Does temperature increase induced by tableting contribute to tablet quality?

The aim of this paper is to determine temperature and structural changes caused by tableting and to deduce from the combination of temperature measurement and the determination of structural changes whether temperature increase induced by tableting contributes to tablet quality. Tablets were produced of microcrystalline cellulose (MCC), spray-dried lactose, pregelatinized starch, and dicalcium phosphate dihydrate (DCPD) with an instrumented single punch tableting machine. The temperature pattern at the surface of the tablets was measured starting directly after tableting with an infrared thermoviewer and an infrared sensor. Powder and tablets were analyzed by FT-Raman spectroscopy, the tablets were analyzed directly after tableting and after one month of storage. The crushing force of the resulting tablets was determined. For all materials a temperature increase (TI) induced by tableting was determined with both methods used. The order of the temperature increase was the same for both methods used: TI (MCC)>TI (spray-dried lactose)>TI (pregelatinized starch)>TI (DCPD). The order was also identical for the crushing force of the tablets. The extent of differences in the spectra followed the same ranking. In conclusion, the temperature increase contributed to the changes in material structure and thus temperature increase is one factor which determined crushing force and thus tablet properties. This revised version was published online in July 2006 with corrections to the Cover Date.     

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.     

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.     

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.     

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.     

Influence of tabletting speed on compactibility and compressibility of two direct compressible powders under high speed compression

To examine the influence of tabletting speed on compactibility and compressibility under high speed compression, two direct compressible powders, alpha-lactose monohydrate and microcrystalline cellulose of different particle size ranges were compressed using an instrumented rotary press with varying tabletting speed and compression force. The maximum applied force and total time during compression (contact time) were determined from a time-force profile, and the relation between these parameters and properties of compacts was examined. For all lactose tablets, the porosity and tensile strength of compacts were less affected by compression rate though they depended on the applied force. However, the properties of microcrystalline cellulose tablets were varied depending on the tabletting speed in addition to the applied force. In an attempt to quantitatively evaluate the effect of compression rate on the compactibility, an empirical equation was derived from the numerical analysis of the experimental data. The compactibility parameters deduced from the equation well elucidated the effect of tabletting speed on the properties of microcrystalline cellulose tablets and lactose tablets made of various particle size powders.     

Comparing microcrystalline with spherical nanocrystalline cellulose from waste cotton fabrics

Microcrystalline cellulose (MCC) and spherical nanocrystalline cellulose (SNCC) were successfully prepared from waste cotton fabrics through acid hydrolysis. The comparative analysis of the morphology and structure between the obtained MCC and SNCC was carried out. The SNCC suspension exhibited higher stability than the MCC suspension. Transmission electron microscopy in combination with atomic force microscopy showed that the cellulose nanospheres with average size of 35?nm were achieved, while the average particle size of MCC was 49?μm. The MCC and SNCC had similar functional groups and crystalline structure as confirmed by Fourier transform infrared spectroscopy and X-ray diffraction analysis, respectively. Viscometric average molecular weight measurement and thermo gravimetric analysis indicated that the degree of polymerization and thermal stability of SNCC was lower than that of MCC. These results should improve understanding of the characteristics of MCC and SNCC derived from waste cotton fabrics and lead to many new applications.     

The relevance of glass transition temperature for the process of tablet formation

The aim was to determine the relevance of the glass transition temperature (T_g) on the compressibility and compactibility of different excipients as celluloses, cellulose derivatives, lactoses, starch, maltodextrin and carrageenan. Their T_g was determined, they were tableted on an instrumented eccentric tableting machine and crushing force was analyzed. Using force, time and displacement tableting behavior was analyzed by 3D modeling. The parameters obtained, d (time plasticity), e (pressure plasticity) and w (fast elastic decompression), show different deformation mechanisms for the materials in relation to their T_g. Further, if the T_g can be reversibly exceeded during tableting, crushing force is high, otherwise crushing force is lower. This revised version was published online in July 2006 with corrections to the Cover Date.     

Preparation of antipyretic analgesic by direct compression and its evaluation

Direct compression is able to produce tablets at a lower cost than wet granulation and tableting method, due to a fewer items of process validation. In this study, acetaminophen was used as a medicine with various granular diameters to formulate tablets by direct compression, thus evaluating their physical properties. Consequently, direct compression was found effective in formulating tablets with excellent physical properties, with the granular diameter taken into account. It was confirmed that tablets produced by direct compression were similar in physical properties in tablets produced by wet granulation and tableting method. Further, it was suggested that use of a dry-type binder would make it possible to provide a tablet having higher content of the medicine with excellent physical properties.     

