Compressional Behavior of a Mixture of Granules Containing High Load of Phyllanthus niruri Spray-Dried Extract and Granules of Adjuvants: Comparison between Eccentric and Rotary Tablet Machines

The purpose of this paper was to evaluate the compressional behavior of granules containing high load of a Phyllanthus niruri spray-dried extract in eccentric (ETM) and rotary (RTM) tablet presses. Tablets were constituted by spray-dried extract granules (SDEG, 92%), excipient granules (EXCG, 7.92%), and magnesium stearate (0.08%). SDEG was obtained by dry granulation and EXCG, composed of microcrystalline cellulose (62.9%) and sodium starch glycolate (37.1%), by wet granulation. Particle size distribution was fixed between 0.250 and 0.850 mm. Tablets did not evidence any mechanical failures, such as lamination or capping, or anomalous weight variation in either tablet machine types. Upper and lower tablet surface photomicrographs from ETM and RTM tablets showed differences in porosity and texture. Different RTM speeds suggested the visco-plastic behavior of the formulation, since, by slowing down rotation speeds, the tensile strength of the tablets increased significantly, but the porosity and disintegration time were not affected. Tablets produced in RTM showed lower friability and porosity than ETM tablets, which did not reflect on higher tensile strength. The EXCG distribution at upper and lower surfaces from ETM and RTM tablets was quantified by image analysis and evaluated through statistical methods. Spray-dried extract release was not influenced by the type of equipment or operational conditions to which the compacts were submitted. Construction and operation differences between both tablet presses influenced the final product, since tablets with similar tensile strength, made by distinct tablet machines, exhibited different quality parameters.     

Development of a Melting Tablet Containing Promethazine HCl Against Motion Sickness

The purpose of this study was to design a 'Traveller Friendly Drug Delivery System' for PM-HCl. Conventional promethazine (PM-HCl) tablets are bitter, need to be taken 1 h before symptoms and water is also needed. Taste-masked granules were produced with Eudragit E100 by extrusion, and analyzed with FTIR, DSC, and XRD. Tablets formulated from granules by direct compression using Ac-Di-Sol, Polyplasdone-XL, Primojel and ion-exchanger Tulsion339 and evaluated for mass uniformity, friability, tensile strength, drug content uniformity, water absorption ratio, in-vitro and in-vivo disintegration time and in-vitro dissolution studies. The observed drug-polymer interactions and reduced crystallinity may be reasons for increased dissolution rates. The formulated tablets were disintegrated within 15 s. Tablets (25 mg PM-HCl) with Ac-Di-Sol (4%) showed complete release within 1 min, while marketed conventional tablets (Phenergan; Rhone-Poulec) release 25% during the same period. A preliminary stability studies for the prepared tablets carried at 30 +/- 2 degrees C/60 +/- 5% RH, and 40 +/- 2 degrees C/75 +/- 5%RH for 3 months showed no significant changes in the tablets quality at 30 +/- 2 degrees C/60 +/- 5% RH. However, at 40 +/- 2 degrees C/75 +/- 5%RH marked increase in in-vitro disintegration time, tensile strength and decrease in friability and water absorption ratio was found. The present studies indicate the abilities of Eudragit E 100 for taste masking and improving the dissolution profile of PM-HCl after complexation. In addition, by employing cost effective direct compression method, fast-dissolving tablets of 400 mg total weight with an acceptable quality could be prepared.     

Ultrasound Transmission Technique as a Potential Tool for Physical Evaluation of Monolithic Matrix Tablets

The aim of this study was to investigate the effects of tablet porosity and particle size fraction of compacted Starch acetate powders, with and without model drug caffeine, on acoustic properties of tablets. The ultrasound velocity was determined from the transmission measurements. Tablets of starch acetate (SA DS 2.7) powder with two particle size fractions of 0–53 and 0–710 μm were compressed with a compaction simulator. Porosities of tablets varied in the range from 12% to 43% for both particle size fractions. Strong associations were found between the ultrasound velocity and physical properties of the tablets such as porosity and particle size fraction. Interestingly, ultrasound velocity was practically insensitive to inclusion of the model drug caffeine with the concentrations used. Based on this study ultrasound transmission method is a potential non-destructive tool for studying structural changes of tablets and other solid dosage forms.     

