Relationship between breaking force and pore structure of lactose,glucose and mannitol tablets

The aim of this study was to determine the relationship between the breaking force of lactose, glucose and mannitol tablets and the pore structure characterised by numeric porosity parameters: total pore volume, total pore surface area, mean pore diameter, median pore diameter and volume-size distribution of pores, obtained by mercury porosimetry. A clear overall relationship was found between breaking force of tablets and the median of the cumulative pore volume-pore diameter curve and pore volume-size distribution. The dependence of the breaking force on total surface area of pores was less evident. Fragmentation of granules contributes to the creation of large intergranular and intragranular pores, and further fragmentation and plastic deformation of the primary particles contributes to their reduction in number and size. According to pore volume-size distributions, the decrease in the volume of large pores and the shift of the maximum for volume-size distribution towards smaller pore diameter were related to the increased breaking force of tablets.     

Compression of Lactose,Glucose and Mannitol Granules

The effect of the amount of granulation liquid, compression speed and maximum compression force on the compressibility and compactibility of lactose, glucose and mannitol granules was studied. The porosity based on the geometrical shape and the uniformity of weight of tablets was also studied. Lactose and mannitol granules showed a greater compressibility than glucose granules. Mannitol granules produced the hardest tablets and lactose and glucose the weakest. The change in the amount of granulation liquid caused changes both in the granule porosity and in the amount of binder; this was attributed to differences in tablet strength. All parameters studied were relatively insensitive to changing speeds of compression in the range used, except for the breaking force of mannitol tablets, which was greatest with the lowest speed of compression. All granule masses showed a relatively good continuous flow suitable for tablet production. Tablets compressed from lactose granules had the best uniformity of weight of the tablets studied.     

Mercury porosimetry of microcrystalline cellulose tablets: effect of scanning speed and moisture.

The effect of pretreatment and scanning speed of mercury porosimetry on the porosity result of microcrystalline cellulose tablets was studied. The porosity parameters followed were total pore volume, mean and median pore size, and volume pore size distribution. Scanning speed did not affect the total pore volume of tablets compressed from microcrystalline cellulose. With increasing speed, the smallest pores of powder tablets were not properly determined, which increased the mean pore size. The median pore size of tablets compressed from powder and granules decreased and the maximum at the pore size range 500-1000 nm changed towards smaller pores with increasing scanning speed. Scanning speed appears to affect in different ways the samples with different physical structures. In tablet samples, scanning speed affects the volume of the pores at the whole pore size range determined. Thus, it is important to use about the same, reasonably low scanning speed in the measurements when comparing the samples. Swelling of microcrystalline cellulose in tablet samples is observed by mercury porosimetry measurement; a change in the pore structure is detected after storage at 88% relative humidity as increased total pore volumes and median pore sizes. Due to swelling, the maximum at the pore size range 500-2000 nm changed towards larger pores with increasing moisture. Swelling is observed similarly in tablets manufactured from powder and granules. When storing in humid conditions, water fills the smallest pores of microcrystalline cellulose powder tablets, hinders the intrusion of mercury and, thus, the mean pore size increases. Contrary to this, the volume of the smallest pores of granule tablets compressed with the highest compression pressure increased with increasing moisture. Careful pretreatment before the measurements is important.     

Mercury porosimetry of mannitol tablets: effect of scanning speed and moisture

Purpose of the work was to study the effect of the scanning speed of mercury porosimetry and moisture content of the sample on the mercury porosimetry result for mannitol tablets. Tablets were compressed at three different compression pressures from nonhygroscopic mannitol powder and granules. Pore structure of tablets was determined with three different scanning speeds of a high-pressure mercury porosimeter after storage in three different moisture conditions. With low scanning speed, smallest pores of tablets were determined more accurately. Small amounts of moisture, even as low as 1%, before evacuation in nonhygroscopic mannitol tablets decrease the porosity. Decrease in porosity was observed at a pore diameter range of 50-1000 nm, not at the smallest determined pores. Thus, the role of water in pharmaceutical samples appears to be complicated. Reasonably slow scanning is recommended in high-pressure mercury porosimetry. If total pore volume is the only parameter of interest, fast scanning can be used. Pretreatment of the samples by proper drying before mercury porosimetry is important.     

The effect of shape and porosity on the compression behaviour and tablet forming ability of granular materials formed from microcrystalline cellulose.

