Simultaneous Comparison of Two Roller Compaction Techniques and Two Particle Size Analysis Methods.

A new dry granulation technique, gas-assisted roller compaction (GARC), was compared with conventional roller compaction (CRC) by manufacturing 34 granulation batches. The process variables studied were roll pressure, roll speed, and sieve size of the conical mill. The main quality attributes measured were granule size and flow characteristics. Within granulations also the real applicability of two particle size analysis techniques, sieve analysis (SA) and fast imaging technique (Flashsizer, FS), was tested. All granules obtained were acceptable. In general, the particle size of GARC granules was slightly larger than that of CRC granules. In addition, the GARC granules had better flowability. For example, the tablet weight variation of GARC granules was close to 2%, indicating good flowing and packing characteristics. The comparison of the two particle size analysis techniques showed that SA was more accurate in determining wide and bimodal size distributions while FS showed narrower and mono-modal distributions. However, both techniques gave good estimates for mean granule sizes. Overall, SA was a time-consuming but accurate technique that provided reliable information for the entire granule size distribution. By contrast, FS oversimplified the shape of the size distribution, but nevertheless yielded acceptable estimates for mean particle size. In general, FS was two to three orders of magnitude faster than SA.

Fast tablet tensile strength prediction based on non-invasive analytics.

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

Direct compression of cellulose and lignin isolated by a new catalytic treatment.

Tablet compression of softwood cellulose and lignin prepared by a new catalytic oxidation and acid precipitation method were investigated and compared with the established pharmaceutical direct compression excipients. Catalytic pretreated softwood cellulose (CPSC) and lignin (CPSL) were isolated from pine wood (Pinus sylvestris). The compaction studies were carried out with an instrumented eccentric tablet machine. The plasticity and elasticity of the materials under compression were evaluated using force-displacement treatment and by determining characteristic plasticity (PF) and elasticity (EF) factors. With all biomaterials studied, the PF under compression decreased exponentially as the compression force increased. The compression force applied in tablet compression did not significantly affect the elasticity of CPSC and microcrystalline cellulose (MCC) while the EF values for softwood lignins increased as compression force increased. CPSL was clearly a less plastically deforming and less compactable material than the two celluloses (CPSC and MCC) and hardwood lignin. CPSL presented deformation and compaction behaviour almost identical to that of lactose monohydrate. In conclusion, the direct tablet compression behaviour of native lignins and celluloses can greatly differ from each other depending on the source and isolation method used.

Rapid formulation screening with a Multipart Microscale Fluid bed Powder processor.

The aim of this study was to investigate early formulation screening in small scale with a miniaturized fluid bed device. Altogether eight different batches were granulated in a Multipart Microscale Fluid bed Powder processor (MMFP) with constant process conditions using electrostatic atomization. Atomization voltage and granulation liquid flow rate were kept constant. Acid acetylsalicylic was used as model active pharmaceutical ingredient (API), lactose monohydrate, microcrystalline cellulose and polyvinylpyrrolidone were used as excipients. Granule size distributions were measured with spatial filtering technique. Friability test was performed by spinning granules in the mixer with glass beads. Compressibility of the granules was evaluated by tableting and the breaking force of the tablets was measured. Multivariate analysis, namely partial least squares regression and multilinear regression were applied to the data. It was possible to generate granules of different compositions rapidly employing MMFP with electrostatic atomization fast and acquire reliable and logical results with only small amount of material. However, a major challenge was to find suitable analytical methods for such small batches.

3D simulation of internal tablet strength during tableting.

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

Rapid particle size measurement using 3D surface imaging.

The present study introduces a new three-dimensional (3D) surface image analysis technique in which white light illumination from different incident angles is used to create 3D surfaces with a photometric approach. The three-dimensional features of the surface images created are then used in the characterization of particle size distributions of granules. This surface image analysis method is compared to sieve analysis and a particle sizing method based on spatial filtering technique with nearly 30 granule batches. The aim is also to evaluate the technique in flowability screening of granular materials. Overall, the new 3D imaging approach allows a rapid analysis of large amounts of sample and gives valuable visual information on the granule surfaces in terms of surface roughness and particle shape.

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.

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 microm) 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.

Image-based characterization of powder flow to predict the success of pharmaceutical minitablet manufacturing.

Powder flowability plays an important role in die filling during tablet manufacturing. The present study introduces a novel small-scale measuring technique for powder flow. Based on image analysis, the flow was defined depending on the variation of luminous intensity and the movement of powder inside the measurement cuvette. Using quantities around 100 mg it was possible to characterize a wide range of common pharmaceutical powders, especially in distinguishing subtle differences in flow caused by minor changes in samples characteristics. The method was compared with powder rheometry, which is widely used in the pharmaceutical literature, and showed a significant improvement in predicting the success of pharmaceutical minitablet manufacture (d = 5 mm). Tablet weight variation (RSD) was defined as the most efficient way to assess relevant powder flow behaviour in tablet production when using the novel device. The proposed method was distinguished from others by its ability to classify different grades of microcrystalline cellulose in the die-filling process. Subsequently, eight common pharmaceutical powders, both excipients and APIs, were properly ranked as a function of flowability based on their physical properties. The method showed a high repeatability, with a relative standard deviation not more than 10%.