琥珀酸美托洛尔与美托洛尔对慢性充血性心衰患者心功能的影响

目的：探讨琥珀酸美托洛尔缓释片与美托洛尔片对慢性心力衰竭患者的心功能的影响。方法：选取慢性充血性心衰患者182例临床患者资料,排除67例不符合入选标准病例后,按照服用美托洛尔剂型（缓释片、平片）分为两组,两组均为常规利尿剂ACEI等治疗。美托洛尔组患者服用每日服用25mg-50mg的美托洛尔治疗,均分2次服用。琥珀酸美托洛尔组每日服用23．75-95mg琥珀酸美托洛尔缓释片进行治疗。评价治疗前和治疗12个月后的相关指标,包括：一日5次的平均心率（晨起前,8时,12时,16时,夜间休息前共5次平均心率）、LVDd、EF、BUN、Crea。结果：治疗12个月后,两组患者心率均下降．琥珀酸美托洛尔组与美托洛尔组相比下降更明显（64．0±5．4VS69．5±7．6,P〈0．05）、LVDd、EF、BUN、Crea等指标在两组之间没有差别。结论：慢性充血性心衰患者应用琥珀酸美托洛尔较美托洛尔平片相比可明显降低平均心率。但对于心功能肾功能的影响。琥珀酸关托洛尔较美托洛尔平片相比无明显差异。     

Acid-treated yeast cell wall as a binder displaying function of disintegrant

This investigation examined the application of acid-treated yeast cell wall (AYC) as a binder functioning as a disintegrant. Acetylsalicylic acid (ASA) was granulated with AYC, hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), or pullulan (PUL) and compressed into a tablet in the absence of disintegrant. Particle size and angle of repose of the granules, tensile strength, disintegration time, and water absorption behavior of the tablets and ASA release profiles from the tablets were measured. The surface of AYC-granules was observed with a scanning electron microscope. As was the case with the granules of HPC, PVP, or PUL, D50 of the granules of AYC increased with increasing AYC addition percentage, indicating that it is possible to granulate ASA with AYC. Tablets incorporating HPC, PVP, and PUL failed to disintegrate within 30 minutes at all percentages of binder addition because in the case of the HPC, PVP, or PUL tablets in the dissolution medium, water scarcely penetrated into the inner region of the tablet, causing no disintegration. In the case of the AYC tablets, disintegration was not detected at 3% or less of AYC. When AYC was equal to or greater than 5%, AYC tablets disintegrated in approximately 4 minutes and rapid ASA release from the tablets was observed. These results may have been caused by the following. In the case of the AYC 3% granules, ungranulated aspirin powder remained, but in the case of the AYC 5% granules, ASA powder was granulated and covered with AYC. Water absorption was observed initially; however, a plateau was reached in the case of the AYC 3%-tablet. In contrast, in the cases of the AYC 5% and more tablets, water absorption was greater and increased with time. The angle of repose of the AYC 5% granules was 25.7°, which represented high fluidity. The tablets produced by compressing the granules demonstrated sufficient tensile strength greater than 0.8 MPa. The tablets rapidly disintegrated and rapid ASA release was obtained. AYC functioned as a binder at granulation; additionally, AYC served as a disintegrant in the dissolution of drug from the tablets. These results indicate that AYC affords high utility as a unique pharmaceutical additive possessing contrary functions such as binding and disintegration.     

Comparison of the dissolution of metaxalone tablets (Skelaxin) using<Emphasis Type="Italic">USP</Emphasis> apparatus 2 and 3

The purpose of this study was to evaluate the effect of pH on the dissolution behavior of metaxalone in the marketed product Skelaxin tablets. The dissolution was evaluated using United States Pharmacopeia (USP) dissolution Apparatus 2 and 3 at pHs ranging from 1.5 to 7.4 Results from these studies show that the dissolution of this product is pH dependent. At low pH (simulated gastric fluid, pH 1.5), the dissolution of metaxalone from Skelaxin tablets, was less than 10% over 75 minutes; whereas, dissolution at pH 4.5 showed greater than 90% release in the same time period. These results were consistent for both Apparatus 2 and 3. This suggests that Skelaxin Tablets should be considered a delayed release dosage form.     

