Mannitol Tablets Research Articles

Discriminating polymorph distributions in pharmaceutical tablets using stimulated Raman scattering microscopy

AbstractStimulated Raman scattering (SRS) imaging is used to probe active pharmaceutical ingredient exhibiting polymorphism within compact tablets. We show that few SRS images performed at selected wavenumbers allow to access both active pharmaceutical ingredients polymorphs and excipients from which molecular mapping is retrieved over millimetre‐size areas. We exemplified the approach using SRS images acquired at five wavenumbers to map clopidogrel and amibegron polymorphs embedded into excipients (polyethylene glycol, corn starch, and mannitol tablets). Our study demonstrates that SRS imaging can be used as a novel fast molecular mapping technique for pharmaceutical tablets characterization.

On Identification of Critical Material Attributes for Compression Behaviour of Pharmaceutical Diluent Powders.

As one of the commonly-used solid dosage forms, pharmaceutical tablets have been widely used to deliver active drugs into the human body, satisfying patient’s therapeutic requirements. To manufacture tablets of good quality, diluent powders are generally used in formulation development to increase the bulk of formulations and to bind other inactive ingredients with the active pharmaceutical ingredients (APIs). For formulations of a low API dose, the drug products generally consist of a large fraction of diluent powders. Hence, the attributes of diluents become extremely important and can significantly influence the final product property. Therefore, it is essential to accurately characterise the mechanical properties of the diluents and to thoroughly understand how their mechanical properties affect the manufacturing performance and properties of the final products, which will build a sound scientific basis for formulation design and product development. In this study, a comprehensive evaluation of the mechanical properties of the widely-used pharmaceutical diluent powders, including microcrystalline cellulose (MCC) powders with different grades (i.e., Avicel PH 101, Avicel PH 102, and DG), mannitol SD 100, lactose monohydrate, and dibasic calcium phosphate, were performed. The powder compressibility was assessed with Heckel and Kawakita analyses. The material elastic recovery during decompression and in storage was investigated through monitoring the change in the dimensions of the compressed tablets over time. The powder hygroscopicity was also evaluated to examine the water absorption ability of powders from the surroundings. It was shown that the MCC tablets exhibited continuous volume expansion after ejection, which is believed to be induced by (1) water absorption from the surrounding, and (2) elastic recovery. However, mannitol tablets showed volume expansion immediately after ejection, followed by the material shrinkage in storage. It is anticipated that the expansion was induced by elastic recovery to a limited extent, while the shrinkage was primarily due to the solidification during storage. It was also found that, for all powders considered, the powder compressibility and the elastic recovery depended significantly on the particle breakage tendency: a decrease in the particle breakage tendency led to a slight decrease in the powder compressibility and a significant drop in immediate elastic recovery. This implies that the particle breakage tendency is a critical material attribute in controlling the compression behaviour of pharmaceutical powders.

Physicochemical characterization of dipeptidyl peptidase-4 inhibitor alogliptin in physical mixtures with excipients

Alogliptin (ALG) is a hypoglycemic drug used in diabetes which inhibits the enzyme dipeptidyl peptidase-4 (DPP-4), preventing the degradation of incretins, stimulating insulin secretion. The physicochemical characteristics of ALG were evaluated by differential scanning calorimetry (DSC), thermogravimetry (TG) and scanning electron microscopy equipped with energy-dispersive X-ray spectrometer (SEM/EDS). The compatibility studies were carried out between ALG and excipients (physical mixtures, 1:1) using DSC, TG, diffuse reflectance Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD) and hot-stage microscopy. ALG presented purity near to 99%, melted in the range of 179.4–187.2 °C, followed by decomposition which started in 198.0 °C. SEM/EMS analysis of ALG presented irregular crystals and traces of impurities as copper and lead. DSC investigations obtained by physical mixtures showed minor alterations in the melting ranges of ALG with mannitol, magnesium stearate and commercial tablets. Solubilization of ALG in the fused excipient was observed by hot-stage microscopy between mannitol and ALG, and in tablets. The interaction observed in the mixture with magnesium stearate is due to the melting of the excipient and drug separately, first the excipient and then the drug. FTIR showed additional bands related to the excipients. XRPD proved that ALG has a crystal form and no alterations in the ALG profile were observed after the mixtures. ALG was compatible with all excipients tested. These results were important to understand the characteristics, stability and compatibility of the drug, and proved to be useful in preformulation studies.

Influence of mannitol concentration on the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol

Mannitol is a pharmaceutical excipient that is receiving increased popularity in solid dosage forms. The aim of this study was to provide comparative evaluation on the effect of mannitol concentration on the physicochemical, mechanical, and pharmaceutical properties of lyophilised mannitol. The results showed that the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol powders are strong functions of mannitol concentration. By decreasing mannitol concentration, the true density, bulk density, cohesivity, flowability, netcharge-to-mass ratio, and relative degree of crystallinity of LM were decreased, whereas the breakability, size distribution, and size homogeneity of lyophilised mannitol particles were increased. The mechanical properties of lyophilised mannitol tablets improved with decreasing mannitol concentration. The use of lyophilised mannitol has profoundly improved the dissolution rate of indomethacin from tablets in comparison to commercial mannitol. This improvement exhibited an increasing trend with decreasing mannitol concentration. In conclusion, mannitols lyophilised from lower concentrations are more desirable in tableting than mannitols from higher concentrations due to their better mechanical and dissolution properties.