The compression behaviour of two types of granules prepared from microcrystalline cellulose was evaluated. Three sets (low, intermediate and high intragranular porosity) of irregular granules and three sets of nearly spherical granules (called pellets) were prepared from microcrystalline cellulose by wet agglomeration or wet agglomeration followed by extrusion/spheronisation. The granules and pellets were similar in size. The range of intragranular porosity, although wide, was also similar for both types. The compression behaviour was evaluated in terms of the degree of compression, the appearance of the tablets and the size distribution of retrieved aggregates (after deaggregation). The compactability of the granules and pellets was also studied. Both types of granules kept their integrity during compression. The dominant mechanism during compression appeared to be permanent deformation. However, during compression of high porosity granules, fragmentation or attrition seemed to occur alongside deformation. Tablets formed from granules had a closer pore structure than those formed from pellets of equal intragranular porosity and the granules seemed to deform to a higher degree during compression. The total tablet porosity was almost independent of the intragranular porosity and the shape of the granules before compression. It is suggested that the degree of granule deformation was controlled by the intragranular porosity and voidage of each bed of granules before compression. The tensile strength of the tablets was also dependent on the porosity and the shape of the granules; tablets formed from irregular granules were stronger than those formed from pellets of an equal intragranular porosity.     

New method of preparing high-porosity rapidly saliva soluble compressed tablets using mannitol with camphor,a subliming material

Compressed tablets of a water-soluble material, prepared using mannitol, did not rapidly dissolve in water since it is difficult for water to penetrate into the tablets due to their low porosity. To increase the porosity of the tablets which are prepared by direct compression using mannitol, we developed a novel method whereby camphor, a subliming material, is removed by sublimation from compressed tablets prepared using a mixture of mannitol and camphor. A high porosity was achieved due to the formation of many pores where camphor particles previously existed in the compressed mannitol tablets prior to sublimation of the camphor. These compressed tablets which have high porosity (approximately 30%) rapidly dissolved within 15 s in saliva in the mouth. We developed a direct compression method for the preparation, using mannitol and camphor, of a meclizine (antidinic agent) tablet with high porosity which dissolves rapidly in saliva.     

压缩方程评价不同孔体积微丸的压缩特性

采用Kawakita压缩方程评价不同孔体积微丸的压缩特性，为微丸压片工艺的研究提供科学依据。采用不同体积比例的乙醇/水混合液作黏合剂，以微晶纤维素 (MCC)、磷酸二氢钙 (DCP) /MCC (4∶1, w/w)、乳糖 (Lac) /MCC (4∶1) 为填充剂，挤出-滚圆工艺分别制备不同孔体积微丸。以Kawakita压缩方程评价前述微丸的压缩特性，结果表明高孔体积MCC微丸可压性最好，而3种孔体积的DCP/MCC (4∶1) 微丸和Lac/MCC (4∶1) 微丸没有显著差别，这与微丸压缩过程中发生的压缩机制有关，MCC微丸主要发生了塑性变形, 另外两类辅料制成的微丸则主要发生破碎，扫描电镜图直观说明了这一现象。研究结果提示微丸压片工艺发生的机制复杂, 选用不同辅料制备微丸的压缩特性各异，而高孔体积MCC微丸和不同孔体积的DCP/MCC微丸和Lac/MCC微丸可作为微丸压片过程中的缓冲颗粒，以保护含药微丸使之在压片过程中保持原有的形态和释放行为。

     

Tablet and capsule hydrophilic matrices based on heterodisperse polysaccharides having porosity-independent in vitro release profiles

The purpose of the study was to investigate the release-controlling action of a swellable hydrophilic material based on heterodisperse polysaccharides (HP) in relation to the initial pore structure of the formulations. HP-based granules were produced under carefully controlled conditions and compacted into matrix tablets having equivalent tablet thickness. Quantification of pore structure using mercury porosimetry showed that the tablets had substantially different pore volumes and pore size distributions. Dissolution studies demonstrated that release of a water-soluble model compound, benzamide, from swollen matrices was affected neither by total porosity nor median pore diameter of the initial dry matrix. To extend the concept of porosity-independent release further, HP-based formulations containing either diclofenac sodium or propranolol HCl were contained within hard gelatin capsules in the form of uncompacted granules. This produced a dosage form with a high intraparticulate porosity in the dry state. Equivalent weights of the same formulations were also compacted into tablets. The in vitro release profiles from matrix tablets compacted from any of the formulations did not differ significantly from release profiles obtained when the same materials were contained uncompacted in hard gelatin capsules.     