Spray-Dried Cellulose Nanofibers as Novel Tablet Excipient

The purpose of this study was to evaluate the potential of cellulose nanofibers (also referred as microfibrillated cellulose, nanocellulose, nanofibrillated, or nanofibrillar cellulose) as novel tabletting material. For this purpose, physical and mechanical properties of spray-dried cellulose nanofibers (CNF) were examined, and results were compared to those of two commercial grades of microcrystalline cellulose (MCC), Avicel PH101 and Avicel PH102, which are the most commonly and widely used direct compression excipients. Chemically, MCC and CNF are almost identical, but their physical characteristics, like mechanical properties and surface-to-volume ratio, differ remarkably. The novel material was characterized with respect to bulk and tapped as well as true density, moisture content, and flow properties. Tablets made of CNF powder and its mixtures with MCC with or without paracetamol as model compound were produced by direct compression and after wet granulation. The tensile strength of the tablets made in a series of applied pressures was determined, and yield pressure values were calculated from the measurements. With CNF, both wet granulation and direct compression were successful. During tablet compression, CNF particles were less prone to permanent deformation and had less pronounced ductile characteristics. Disintegration and dissolution studies showed slightly faster drug release from direct compression tablets with CNF, while wet granulated systems did not have any significant difference.     

Bio-fluid uptake and release of Indomethacin of direct-compressed HPMC tablets

Tablets of three different grades of hydroxypropyl methyl cellulose (HPMC), having different viscosity, were prepared using the direct-compression technique with no additive or binder. The fluid uptake behavior of these HPMC tablets was studied in three types of bio-media – water, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF). The amount of fluid uptake by the tablets followed a power law relationship with time for all three media. Variants such as pH value, type of salts and salt concentration in the media were found to have little influence on the swelling process for the tablet. On the contrary, viscosity and molecular weight of HPMC were the controlling parameters for the swelling process. Subsequently, Indomethacin was added in certain percentage to the tablets as a model drug. It was to examine and elucidate drug releasing properties of the HPMC tablets. The possible mechanisms involved in the process of drug dispersion are proposed and discussed.     

Comparison of the dissolution of metaxalone tablets (Skelaxin) usingUSP apparatus 2 and 3

The purpose of this study was to evaluate the effect of pH on the dissolution behavior of metaxalone in the marketed product Skelaxin tablets. The dissolution was evaluated using United States Pharmacopeia (USP) dissolution Apparatus 2 and 3 at pHs ranging from 1.5 to 7.4 Results from these studies show that the dissolution of this product is pH dependent. At low pH (simulated gastric fluid, pH 1.5), the dissolution of metaxalone from Skelaxin tablets, was less than 10% over 75 minutes; whereas, dissolution at pH 4.5 showed greater than 90% release in the same time period. These results were consistent for both Apparatus 2 and 3. This suggests that Skelaxin Tablets should be considered a delayed release dosage form.KeyWords: Metaxalone, dissolution, pH dependence, apparatus 3     

Quantitation of drug content in a low dosage formulation by transmission near infrared spectroscopy

A transmission near infrared (NIR) spectroscopic method has been developed for the nondestructive determination of drug content in tablets with less than 1% weight of active ingredient per weight of formulation (m/m) drug content. Tablets were manufactured with drug concentrations of ∼0.5%, 0.7%, and 1.0% (m/m) and ranging in drug content from 0.71 to 2.51 mg per tablet. Transmission NIR spectra were obtained for 110 tablets that constituted the training set for the calibration model developed with partial least squares regression. The reference method for the calibration model was a validated UV spectrophotometric method. Several data preprocessing methods were used to reduce the effect of scattering on the NIR spectra and base the calibration model on spectral changes related to the drug concentration changes. The final calibration model included the spectral range from 11 216 to 8662 cm⁻¹ the standard normal variate (SNV), and first derivative spectral pretreatments. This model was used to predict an independent set of 48 tablets with a root mean standard error of prediction (RMSEP) of 0.14 mg, and a bias of only −0.05 mg per tablet. The study showed that transmission NIR spectroscopy is a viable alternative for nondestructive testing of low drug content tablets, available for the analysis of large numbers of tablets during process development and as a tool to detect drug agglomeration and evaluate process improvement efforts. Published: March 24, 2006     

