The Effects of Fillers and Binders on the Accuracy of Tablet Subdivision

The effects of excipients on the accuracy of tablet subdivision are severely underinvestigated. In this study, placebo tablets were prepared using a combined mixture design of fillers and binders to evaluate the effect of these excipients on subdivision accuracy. The responses assessed were mass loss, mass variation, tablet fragmentation, and increased friability. Dicalcium phosphate dihydrate (DCP) gave rise to more uniform and denser tablets than microcrystalline cellulose (MCC), thus resulting in greater subdivision accuracy. The binder type, hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (PVP), did not affect the subdivision of DCP tablets. On the contrary, the structural similarity between HPC and MCC led to improved subdivision accuracy for MCC tablets. A less accurate subdivision was observed in tablets prepared with a DCP–MCC combination; this finding could be attributed to irregular binder distribution in this matrix. An optimized response was built using desirability analysis. This study helps to illuminate the relationship between fillers and binders to guide formulation scientists in the development of tablets with better subdivision performance.     

Evidence-Based Nanoscopic and Molecular Framework for Excipient Functionality in Compressed Orally Disintegrating Tablets

The work investigates the adhesive/cohesive molecular and physical interactions together with nanoscopic features of commonly used orally disintegrating tablet (ODT) excipients microcrystalline cellulose (MCC) and D-mannitol. This helps to elucidate the underlying physico-chemical and mechanical mechanisms responsible for powder densification and optimum product functionality. Atomic force microscopy (AFM) contact mode analysis was performed to measure nano-adhesion forces and surface energies between excipient-drug particles (6-10 different particles per each pair). Moreover, surface topography images (100 nm²–10 µm²) and roughness data were acquired from AFM tapping mode. AFM data were related to ODT macro/microscopic properties obtained from SEM, FTIR, XRD, thermal analysis using DSC and TGA, disintegration testing, Heckel and tabletability profiles. The study results showed a good association between the adhesive molecular and physical forces of paired particles and the resultant densification mechanisms responsible for mechanical strength of tablets. MCC micro roughness was 3 times that of D-mannitol which explains the high hardness of MCC ODTs due to mechanical interlocking. Hydrogen bonding between MCC particles could not be established from both AFM and FTIR solid state investigation. On the contrary, D-mannitol produced fragile ODTs due to fragmentation of surface crystallites during compression attained from its weak crystal structure. Furthermore, AFM analysis has shown the presence of extensive micro fibril structures inhabiting nano pores which further supports the use of MCC as a disintegrant. Overall, excipients (and model drugs) showed mechanistic behaviour on the nano/micro scale that could be related to the functionality of materials on the macro scale.     

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.     

Application of Crustacean Chitin as a Co-diluent in Direct Compression of Tablets

A “simplex-centroid mixture design” was used to study the direct-compression properties of binary and ternary mixtures of chitin and two cellulosic direct-compression diluents. Native milled and fractioned (125–250 μm) crustacean chitin of lobster origin was blended with microcrystalline cellulose, MCC (Avicel® PH 102) and spray-dried lactose–cellulose, SDLC Cellactose® (composed of a spray-dried mixture of alpha-lactose monohydrate 75% and cellulose powder 25%). An instrumented single-punch tablet machine was used for tablet compactions. The flowability of the powder mixtures composed of a high percentage of chitin and SDLC was clearly improved. The fractioned pure chitin powder was easily compressed into tablets by using a magnesium stearate level of 0.1% (w/w) but, as the die lubricant level was 0.5% (w/w), the tablet strength collapsed dramatically. The tablets compressed from the binary mixtures of MCC and SDLC exhibited elevated mechanical strengths (>100 N) independent of the die lubricant level applied. In conclusion, fractioned chitin of crustacean origin can be used as an abundant direct-compression co-diluent with the established cellulosic excipients to modify the mechanical strength and, consequently, the disintegration of the tablets. Chitin of crustacean origin, however, is a lubrication-sensitive material, and this should be taken into account in formulating direct-compression tablets of it.     