Pore size distribution in tablets measured with a morphological sieve

Porosity and pore structure are important characteristics of tablets, since they influence mechanical strength and many other properties. This paper proposes an alternative method for the characterization of pore structure based on image analysis of SEM micrographs. SEM images were made of sodium chloride tablets made with three different particle sizes. The pore size distribution in these images was determined with a technique referred to as a morphological sieve. The results were compared to the pore size distributions as obtained with mercury porosimetry. The SEM images display small cracks inside the grains and small 'floating' grains inside the pore space. As these artifacts are induced in sample preparation, they need to be identified and removed from the images before analysis. The influence of the size of the discarded structures on the total porosity and the pore size distribution was investigated. The small 'floating' grains prevented the determination of the size of large pores, but had a negligible effect on the porosity. The removal of small cracks inside the grains had no effect on the pore size distribution but a large effect on the porosity. Based on the comparison of these results with the experimentally determined porosity, a maximum size for the structures that were to be removed was determined. The resulting pore size distributions were in the same order of magnitude as the results obtained with mercury porosimetry. Both methods display a comparable relative shift of the pore size distributions to larger sizes for tablets with increasing particle size. Therefore, it can be concluded this image analysis technique is a good method for the characterization of pore structure.     

Rapidly disintegrating tablets prepared by the wet compression method: mechanism and optimization.

To make rapidly disintegrating tablets with sufficient mechanical integrity, tablets were prepared by compressing wet granules under low compression force and then drying the resulting wet mass in a circulating-air oven (wet compression method). Lactose with various particle sizes was used as the excipient, and water was used as a wetting agent. The effect of drying time, compression force, size of lactose particles, and moisture content of wet granules on tablet properties indicated that the formation and disintegration time of tablets were related to the effect of the formation of solid bridges between lactose particles. By optimizing compression force, size of lactose particles, and moisture content of the granules, tablets meeting tensile strength greater than 0.5 MPa and disintegration time shorter than 15 s were obtained by the wet compression method.     

Tablet and Capsule Hydrophilic Matrices Based on Heterodisperse Polysaccharides Having Porosity-Independent In Vitro Release Profiles

The purpose of the study was to investigate the release-controlling action of a swellable hydrophilic material based on heterodisperse polysaccharides (HP) in relation to the initial pore structure of the formulations. HP-based granules were produced under carefully controlled conditions and compacted into matrix tablets having equivalent tablet thickness. Quantification of pore structure using mercury porosimetry showed that the tablets had substantially different pore volumes and pore size distributions. Dissolution studies demonstrated that release of a water-soluble model compound, benzamide, from swollen matrices was affected neither by total porosity nor median pore diameter of the initial dry matrix. To extend the concept of porosity-independent release further, HP-based formulations containing either diclofenac sodium or propranolol HCl were contained within hard gelatin capsules in the form of uncompacted granules. This produced a dosage form with a high intraparticulate porosity in the dry state. Equivalent weights of the same formulations were also compacted into tablets. The in vitro release profiles from matrix tablets compacted from any of the formulations did not differ significantly from release profiles obtained when the same materials were contained uncompacted in hard gelatin capsules.     

Use of mercury porosimetry, assisted by nitrogen adsorption in the investigation of the pore structure of tablets

The microstructure of pharmaceutical solid dosage forms (porosity, pore volume-size distribution, specific surface area) can be investigated by different methods. Mercury porosimetry and nitrogen gas adsorption have been widely used to characterize the pore structure of tablets because these methods enable the determination of porosity and pore size distribution in one step. The two techniques are based on different physical interactions and cover specific ranges of pore size. Mercury porosimetry determines mesopores and macropores, whereas gas adsorption covers the micropore range. The aim of this study was to investigate the relationship between the compression force and the structure of tablets containing theophylline. The porosity parameters determined with mercury porosimetry and nitrogen adsorption were compared. The results indicated a good correlation between the applied compression forces and the porosity parameters of the tablets. The pore volume-size distributions, the pore size frequencies and the specific surface areas obtained with mercury porosimetry and nitrogen adsorption were not equal, which can be attributed to the different measurement ranges and to the complexity of the pore structures. Our results allow the conclusion that mercury porosimetry, assisted by nitrogen adsorption as a complementary technique, is an acceptable method to achieve a proper characterization of the internal structure of tablets.     