Fast Tablet Tensile Strength Prediction Based on Non-Invasive Analytics

In this paper, linkages between tablet surface roughness, tablet compression forces, material properties, and the tensile strength of tablets were studied. Pure sodium halides (NaF, NaBr, NaCl, and NaI) were chosen as model substances because of their simple and similar structure. Based on the data available in the literature and our own measurements, various models were made to predict the tensile strength of the tablets. It appeared that only three parameters—surface roughness, upper punch force, and the true density of material—were needed to predict the tensile strength of a tablet. Rather surprising was that the surface roughness alone was capable in the prediction. The used new 3D imaging method (Flash sizer) was roughly a thousand times quicker in determining tablet surface roughness than traditionally used laser profilometer. Both methods gave practically analogous results. It is finally suggested that the rapid 3D imaging can be a potential in-line PAT tool to predict mechanical properties of tablets in production.     

Challenges in Detecting Magnesium Stearate Distribution in Tablets

Magnesium stearate (MS) is the most commonly used lubricant in pharmaceutical industry. During blending, MS particles form a thin layer on the surfaces of the excipient and drug particles prohibiting the bonding from forming between the particles. This hydrophobic layer decreases the tensile strength of tablets and prevents water from penetrating into the tablet restraining the disintegration and dissolution of the tablets. Although overlubrication of the powder mass during MS blending is a well-known problem, the lubricant distribution in tablets has traditionally been challenging to measure. There is currently no adequate analytical method to investigate this phenomenon. In this study, the distribution of MS in microcrystalline cellulose (MCC) tablets was investigated using three different blending scales. The crushing strength of the tablets was used as a secondary response, as its decrease is known to result from the overlubrication. In addition, coating of the MCC particles by MS in intact tablets was detected using Raman microscopic mapping. MS blending was more efficient in larger scales. Raman imaging was successfully applied to characterize MS distribution in MCC tablets despite low concentration of MS. The Raman method can provide highly valuable visual information about the proceeding of the MS blending process. However, the measuring set-up has to be carefully planned to establish reliable and reproducible results.     

Stresses in the closed mitral valve: a model study

In the present model study on the closed mitral valve, tensile force in the chordae tendineae is related to transvalvular pressure using a mathematical model of mechanics of the closed mitral valve. Circumferential stress as well as bending stress in the valve leaflets were neglected. Without precisely knowing the mechanical properties of the leaflet material, geometry of the leaflets was estimated by applying Laplace's law, which relates leaflet stress to leaflet curvature. Independent of shape of the mitral valve orifice, under all circumstances tensile force in the chordae tendineae was calculated to be equal or greater than half the force exerted on the mitral valve orifice by the transvalvular pressure.     

Neem Gum as a Binder in a Formulated Paracetamol Tablet with Reference to Acacia Gum BP

This study determined the physical, compressional, and binding properties of neem gum (NMG) obtained from the trunk of Azadirachta indica (A Juss) in a paracetamol tablet formulation in comparison with official Acacia gum BP (ACA). The physical and flow properties were evaluated using density parameters: porosity, Carr’s index, Hausner’s ratio, and flow rate. Compressional properties were analyzed using Heckel and Kawakita equations. The tensile strength, brittle fracture index, and crushing strength–friability/disintegration time ratio were used to evaluate the mechanical properties of paracetamol tablets while the drug release properties of the tablets were assessed using disintegration time and dissolution times. Tablet formulations containing NMG exhibited faster onset and higher amount of plastic deformation during compression than those containing ACA. Neem gum produced paracetamol tablets with lower mechanical strength; however, the tendency of the tablets to cap or laminate was lower when compared to those containing ACA. Inclusion of NMG improved the balance between binding and disintegration properties of paracetamol tablets produced than those containing ACA. Neem gum produced paracetamol tablets with lower disintegration and dissolution times than those containing ACA.     

