in Hyperspectral Imaging equipment have made possible the use of this analytical technique for fast scanning of sample surfaces. This technique has turned out to be especially useful in Pharmacy, where information about the distribution of the components in the surface of a tablet can be obtained. One particular application of Hyperspectral Chemical Imaging is the search for singularities inside pharmaceutical tablets, e.g. coating defects. Nevertheless, one problem has to be faced: how to analyze a sample without any previous knowledge about it, or having only the minimum information about the tablet.In this work a new methodology, based on correlation coefficients, is introduced to obtain valuable information about one Hyperspectral Image (detection of defects, punctual contaminants, etc.) without any previous knowledge. The methodology combines Principal Component Analysis (PCA), correlation coefficient between one specific pixel included in the image and the rest of the image; and a new enhanced contrast function to obtain more selective chemical and spatial information about the image. To illustrate the applicability of the proposed methodology, real tablets of ibuprofen have been studied.The proposed methodology is presented as a control technique to detect batch variability, defects in final tablets and punctual contaminants, being a potential supplementary tool for quality controls. In addition, the usefulness of the proposed methodology is not exclusive to NIR-CI devices, but to any hyperspectral and multivariate image system.     

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.     

粉末压片-X-射线荧光光谱法分析砂岩型铀矿制样中粘结剂用量的探讨

由于砂岩型铀矿的成矿特性,样品粉末的内聚力小,采用直接压片法有时难以成型,样片表面常见裂纹,上机测量易碎裂。混合压片法适应性强,制样成功率高,但常见的问题是样品经粘结剂稀释会影响元素的检出限及结果的准确性。本文对粉末压片-X射线荧光光谱法测定砂岩型铀矿地质样品时,前期制样中添加粘结剂的比例进行了研究。试验按照不同比例在铀矿石标准物质GBW04101、GBW04102中添加粘结剂,在扫描电镜下观察到随着粘结剂用量的增加样片表面的光滑度及致密度都呈上升趋势,在X-射线荧光光谱仪上对主量元素进行测定后发现X射线强度在粘结剂添加量大于0.2 g时明显下降,经与GBW04101、GBW04102标准值进行对比后优选出粘结剂与样品的最佳比例为1：20,在此比例下制成的样片光滑平整,不易碎裂,用粉末压片-X射线荧光光谱法进行测定,标准物质测定结果的相对误差为0.56%～6.76 %,相对标准偏差(RSD,n=12)为0.013 %～7.68 %,均达到了《地质矿产实验室测试质量管理规范》DZ/T 0130-2006的要求。本文为粉末压片-X射线荧光光谱法分析砂岩型铀矿地质样品提供了可靠的实验参考依据。     

Development of formulation, manufacturing technology, and standardization of solid pharmaceutical dosage form of Dilept, a novel atypical neuroleptic

The optimum formulation, manufacturing technology, and analytical techniques were developed for an atypical neuroleptic Dilept in a solid dosage form (tablets). It has been shown that the direct compression of a tableting mass with a 1 : 9 ratio of substance to ludipress will be the optimum method for manufacturing these tablets. The proposed procedures for identifying and determining the impurity content and dosage uniformity, as well as for quantitatively determining the substance content in a tablet, are based on the HPLC method. UV spectrophotometry is recommended as a method for the quantitative assessment of the therapeutic substance released from tablets during the dissolution test. Using the accelerated aging test, it has been shown that the quality of tablets during a period equivalent to a two-year shelf life under natural storage conditions is preserved.     

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.     

Development of a Validated Stability-Indicating LC Method for Nitazoxanide in Pharmaceutical Formulations

A reversed-phase liquid chromatographic (LC) method was developed for the assay of nitazoxanide (NTZ) in solid dosage formulations. An isocratic LC separation was performed on a Phenomenex Synergi Fusion C₁₈ column (250 mm × 4.6 mm, i.d., 4 μm particle size) using a mobile phase of 0.1% o-phosphoric acid solution, pH 6.0: acetonitrile (45:55, v/v) at a flow rate of 1.0 mL min⁻¹. Detection was achieved with a photodiode array detector at 240 nm. The detector response for NTZ was linear over the concentration range from 2 to 100 μg mL⁻¹ (r = 0.9999). The specificity and stability-indicating capability of the method were proved using stress conditions. The RSD values for intra-day precision were less than 1.0% for tablets and powder for oral suspension. The RSD values for inter-day precision were 0.6 and 0.7% for tablets and powder for oral suspension. The accuracy was 100.4% (RSD = 1.8%) for tablets and 100.9% (RSD = 0.3%) for powder for oral suspension. The limits of quantitation and detection were 0.4 and 0.1 μg mL⁻¹. There was no interference of the excipients on the determination of the active pharmaceutical ingredient. The proposed method was precise, accurate, specific, and sensitive. It can be applied to the quantitative determination of drug in tablets and powder for oral suspension.     

An insight into the process of tablet formation of microcrystalline cellulose

The present paper aims to show whether the shrinking of the microcrystalline cellulose (MCC) tablets can be derived from underlying processes and whether these processes can be visualized on a nanoscale level. Tableting of MCC was performed on an instrumented eccentric tableting machine to a maximum relative density (ρ_rel,max) of 0.90 of the tablets. The apparent density of the tablets was analyzed by helium pycnometry after tableting. The breaking surface of a MCC tablet was analyzed directly after tableting continuously by video in an environmental scanning electron microscope (ESEM) at constant humidity. Further the breaking surface was analyzed by transmission electron microscopy (TEM) after freeze fracturing. The results show that firstly apparent density by helium pycnometry increases after tableting and that secondly inside the tablet the fiber strength decreased while also the gaps between the fibers increased as was visualized by ESEM. Further the results by TEM indicate that the decrease in fiber strength is caused by a parallel orientation of the MCC microcrystals which is induced by a mechanical activation due to tableting. In conclusion the measured shrinking MCC tablets after tableting is caused by processes on a nanoscale level.     

Release from or through a wax matrix system. V. Applicability of the square-root time law equation for release from a wax matrix tablet

To obtain basic and clear release properties, wax matrix tablets were prepared from a physical mixture of drug and wax powder at a fixed mixing ratio. Properties of release from the single flat-faced surface, curved side surface, and/or whole surface of the wax matrix tablet were examined. Then tortuosity and the applicability of Higuchi's square-root time law equation were examined. The Higuchi equation well analyzed the release processes of different release manners. However, the region fitted to the Higuchi equation differed with the release manner. Tortuosity obtained with release from the single flat-faced surface and curved side surface was comparable with that obtained with the release from a reservoir device tablet, whereas tortuosity obtained with release from the whole surface was larger. As the wax matrix tablets were prepared at a fixed mixing ratio, their internal structures should be similar. Therefore changes in the matrix volume or volume fraction with release were examined, and an extra volume where dissolved drug stray becomes large with release time in the case of release from the whole surface. These factors should be taken into account for evaluation of applicability and release properties. Furthermore, the entire release process should be analyzed using a combination of the square-root time law and other suitable equations in accordance with release manner or condition.