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 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).     

Studies on internal structure of tablets. III. Manufacturing of tablets containing microcapsules

The aim of this study was to establish the best manufacturing conditions for preparation by the direct compression method of tablets which contain microcapsules having a minimal destruction rate of the coating wall, show the same dissolution pattern as microcapsules, and have enough mechanical strength for practical use, and to elucidate the internal structure of the tablets under the best manufacturing conditions. Degree of destruction of the microcapsule wall was evaluated by the dissolution rate of the medicine in the microcapsules. To learn the mechanical strength of tablets, the crushing strength and friability were measured; their internal structure was analyzed by the porosity and pore size distribution. The best manufacturing conditions for the tablets were thus determined, and it was clarified by analysis of the internal structure that these conditions are markedly affected by the flowability of prescribed powders and the packing state at compression.     

Enhanced Characterization of Naproxen Formulation by Near Infrared Spectroscopy

Near infrared spectroscopy in combination with appropriate chemometric methods is an effective technique for quantitative analysis of parameters of interest for the pharmaceutical industry. In this study, the artificial neural network (ANN) was applied to monitor critical parameters (compression force, tablet hardness, mean particle size, and active pharmaceutical ingredient concentration of tablets) in the process of naproxen pharmaceutical preparation. The performance of ANN was compared to linear methods (partial least squares regression (PLS) and synergy interval partial squares (siPLS)). The ANN models for compression force, tablet hardness, mean particle size, and active pharmaceutical ingredient concentration of tablets yielded the low root mean square error of prediction (RMSEP) values of 0.936 KN, 0.302 kg, 4.49 mg, and 2.14 µm, respectively. The predictive ability of the PLS model was improved by siPLS with selection of spectral regions and the best performance among all calibration methods was showed by the nonlinear method (ANN). Effective models were built by using these approaches using near infrared spectroscopy.     

Development of a rapid process monitoring method for dry-coated tableting process by using near-infrared spectroscopy

A nondestructive transmittance near-infrared (NIR) method for detecting off-centered cores in dry-coated (DC) tablets was developed as a monitoring system in the DC tableting process. Caffeine anhydrate was used as a core active pharmaceutical ingredient (API), and DC tablets were made by the direct compression method. NIR spectra were obtained from these intact DC tablets using the transmittance method. The reference assay was performed with HPLC. Calibration models were generated by partial least squares (PLS) regression and principal component regression (PCR) utilizing external validations. Hierarchical cluster analysis (HCA) of the results confirmed that NIR spectroscopy correctly detected off-centered cores in DC tablets. We formulated and used the Centering Index (CI) to evaluate the precision of core alignment and generated an NIR calibration model that could correctly predict this index. The principal component (PC) 1 loading vector of the final calibration model indicated that it could specifically detect the misalignment of tablet cores. The model also had good linearity and accuracy. The CIs of unknown sample tablets predicted by the final calibration model and those calculated through the HPLC analysis were closely parallel with each other. These results demonstrate the validity of the final calibration model and the utility of the transmittance NIR spectroscopic method developed in this study as a monitoring system in DC tableting process.     

Quantitative Analysis of Uncoated Eszopiclone Tablets by Near-Infrared Spectroscopy

This study employed near-infrared (NIR) spectroscopy to analyze content uniformity, moisture content, compression force, tablet hardness, average particle size, and particle-size distribution. The content uniformity, moisture content, compression force, tablet hardness, and average particle size models yielded high correlation coefficients (R²) of 0.99582, 0.99725, 0.99620, 0.96294, and 0.98421, respectively, whereas the particle size distribution models showed good predictive ability. Conventional criteria such as R², root-mean-square error of calibration, and the root-mean-square error of prediction were used to evaluate the accuracy and precision of the model. To ensure the accuracy and predictability of the content model for low-dose tablets, additional validation and reliability evaluations were performed using 70%, 80%, 100%, 120%, and 130% drug concentrations as well as 90% and 110% active content formulations. Near-infrared spectroscopy with multivariate modeling is a rapid, nondestructive technique for the characterization of the manufacturing process.     