Co-Processed Excipients for Dispersible Tablets–Part 1: Manufacturability

Co-processed excipients may enhance functionality and reduce drawbacks of traditional excipients for the manufacture of tablets on a commercial scale. The following study aimed to characterise a range of co-processed excipients that may prove suitable for dispersible tablet formulations prepared by direct compression. Co-processed excipients were lubricated and compressed into 10.5-mm convex tablets using a Phoenix compaction simulator. Compression profiles were generated by varying the compression force applied to the formulation and the prepared tablets were characterised for hardness, friability, disintegration and fineness of dispersion. Our data indicates that CombiLac, F-Melt type C and SmartEx QD100 were the top 3 most suitable out of 16 co-processed excipients under the conditions evaluated. They exhibited good flow properties (Carr’s index ? 20), excellent tabletability (tensile strength >?3.0 MPa at 0.85 solid fraction), very low friability (<?1% after 15 min), rapid disintegration times (27–49 s) and produced dispersions of ideal fineness (<?250 μm). Other co-processed excipients (including F-Melt type M, Ludiflash, MicroceLac, Pharmaburst 500 and Avicel HFE-102) may be appropriate for dispersible tablets produced by direct compression providing the identified disintegration and dispersion risks were mitigated prior to commercialisation. This indicates that robust dispersible tablets which disintegrate rapidly could be manufactured from a range of co-processed excipients.     

Quantifying the effects of root reinforcement of Persian Ironwood (Parrotia persica) on slope stability; a case study: Hillslope of Hyrcanian forests,northern Iran

Forest vegetation is known to enhance the stability of slopes by reinforcing soil and increasing its shear resistance through root system. The effects of root reinforcement depend on the morphological characteristics of the root system, the tensile strength of single roots, and the spatial distribution of the roots in soil. In the present study the results of research carried out in order to evaluate the biotechnical characteristics of the root system of Persian Ironwood (Parrotia persica), in northern Iran are presented. Profile trenching method was used to obtain root area ratio (RAR) values for uphill and downhill sides of the individual trees. For each species, single root specimens were sampled and tested for their tensile strength. It was found that root density generally decreases with depth according to an exponential law. Maximum RAR values were located within the first 0.1 m, with maximum rooting depth at about 0.65 m. RAR values ranged from 0.001% at lower depths to 1.39% near the surface, at upper 0.1 m depth. Significant differences of RAR values, rooting depth and root cohesion between uphill and downhill were observed, however, the differences were not significant for number of roots (ANCOVA). Downhill profiles had higher RAR values, rooting depth and root cohesion. In general, root tensile strength tends to decrease with diameter according to a power law, as observed by other researchers. Downhill roots were significantly stronger in tensile strength than uphill ones. Inter-species variation of tensile strength in downhill roots was also observed. The resulting data were used to evaluate the reinforcing effects in terms of increased shear strength of the soil, using Wu/Waldron Model. The root reinforcement provided by Persian Ironwood is about 46.0 kPa in the upper layers and 0.3 kPa in the deeper horizons. The results of Spearman test revealed a significant correlation between RAR and c_r and that best followed by a power law. The results presented in this paper contribute to expanding the knowledge on biotechnical characteristics of Persian Ironwood on slope reinforcement.     

Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapid-disintegrating tablets

The purpose of this research was to mask the intensely bitter taste of ondansetron HCl and to formulate a rapiddisintegrating tablet (RDT) of the taste-maske drug. Taste masking was done by complexing ondansetron HCl with aminoalkyl methacrylate copolymer (Eudragit EPO) in different ratios by the precipitation method. Drug-polymer complexes (DPCs) were tested for drug content, in vitro taste in simulated salivary fluid (SSF) of pH 6.2, and molecular property. Complex that did not release drug in SSF was considered taste-masked and selected for formulation RDTs. The complex with drug-polymer ratio of 8∶2 did not show drug release in SSF; therefore, it was selected. The properties of tablets such as tensile strength, wetting time, water absorption ratio, 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 spray-dried mannitol and microcrystalline cellulose in the ratio 1∶1 and 7% wt/wt Polyplasdone XL-10 showed faster disintegration, within 12.5 seconds, than the marketed tablet (112 seconds). Good correlation between in vitro disintegration behavior and in the oral cavity was recognized. Taste evaluation of RDT in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value (0.5) ultimately reaching to 0 within 15 minutes, whereas ondansetron HCl was rated intensely bitter with a score of 3 for 10 minutes. Tablets of batch F4 also revealed rapid drug release (t₉₀, 60 seconds) in SGF compared with marketed formulation (t₉₀, 240 seconds;P<.01). Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity. Published: June 22, 2007     