Pore formation in tablets compressed from binary mixtures as a result of deformation and relaxation of particles.

This paper describes the internal structure of tablets compressed from binary mixtures of sodium chloride and pregelatinised starch. The minimum particle diameter of pregelatinised starch inside tablets compressed from mixtures was calculated from the difference between the initial pore size distribution and the pore size distribution after removal of the starch particles by burning. Subsequently, the tablets were carefully crushed. These powders, consisting of almost only sodium chloride particles, were measured by laser diffraction. It was found that the diameter of the sodium chloride particles hardly changed, whereas the minimum diameter of starch particles strongly decreased during the compaction process. As an effect of the difference in yield pressure, the harder sodium chloride particles cause deformation of the softer starch particles, resulting in a change in particle shape. The pore size distribution of tablets compressed from mixtures of sodium chloride and starch is typically that of viscoelastic materials; the larger pores (>5 microm) change, while the small pores stay constant in number and size. The median pore diameter in tablets compressed from the mixtures is higher than the median pore diameter in tablets compressed from the pure materials. This paper shows that the formation of large pores was the result of the extra porosity expansion of tablets compressed from binary mixtures of sodium chloride and pregelatinised starch.     

The effect of granule properties on the pore structure of tablets of sucrose and lactose

Air permeability and liquid penetration of tablets of sucrose and lactose have been measured. The tablets had been compressed over a wide pressure range from granules which varied in bulk density, size and strength. The degree to which inter- and intra-granular pore structure within the tablet was sustained varied with these properties; low pressure, high density, high strength and large size promoting a more open but less uniform structure. Such structures allowed rapid penetration of liquid through a coarse pore network which isolated a large fraction of the total pore space. Thus tablets of high permeability gave low final degrees of saturation whereas less permeable tablets became fully saturated.     

Compression behaviour of κ-carrageenan pellets

The compression behavior of high- and low drug strength pellets containing κ-carrageenan as pelletisation aid was investigated. Model drugs and fillers with different compression mechanisms were used and the effects of compression force and turret speed were examined. Regardless of the compression behavior of their starting components, all pellet formulations exhibited minimal to absent fragmentation and underwent compression by deformation, confirmed by increased equivalent diameter and aspect ratio and decreased roundness factor of the pellets retrieved after de-aggregation of tablets prepared from lubricated pellets. The retrieved pellets showed also higher fracture resistance in three of the tested formulations and no statistically significant difference in the remaining one thus excluding significant crack formation. A densification mechanism was suggested by decreased total porosity and reduced median pore radius of the compressed pellets. No effect of the process parameters on the degree of pellet deformation was reported. The tensile strength of the tablets prepared from unlubricated pellets increased slightly with increased compression force. Compression of pellets with high density silicified microcrystalline cellulose (SMCC HD 90) as embedding powder protected them from severe deformation and resulted in tablets with sufficient tensile strength, minimal friability, negligible elastic recovery and short disintegration time. The percentage of the pellets and the compression force affected the tensile strength of the prepared tablets whereas no influence of the turret speed and the pre-compression force was observed.     

Effect of spatial distribution of contaminant microorganisms within tablet formulations on subsequent inactivation through compaction

A wet granulation process, employing an aqueous suspension of Bacillus megaterium spores as binder, was used to prepare contaminated granules of three direct compression vehicles, Emdex, lactose and potassium chloride. Granules were also prepared with sterile water as binder and directly contaminated by dry mixing with B. megaterium spores, as were the original direct compression vehicles. Particle size distributions for the granules and the direct compression vehicles were similar. Survival of B. megaterium was assessed, following compaction (500 mg) at various pressures (0–271 MN · m⁻²) using a 1 cm flat-faced punch and a 10 ton hydraulic press. In all cases the degree of killing was directly proportionate to the compaction pressure. For those materials compacting by fracture, lactose and Emdex, then the degree of killing was similar for the dry contaminated direct compression vehicle and those granules prepared with contaminated binding fluid, but significantly greater in the dry contaminated granules and greater overall for lactose rather than Emdex. For potassium chloride, a material which plastically deforms, then the degree of killing was significantly enhanced by incorporation of the contaminant into the binding fluid.     