Evaluation of powder and tableting properties of chitosan

The aim of this study was to analyze the process of tablet formation and the properties of the resulting tablets for 3 N-deacetylated chitosans, with a degree of deacetylation of 80%, 85%, or 90%. Material properties, such as water content, particle size and morphology, glass transition temperature, and molecular weight were studied. The process of tablet formation was analyzed by 3-D modeling, Heckel analysis, the pressure time function, and energy calculations in combination with elastic recovery dependent on maximum relative density and time. The crushing force and the morphology of the final tablets were analyzed. Chitosans sorb twice as much water as microcrystalline cellulose (MCC), the particle size is comparable to Avicel PH 200, a special type of MCC, the particles look like shells, and the edges are bent. Molecular weight ranges from 80 000 to 210 000 kDa, the glass transition temperature (Tg) was not dependent on molecular weight. The chitosans deform ductilely as MCC; however, plastic deformation with regard to time and also pressure plasticity are higher than for MCC, especially for Chit 85, which has the lowest crystallinity and molecular weight. At high densification, fast elastic decompression is higher. 3-D modeling allowed the most precise analysis. Elastic recovery after tableting is higher than for MCC tablets and continues for some time after tableting. The crushing force of the resulting tablets is high owing to a reversible exceeding of Tg in the amorphous parts of the material. However, the crushing force is lower compared with MCC, since the crystallinity and the Tg of the chitosans are higher than for MCC. In summation, chitosans show plastic deformation during compression combined with high elasticity after tableting. Highly mechanically stable tablets result. Published: September 8, 2006     

A study on moisture isotherms of formulations: the Use of polynomial equations to predict the moisture isotherms of tablet products

The objectives of this study were to investigate the effects of manufacturing parameters on the moisture sorption isotherms of some tablet formulations and to predict the moisture isotherms of the final formulations using polynomial equations. Three tablet formulations including a placebo and 2 drug products were prepared through wet granulation, drying, compression, and coating processes. Equilibrium moisture content of excipients and granules at 25°C with different relative humidities were determined using a dynamic moisture sorption microbalance, while such data for tablets were determined using desiccators. Moisture sorption isotherms were expressed in polynomial equations. Excipient isotherms were used to predict the moisture sorption isotherms of the 3 tablet products. Results showed that different physical properties of granules and tablets, such as particle size distribution, density, and porosity resulting from different granulation and compression conditions did not have significant effect on the moisture isotherms of the materials. Changing coating materials from a powder mixture to a film also did not change the moisture sorption characteristics significantly. The predicted moisture sorption isotherms of the formulations agreed well with the experimental results. These results show that moisture isotherms of solid pharmaceutical products manufactured with conventional processes may be predicted using the isotherms of excipients, and polynomial equations may be used as a tool for the prediction of moisture isotherms.     

The Development of Self-nanoemulsifying Liquisolid Tablets to Improve the Dissolution of Simvastatin

The aim of this work was to develop self-nanoemulsifying liquisolid tablets (SNELT) to enhance the dissolution profile of poorly water-soluble simvastatin. SNELT present a unique technique of incorporating self-nanoemulsifying drug delivery systems (SNEDDS) into tablets. Optimized SNEDDS containing different oils, Cremophor^® RH 40 (surfactant) and Transcutol^® HP (co-surfactant), at different ratios, were used as liquid vehicles and loaded on carrier material, microcrystalline cellulose (MCC), and coating material, Cab-o-sil^® H-5 (nanosize colloidal silicon dioxide) powders at different loading factors (L _f ) and fixed excipient ratio (R?=?20). The effect of using different carrier materials, granulated mannitol, crystalline mannitol, and maltodextrin with MCC at different ratios, and different coating materials, Aeroperl^® 300 (granulated silicon dioxide) at different excipient ratios (R), was also emphasized. Liquisolid powders with acceptable flowability, compressibility, and tablet weight were compressed into tablets. Results revealed that powders with L _f ?=?0.2 possessed the most preferable properties to be tableted. SNELT with MCC and Cab-o-sil^® H-5 were able to generate nanoemulsions and to enhance the cumulative percent of drug dissolved at 60 min significantly to reach up to 90%. Furthermore, using carrier material (granulated mannitol/MCC at ratio 3:1) enabled SNELT to disperse into nanoemulsion (Z-average?=?25.7 nm) and improved the dissolution profile significantly to reach 99% at 60 min. Cab-o-sil^® H-5 proved to be a better coating material compared to Aeroperl^® 300. In conclusion, developed SNELT were promising in enhancing in vitro dissolution of simvastatin and excipients highly affect SNELT’s performance.     