3D Simulation of Internal Tablet Strength During Tableting

This study presents a new approach to model powder compression during tableting. The purpose of this study is to introduce a new discrete element simulation model for particle–particle bond formation during tablet compression. This model served as the basis for calculating tablet strength distribution during a compression cycle. Simulated results were compared with real tablets compressed from microcrystalline cellulose/theophylline pellets with various compression forces. Simulated and experimental compression forces increased similarly. Tablet-breaking forces increased with the calculated strengths obtained from the simulations. The calculated bond strength distribution inside the tablets showed features similar to those of the density and pressure distributions in the literature. However, the bond strength distributions at the center of the tablets varied considerably between individual tablets.     

Comparative Study of Propranolol hydrochloride Release from Matrix Tablets with Kollidon®SR or Hydroxy Propyl Methyl Cellulose

The release of propranolol hydrochloride from matrix tablets with hydroxy propyl methyl cellulose (HPMC K15M) or KollidonSR at different concentrations was investigated with a view to developing twice daily sustained release dosage form. A hydrophilic matrix-based tablet using different concentrations of HPMC K15M or KollidonSR was developed using direct compression technique to contain 80 mg of propranolol hydrochloride. The resulting matrix tablets prepared with HPMC K15M or KollidonSR fulfilled all the official requirements of tablet dosage forms. Formulations were evaluated for the release of propranolol hydrochloride over a period of 12 h in pH 6.8 phosphate buffer using USP type II dissolution apparatus. Propranolol hydrochloride and pure KollidonSR or HPMC K15M compatibility interactions was investigated by using Fourier-transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). FTIR spectroscopic and DSC studies revealed that there was no well defined chemical interaction between propranolol hydrochloride with KollidonSR or HPMC K15M. Tablets were exposed to 40 degrees C/75% of RH in open disc for stability. The in vitro drug release study revealed that HPMC K15 at a concentration of 40% of the dosage form weight was able to control the release of propranolol hydrochloride for 12 h, exhibit non-Fickian diffusion with first-order release kinetics where as at 40% KollidonSR same dosage forms show zero-order release kinetics. In conclusion, the in vitro release profile and the mathematical models indicate that release of propranolol hydrochloride can be effectively controlled from a single tablet using HPMC K15M or KollidonSR matrix system.     

Mucoadhesive bilayer tablets of propranolol hydrochloride

The purpose of this research was to study mucoadhesive bilayer buccal tablets of propranolol hydrochloride using the bioadhesive polymers sodium alginate (Na-alginate) and Carbopol 934P (CP) along with ethyl cellulose as an impermeable backing layer. The tablets were evaluated for weight variation, thickness, hardness, friability, surface pH, mucoadhesive strength, swelling index, in vitro drug release, ex vivo drug permeation, ex vivo mucoadhesion, and in vivo pharmacodynamics in rabbits. Tablets containing Na-alginate and CP in the ratio of 5∶1 (F2) had the maximum percentage of in vitro drug release without disinte-gration in 12 hours. The swelling index was proportional to Na-alginate content and inversely proportional to CP content. The surface pH of all tablets was found to be satis-factory (7.0±1.5), close to neutral pH; hence, buccal cavity irritation should not occur with these tablets. The mechanism of drug release was found to be non-Fickian diffusion and followed zero-order kinetics. The formulation F4 was optimized based on good biodhesive strength (28.9±0.99 g) and sustained in vitro drug permeation (68.65%±3.69% for 12 hours). The behavior of formulation F4 was examined in human saliva, and both the drug and the buccal tablet were found to be stable. The formulation F4 was applied to rabbit oral mucosa for in vivo studies. The formulation inhibited isoprenaline-induced tachycardia. The studies conducted in rabbits confirmed the sustained release as compared with intravenous administration. Published: September 21, 2007