Effects of the diluent type on compressional characteristics of the mixed stem bark extract of Anogeissus leiocarpus and Prosopis africana tablet formulation

The hot water extract of a mixture of stem barks of Anogeissus leiocarpus and Prosopis africana was formulated into tablets using the wet granulation method of massing and screening. The Heckel equation was used to study the compaction characteristics of the extract formulated with lactose (water-soluble) or magnesium carbonate (water-insoluble) as diluents. Granules prepared using magnesium carbonate were found to exhibit two stages of deformation - an initial fragmentation followed by plastic flow while those formulated with lactose consolidated mainly by plastic deformation. Compressibility profiles of the formulations were affected by the diluent type. Tensile strength of granules formulated with magnesium carbonate was found to increase as the compression pressure increased from 56.6 to 113.2 MN m(-2) while the tensile strength of tablets formulated with lactose had its maximum at a compression force of 84.9 MN m(-2).     

Microcrystalline cellulose and its microstructure in pharmaceutical processing.

Mercury porosimetry and nitrogen adsorption methods were used in pore structure and pore surface area characterisation of microcrystalline cellulose powder, granules and tablets. The effect of compression on pore structure and surface area of tablets compressed with three different compression pressures of powder and granules was determined. Densification of MCC in wet granulation led to decreased compactibility in tableting. Effects of granulation on the microstructure of microcrystalline cellulose and plastic deformation of powder during compression were detected with nitrogen adsorption, at the diameter range 3-200 nm. Structure of granules was destroyed during tableting when compression pressures of 196 MPa were used. Fragmentation and deformation of granules were observed from the results determined using both methods. Due to different measurement ranges, different theoretical basis of the methods and behaviour of the samples during analysis, results obtained with mercury porosimetry and nitrogen adsorption methods are not strictly comparable. Results obtained with mercury porosimetry give information on the behaviour of powder and granule particles in granulation or compression, whereas nitrogen adsorption brings out the changes in intraparticular structure of particles. The results obtained using these methods together can be used in the characterisation of behaviour of materials in granulation and tableting.     

Validation of a high-performance liquid chromatographic method for the determination of norfloxacin and its application to stability studies (photo-stability study of norfloxacin)

The development and validation study of a sensitive, rapid, reproducible, easy and precise reversed-phase high-performance liquid chromatographic assay for norfloxacin (NFLX) samples from photo-stability of solid dosage forms, without using gradient elution, extraction methods and without using counter-ion has been carried out. The method showed excellent linearity (r²≥0.999) in the range 1–20 μg ml⁻¹ using a Lichrosorb-RP-8 column (10 μm, 20 cm×g4.6 mm) and UV-detection (278 nm) at ambient temperature. This method showed good efficiency for the analysis of photodegraded NFLX samples, and was applied to study the photo-stability of NFLX tablets under different conditions (direct sun light, ultraviolet light and fluorescent light). It was proven that the use of a disintegrant can increase the photo-stability of the NFLX in the tablets. This effect was studied in directly compressible tablets with microcrystalline cellulose (MCC) and mannitol for direct compression.     

Determination of porosity and pore-size distribution of aspirin tablets relevant to drug stability.

Total porosity and pore-size distribution of aspirin tablets prepared from aspirin, starch USP, and precipitated colloidal silicon dioxide were determined using mercury porosimetry. The model represented a hydrolyzable drug substance in combination with simple excipients. The role of starch and silicon dioxide on the microstructure of the tablets was investigated, as was the chemical stability of various systems. In general, the porosity of tablets containing a constant quantity of starch increased linearly with silicon dioxide concentration. Examination of the pore-size distribution, however, revealed that a low concentrations silicon dioxide functioned primarily to reduce the size and volume of coarse pores representing the spaces between the agglomerates of starch and aspirin particles. This effect was optimum at 3%. A further increase in silicon dioxide concentration produced tablets with relatively larger pore sizes. Studies of changes in the porosity characteristics of tablets as influenced by water vapor over time showed distinct differences in this complex parameter. A unique trend in the change of the pore-size distribution was noted with tablets containing 3% silicon dioxide. These observations are discussed relative to the stability of aspirin tablets in which this concentration of silicon dioxide produced a maximum stabilizing effect.