A pragmatic approach for engineering porous mannitol and mechanistic evaluation of particle performance

The importance of mannitol has increased recently as an emerging diluent for orodispersible dosage forms. The study aims to prepare spray dried mannitol retaining high porosity and mechanical strength for the development of orally disintegrating tablets (ODTs).Aqueous feed of d-mannitol (10% w/v) comprising ammonium bicarbonate, NH4HCO3 (5% w/v) as pore former was spray dried at inlet temperature of 110–170°C. Compacts were prepared at 151MPa and characterized for porosity, hardness and disintegration time. Particle morphology and drying mechanisms were studied using thermal (HSM, DSC and TGA) and polymorphic (XRD) methods.Tablet porosity increased from 0.20±0.002 for pure mannitol to 0.53±0.03 using fabricated porous mannitol. Disintegration time dropped by 50–77% from 135±5.29s for pure mannitol to 75.33±2.52–31.67±1.53s for mannitol 110–170°C. Hardness increased by 150% at 110°C (258.67±28.89N) and 30% at 150°C (152.70±10.58N) compared to pure mannitol tablets (104.17±1.70N). Increasing inlet temperature resulted in reducing tablet hardness due to generation of ‘micro-sponge’-like particles exhibiting significant elastic recovery. Impact of mannitol polymorphism on plasticity/elasticity cannot be ruled out as a mixture of α and β polymorphs formed upon spray drying.

Using Terahertz Reflectance Spectroscopy to Quantify Drug Substance in Tablets

The purpose of this research is to investigate the applicability of terahertz (THz) reflectance spectroscopy for quantification of drug substance in tablets, so as to demonstrate the feasibility for applying this technique to tableting process monitoring. In order to acquire a suitable absorbance spectrum for this purpose, it was necessary to enhance the reflection intensity. By using an aluminum plate as a mirror at the opposite surface of the tablet, a reasonable absorbance spectrum could be acquired to reflect the bulk information of the tablet. To assess the limit of tablet thickness, linearity between the tablet thickness and the absorbance value was investigated using lactose and mannitol tablets. Since linearity was found within 0.75-5.0 mm for both tablets using 0.4 and 0.8 THz region, it was confirmed that THz reflectance spectroscopy is applicable to tablets within at least 5.0 mm thickness. Mannitol tablets containing sodium salicylate as the model drug substance were used to investigate the quantitative performance of this technique. It was confirmed that the established calibration model was acceptable for this quantification because of the root-mean-squared error of cross-validation (RMSECV) being 1.95%. In order to evaluate the applicability of this technique, content quantitative performance in double layered tablets having active and placebo layers were assessed. Since this calibration model achieved the root-mean-squared error of prediction (RMSEP) of 1.42% for the double layered tablets, this technique was considered feasible even if the drug substance is localized in the tablets.

The effect of compression pressure on hardness value in Avicel, lactose and mannitol tablets

The effect of compression pressure on hardness value in Avicel, lactose and mannitol tablets

Compression of lactose, glucose and mannitol granules.

The effect of the amount of granulation liquid, compression speed and maximum compression force on then 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 table production. Tablets compressed from lactose granules had the best uniformity of weight of the tablets studied.

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.

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.

Porosity parameters of lactose, glucose and mannitol tablets obtained by mercury porosimetry

The effect of compression force, compression speed and the amount of granulation liquid on the porosity parameters determined from lactose, glucose and mannitol tablets by high-pressure mercury porosimetry was investigated. Compression force affected all parameters measured, except the total pore surface area of lactose tablets. The changes in tablet microstructure with increasing compression force were particularly well detected from the pore volume size distributions of tablets. Compression speed affected the total pore volume of lactose tablets, both mean and median pore diameters of lactose tablets and mannitol tablets compressed from granules produced with a low amount of liquid, and the median pore diameter of glucose tablets. The compression speed dependence of these parameters was a sign of the time-dependent deformation of materials during compression. The amount of granulation liquid affected the total pore surface area of lactose and mannitol tablets. With a high amount of liquid, the surface area of pores was greater. The mean pore size of all tablets and the median pore diameter of mannitol tablets were smaller when a high amount of granulation liquid was used. Even when compressed with a high force, the pore volume size distributions of mannitol tablets with a low amount of granulation liquid were broader and the maxima were at larger pore diameters. It was concluded that each porosity parameter measured characterised the pore structure of compressed tablets from a different aspect. Thus, the use of all porosity parameters proved to be useful.

Change in porosity parameters of lactose, glucose and mannitol granules caused by low compression force

The change in porosity parameters, i.e., total pore volume, porosity percentage and pore volume size distribution of lactose, glucose and mannitol granules caused by compression with a low force was investigated. In compression, fragmentation of lactose and glucose granules increased total pore volume and porosity percentage, whereas the total pore volume and porosity percentage of mannitol granules was clearly decreased. This was due to the highly porous structure of mannitol granules, which densified easily in compression. Lactose and glucose granules were shown to resist deformation more. The pore volume size distributions of lactose and glucose tablets showed that large pores ( > 14 μm) decreased in size. For mannitol tablets, the large pores vanished and simultaneously the small granule pores ( < 14 μm) reduced in size. The features of the pore structure of granules were detected in the pore volume size distributions of compressed tablets. Mercury porosimetry, assisted by scanning electron microscopy, was shown to be an adequate method to evaluate the deformation of granules in compression.

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.