Assessment of Active Pharmaceutical Ingredient Particle Size in Tablets by Raman Chemical Imaging Validated using Polystyrene Microsphere Size Standards

Particle size is a critical parameter for controlling pharmaceutical quality. The aim of this study was to assess the size of the micrometer-scale active pharmaceutical ingredients (API) in tablets using Raman chemical imaging and to understand the effects of formulation on particle size. Model tablets containing National Institute of Standards and Technology traceable polystyrene microsphere size standards were developed to determine the binarization threshold value of Raman chemical images for API particle sizing in specific formulations and processes. Three sets of model tablets containing 5, 10, and 15 μm polystyrene microspheres, used to mimic API, were prepared using a commercial tablet formulation (Ebastel tablets, mean API particle size was about 5 μm). Raman mapping with a 50× objective (NA, 0.75) was applied to tablet cross-sections, and particle size of polystyrene microspheres was estimated from binary images using several binarization thresholds. Mean particle size for three sets of polystyrene microspheres showed good agreement between pre- and postformulation (the slope = 1.024, R = 1.000) at the specific threshold value ((mean + 0.5σ) of the polystyrene-specific peak intensity histogram), regardless of particle agglomeration, tablet surface roughness, and laser penetration depth. The binarization threshold value showed good applicability to Ebastel tablets, where the API-specific peak intensity histogram showed a pattern similar to that of polystyrene microspheres in model tablets. The model tablets enabled determination of an appropriate binarization threshold for assessing the mean particle size of micrometer-scale API in tablets by utilizing the unique physicochemical properties of polystyrene microspheres.KEY WORDS: binarization threshold, image analysis, particle size, polystyrene microspheres, Raman chemical imaging     

Rates of Dissolution of Tolbutamide Tablets

An investigation was made of the pharmaceutical properties and the in vitro dissolution rates of 18 commercially available brands of tolbutamide tablets, all of which met the limits set by the Food and Drug Regulations for tablets sold in Canada.A marked variation in dissolution rates was found, which bore no relation to the official disintegration time. These wide variations in dissolution rate point to a need for (a) a comprehensive study of the in vivo effects of different tolbutamide tablets, and (b) an official test that sets limits for the rate of dissolution of tolbutamide tablets, in addition to the one that places limits on disintegration time.     

Evaluation of Citrus Fibers as a Tablet Excipient

The consumption of fibers is associated with many health benefits, such as a reduction of cardiovascular and gastrointestinal diseases, control of body weight, and prevention of diabetes. Despite the widespread use of fiber supplements such as capsules or tablets, there is an almost complete lack of information concerning the technological properties of functional fibers used in nutraceutical formulations. The aim of this work was to characterize the technological properties of citrus fibers necessary for their use as a processing aid in tableting. The results obtained showed that citrus fibers share many properties of other polysaccharides used as tableting excipients, such as thermal behavior and compaction mechanism, together with an appreciable tabletability. However, the most interesting properties resulted from their disintegration power. Citrus fibers behaved in a similar manner to the well-known super disintegrant croscarmellose sodium and resulted to be little susceptible to their concentration, to lubricant type, and lubricant concentration. Thus, this work supports the idea of a potential use of citrus fibers as “active” substances and processing aid in the tableting of nutraceutical products and also as functional excipient in pharmaceutical tablets formulation.     

Monitoring Blending of Pharmaceutical Powders with Multipoint NIR Spectroscopy

Blending of powders is a crucial step in the production of pharmaceutical solid dosage forms. The active pharmaceutical ingredient (API) is often a powder that is blended with other powders (excipients) in order to produce tablets. The blending efficiency is influenced by several external factors, such as the desired degree of homogeneity and the required blending time, which mainly depend on the properties of the blended materials and on the geometry of the blender. This experimental study investigates the mixing behavior of acetyl salicylic acid as an API and α-lactose monohydrate as an excipient for different filling orders and filling levels in a blender. A multiple near-infrared probe setup on a laboratory-scale blender is used to observe the powder composition quasi-simultaneously and in-line in up to six different positions of the blender. Partial least squares regression modeling was used for a quantitative analysis of the powder compositions in the different measurement positions. The end point for the investigated mixtures and measurement positions was determined via moving block standard deviation. Observing blending in different positions helped to detect good and poor mixing positions inside the blender that are affected by convective and diffusive mixing.     

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.     

A novel approach in the assessment of polymeric film formation and film adhesion on different pharmaceutical solid substrates

The purpose of this study was to evaluate the nature of film formation on tablets with different compositions, using confocal laser scanning microscopy (CLSM), and to measure film adhesion via the application of a novel “magnet probe test”. Three excipients, microcrystalline cellulose (MCC), spray-dried lactose monohydrate, and dibasic calcium phosphate dihydrate, were individually blended with 0.5% magnesium stearate, as a lubricant, and 2.5% tetracycline HCl, as a fluorescent marker, and were compressed using a Carver press. Tablets were coated with a solution consisting of 7% hydroxypropyl methylcellulose (HPMC) phthalate (HP-55), and 0.5% cetyl alcohl in acetone and isopropanol (11:9). The nature of polymer interaction with the tablets and coating was evaluated using CLSM and a designed magnet probe test. CLSM images clearly showed coating efficiency, thickness, and uniformity of film formation, and the extent of drug migration into the film at the coating interfaces of tablets. Among the excipients, MCC demonstrated the best interface for both film formation and uniformity in thickness relative to lactose monohydrate and dibasic calcium phosphate dihydrate. The detachment force of the coating layers from the tablet surfaces, as measured with the developed magnet probe test, was in the order of MCC>lactose monohydrate>dibasic calcium phosphate dihydrate. It was also shown that the designed magnet probe test provides reliable and reproducible results when used for measurement of film adhesion and bonding strength.     