Assessment of processing and polymorphic form effect on the powder and tableting properties of microcrystalline celluloses I and II

Microcrystalline cellulose I (MCCI) is an excipient used as a diluent, disintegrant, glidant and binder for the production of pharmaceutical tablets. In this work, microcrystalline cellulose II (MCCII) was obtained from cotton fibers by basic treatment with 7.5 N NaOH followed by an acid hydrolysis. MCCI and MCCII materials were processed by wet granulation, dry granulation and spray drying. Either the polymorphic form or processing had no effects on the particle morphology or particle size. However, MCCII powders had a higher porosity, less packing tendency, degree of crystallinity, degree of polymerization and density, but a faster disintegration than MCCI. The tensile strength of MCCI was highly affected by the wet and dry granulation processes. Most of the resulting powder and tableting properties were dependent on the polymorphic form of cellulose, rather than on the processing employed.     

Pre-formulation studies on moisture absorption in microcrystalline cellulose using differential thermo-gravimetric analysis

A study on the differential thermo-gravimetric (DTG) measurements of microcrystalline cellulose (MCC) containing moisture indicated that particle size affected the amount of bound water and the flow indices. Thermal analysis of 6 commercial grades of MCC powders and MCC/water blends were performed using a thermo-gravimetric analyzer. These MCCs were differentiated by their particle size, bulk and tapped densities, crystallinity and micromeritic properties. From the DTG curves, it was observed that water loss from the MCC/water blends occurred in 3 phases which corresponded to the different states of water associated with the solid particles. Area under the third phase, or the falling rate phase, can be associated with the release of water that was physically shielded or bound to the solid. This water may be referred to as "structured" water. The large particle size grades of MCC-Avicel PH 102, PH 302 and Pharmacel 102 were found to possess smaller quantities of structured water. Water vapor sorption results revealed the monolayer capacities for the respective MCC grades. The amount of structured water appeared to correspond to the existence of bilayers on the surface of the small particle size MCC grades. Using the avalanche flow assessment method, flow properties of small particle size grades of MCC were found to be poorer as indicated by the significant correlation between their flow indices and size, in addition to the longer mean times to avalanche.     

Synthesis and characterization of new copolymers of ethyl methacrylate grafted on tapioca starch as novel excipients for direct compression matrix tablets

In last years, the introduction of new materials for drug delivery matrix tablets has become more important. This paper evaluates the physicochemical and mechanical properties of new graft copolymers of ethyl methacrylate (EMA) on tapioca starch (TS) and hydroxypropylstarch (THS), synthesized by free radical polymerization and dried in a vacuum oven (OD) or freeze-dried (FD). Infrared and ¹³C NMR spectroscopies confirm the change of chemical structure of the copolymers and X-ray diffraction shows up the higher amorphization of copolymers respect to the carbohydrates. Particle size analysis and SEM indicate that graft copolymerization leads to an increase of particle size and a more irregular shape. Graft copolymerization implies decrease of density and moisture content values. Heckel equation shows that copolymers have less densification by particle rearrangement and fragmentation than carbohydrates. Concerning the drying methods, FD products have larger plasticity and lower elasticity than OD copolymers. Graft copolymerization produces a decrease of the applied pressure necessary to obtain tablets, ejection force and friction work. Furthermore, graft copolymers show longer disintegration time than tablets from raw starches. These qualities suggest that these copolymers could be used as excipients in matrix tablets obtained by direct compression, and with a potential use in controlled release.     

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.     

Charging megadalton poly(ethylene oxide)s by electrospray ionization. A charge detection mass spectrometry study

Ions from compounds of megadalton (MDa) molecular weight were produced in an electrospray ionization source from solutions of poly(ethylene oxide) (PEO) samples with average molecular weights ranging from 1,000,000 to 7,000,000 Da. Charge detection mass spectrometry (CDMS) has been used to determine the mass of the MDa PEOs. Simultaneous measurement of the charge and velocity of individual ions allows the mass determination of the ion, after calibration of the instrument with independent samples. In addition to the mass spectra, CDMS generates charge-versus-mass plots, which allow investigation of the charging of electrosprayed ions over a broad range of masses. The experimental charging capacity of MDa PEOs is compared with a simple model based on the affinity of alkali cations for oxygen sites and on the electrostatic potential energy of the charged polymer. The charging capacity of PEOs was also investigated as a function of the concentration of and the type of alkali ions.