Preparation and Evaluation of Self-nanoemulsifying Tablets of Carvedilol

The purpose of this study was to combine the advantages of self-nanoemulsifying drug delivery systems and tablets as a conventional dosage form emphasizing the excipients’ effect on the development of a new dosage form. Systems composed of HCO-40, Transcutol® HP, and medium-chain triglyceride were prepared. Essential properties of the prepared systems regarding carvedilol solubility, a model drug, and self-emulsification time were determined. In order to optimize self-nanoemulsifying drug delivery systems (SNEDDS), formulation dispersion–drug precipitation test was performed in the absence and presence of cellulosic polymers. Furthermore, SNEDDS was loaded onto liquisolid powders. P-glycoprotein (P-gp) activity of the selected SNEDDS was tested using HCT-116 cells. Carvedilol showed acceptable solubility in the selected excipients. It also demonstrated improvement in the stability upon dilution with aqueous media in the presence of cellulosic polymers. Use of granulated silicon dioxide improved the physical properties of liquisolid powders containing SNEDDS. It improved the compressibility of the selected powders and the tested SNEDDS showed marked P-gp inhibition activity. Prepared self-nanoemulsifying tablet produced acceptable properties of immediate-release dosage forms and expected to increase the bioavailability of carvedilol.     

Development of Tablet Formulation of Amorphous Solid Dispersions Prepared by Hot Melt Extrusion Using Quality by Design Approach

The objective of the study was to identify the extragranular component requirements (level and type of excipients) to develop an immediate release tablet of solid dispersions prepared by hot melt extrusion (HME) process using commonly used HME polymers. Solid dispersions of compound X were prepared using polyvinyl pyrrolidone co-vinyl acetate 64 (PVP VA64), Soluplus, and hypromellose acetate succinate (HPMCAS-LF) polymers in 1:2 ratio by HME through 18 mm extruder. A mixture design was employed to study effect of type of polymer, filler (microcrystalline cellulose (MCC), lactose, and dicalcium phosphate anhydrous (DCPA)), and disintegrant (Crospovidone, croscarmellose sodium, and sodium starch glycolate (SSG)) as well as level of extrudates, filler, and disintegrant on tablet properties such as disintegration time (DT), tensile strength (TS), compactibility, and dissolution. Higher extrudate level resulted in longer DT and lower TS so 60–70% was the maximum amount of acceptable extrudate level in tablets. Fast disintegration was achieved with HPMCAS-containing tablets, whereas Soluplus- and PVP VA64-containing tablets had higher TS. Crospovidone and croscarmellose sodium were more suitable disintegrant than SSG to achieve short DT, and MCC was a suitable filler to prepare tablets with acceptable TS for each studied HME polymer. The influence of extragranular components on dissolution from tablets should be carefully evaluated while finalizing tablet composition, as it varies for each HME polymer. The developed statistical models identified suitable level of fillers and disintegrants for each studied HME polymer to achieve tablets with rapid DT (<15 min) and acceptable TS (≥1 MPa at 10–15% tablet porosity), and their predictivity was confirmed by conducting internal and external validation studies.     

Excipient Stability in Oral Solid Dosage Forms: A Review

The choice of excipients constitutes a major part of preformulation and formulation studies during the preparation of pharmaceutical dosage forms. The physical, mechanical, and chemical properties of excipients affect various formulation parameters, such as disintegration, dissolution, and shelf life, and significantly influence the final product. Therefore, several studies have been performed to evaluate the effect of drug-excipient interactions on the overall formulation. This article reviews the information available on the physical and chemical instabilities of excipients and their incompatibilities with the active pharmaceutical ingredient in solid oral dosage forms, during various drug-manufacturing processes. The impact of these interactions on the drug formulation process has been discussed in detail. Examples of various excipients used in solid oral dosage forms have been included to elaborate on different drug-excipient interactions.     

Extrusion 3D Printing of Paracetamol Tablets from a Single Formulation with Tunable Release Profiles Through Control of Tablet Geometry

An extrusion-based 3D printer was used to fabricate paracetamol tablets with different geometries (mesh, ring and solid) from a single paste-based formulation formed from standard pharmaceutical ingredients. The tablets demonstrate that tunable drug release profiles can be achieved from this single formulation even with high drug loading (>?80% w/w). The tablets were evaluated for drug release using a USP dissolution testing type I apparatus. The tablets showed well-defined release profiles (from immediate to sustained release) controlled by their different geometries. The dissolution results showed dependency of drug release on the surface area/volume (SA/V) ratio and the SA of the different tablets. The tablets with larger SA/V ratios and SA had faster drug release. The 3D printed tablets were also evaluated for physical and mechanical properties including tablet dimension, drug content, weight variation and breaking force and were within acceptable range as defined by the international standards stated in the US Pharmacopoeia. X-ray powder diffraction, differential scanning calorimetry and attenuated total reflectance Fourier transform infrared spectroscopy were used to identify the physical form of the active and to assess possible drug-excipient interactions. These data again showed that the tablets meet USP requirement. These results clearly demonstrate the potential of 3D printing to create unique pharmaceutical manufacturing, and potentially clinical, opportunities. The ability to use a single unmodified formulation to achieve defined release profiles could allow, for example, relatively straightforward personalization of medicines for individuals with different metabolism rates for certain drugs and hence could offer significant development and clinical opportunities.     

Hydrolysis of cellulose in SO₃H-functionalized ionic liquids

Influence of acidity and structure of ionic liquids on microcrystalline cellulose (MCC) hydrolysis was investigated. MnCl₂-containing ionic liquids (ILs) were efficient catalysts and achieved MCC conversion rates of 91.2% and selectivities for 5-hydroxymethyl furfural (HMF), furfural and levulinic acid (LA) of 45.7%, 26.2% and 10.5%, respectively. X-ray diffractometry indicated that catalytic hydrolysis of MCC in ionic liquids resulted in the changes to MCC crystallinity and transformation of cellulose I into cellulose II. SO₃H-functionalized ionic liquids showed higher activities than non-functionalized ILs. The simplicity of the chemical transformation of cellulose provides a new approach for the use this polymer as raw material for renewable energy and chemical industries.     

Stability of Benzocaine Formulated in Commercial Oral Disintegrating Tablet Platforms

Pharmaceutical excipients contain reactive groups and impurities due to manufacturing processes that can cause decomposition of active drug compounds. The aim of this investigation was to determine if commercially available oral disintegrating tablet (ODT) platforms induce active pharmaceutical ingredient (API) degradation. Benzocaine was selected as the model API due to known degradation through ester and primary amino groups. Benzocaine was either compressed at a constant pressure, 20 kN, or at pressure necessary to produce a set hardness, i.e., where a series of tablets were produced at different compression forces until an average hardness of approximately 100 N was achieved. Tablets were then stored for 6 months under International Conference on Harmonization recommended conditions, 25°C and 60% relative humidity (RH), or under accelerated conditions, 40°C and 75% RH. Benzocaine degradation was monitored by liquid chromatography–mass spectrometry. Regardless of the ODT platform, no degradation of benzocaine was observed in tablets that were kept for 6 months at 25°C and 60% RH. After storage for 30 days under accelerated conditions, benzocaine degradation was observed in a single platform. Qualitative differences in ODT platform behavior were observed in physical appearance of the tablets after storage under different temperature and humidity conditions.     

Ultrasound-assisted powder-coating technique to improve content uniformity of low-dose solid dosage forms

An ultrasound-assisted powder-coating technique was used to produce a homogeneous powder formulation of a low-dose active pharmaceutical ingredient (API). The powdered particles of microcrystalline cellulose (MCC; Avicel^® PH-200) were coated with a 4% m/V aqueous solution of riboflavin sodium phosphate, producing a uniform drug layer on the particle surfaces. It was possible to regulate the amount of API in the treated powder. The thickness of the API layer on the surface of the MCC particles increased near linearly as the number of coating cycles increased, allowing a precise control of the drug content. The tablets (n = 950) prepared from the coated powder showed significantly improved weight and content uniformity in comparison with the reference tablets compressed from a physical binary powder mixture. This was due to the coated formulation remaining uniform during the entire tabletting process, whereas the physical mixture of the powders was subject to segregation. In conclusion, the ultrasound-assisted technique presented here is an effective tool for homogeneous drug coating of powders of irregular particle shape and broad particle size distribution, improving content uniformity of low-dose API in tablets, and consequently, ensuring the safe delivery of a potent active substance to patients.Key words: content uniformity, homogeneity, low-dose API, powder coating, ultrasound