Sugar end-capped poly-D,L-lactides as excipients in oral sustained release tablets.

Sugar end-capped poly-D,L-lactide (SPDLA) polymers were investigated as a potential release controlling excipient in oral sustained release matrix tablets. The SPDLA polymers were obtained by a catalytic ring-opening polymerization technique using methyl alpha-D-gluco-pyranoside as a multifunctional initiator in the polymerization. Polymers of different molecular weights were synthesized by varying molar ratios of monomer/catalyst. The matrix tablets were prepared by direct compression technique from the binary mixtures of SPDLA and microcrystalline cellulose, and theophylline was used as a model drug. The tablet matrices showed in vitro reproducible drug release profiles with a zero-order or diffusion-based kinetic depending on the SPDLA polymer grade used. Further release from the tablet matrices was dependent on the molecular weight of the SPDLA polymer applied. The drug release was the fastest with the lowest molecular weight SPDLA grade, and the drug release followed zero-order rate. With the higher molecular weight SPDLAs, more prolonged dissolution profiles for the matrix tablets (up to 8-10 h) were obtained. Furthermore, the prolonged drug release was independent of the pH of the dissolution media. In conclusion, SPDLAs are a novel type of drug carrier polymers applicable in oral controlled drug delivery systems.

Crystal morphology engineering of pharmaceutical solids: tabletting performance enhancement.

Crystal morphology engineering of a macrolide antibiotic, erythromycin A dihydrate, was investigated as a tool for tailoring tabletting performance of pharmaceutical solids. Crystal habit modification was induced by using a common pharmaceutical excipient, hydroxypropyl cellulose, as an additive during crystallization from solution. Observed morphology of the crystals was compared with the predicted Bravais-Friedel-Donnay-Harker morphology. An analysis of the molecular arrangements along the three dominant crystal faces [(002), (011), and (101)] was carried out using molecular simulation and thus the nature of the host-additive interactions was deduced. The crystals with modified habit showed improved compaction properties as compared with those of unmodified crystals. Overall, the results of this study proved that crystal morphology engineering is a valuable tool for enhancing tabletting properties of active pharmaceutical ingredients and thus of utmost practical value.

Predicting tablet tensile strength with a model derived from the gravitation-based high-velocity compaction analysis data.

In the present study, a model was developed to estimate tablet tensile strength utilizing the gravitation-based high-velocity (G-HVC) method introduced earlier. Three different formulations consisting of microcrystalline cellulose (MCC), dicalcium phosphate dihydrate (DCP), hydroxypropyl methylcellulose (HPMC), theophylline and magnesium stearate were prepared. The formulations were granulated using fluid bed granulation and the granules were compacted with the G-HVC method and an eccentric tableting machine. Compaction energy values defined from G-HVC data predicted tensile strength of the tablets surprisingly well. It was also shown, that fluid bed granulation improved the compaction energy intake of the granules in comparison to respective physical mixtures. In addition, general mechanical properties and elastic recovery were also examined for all samples. In this study it was finally concluded, that the data obtained by the method was of practical relevance in pharmaceutical formulation development.

Direct compression properties of chitin and chitosan.

Deformation and compaction properties of native amino poly-saccharides chitin and chitosan were studied and compared with those obtained with established pharmaceutical direct compression excipients. An instrumented single-punch tablet machine was used for tablet compaction. The following compression parameters were evaluated: a ratio of crushing strength and compression pressure, plasticity and elasticity factor (PF and EF), tensile strength and R-value. Chitin and chitosan were found to have a marked tendency to plastic deformation, and both showed a good compression behaviour compared with the other direct compression excipients including microcrystalline cellulose. It is concluded that chitin and chitosan are potential co-excipients for direct compression applications.

Controlling granule size by granulation liquid feed pulsing.

The effects of inlet air humidity, granulation liquid feed rate and granulation liquid feed pulsing on the particle-size distribution of final granules were studied in a laboratory scale fluid-bed granulator using a central composite study design. The factors examined were modelled using three different particle-size measurement techniques (sieve analysis, laser light diffraction and the spatial filtering technique). Best goodness of fit (R2=0.94) and goodness of prediction (Q2=0.90) values were obtained using particle-size results of the spatial filtering technique. Increasing inlet air humidity and granulation liquid feed rate resulted in greater median granule size, as expected. When pulsing (interruption of granulation liquid feed in predetermined sequences) was used, the median granule size decreased clearly. This effect was strong, especially with high inlet air humidity and rapid liquid feed rate processes. Granulation liquid feed pulsing is an effective way to modify the particle size of final granules. Pulsing can be used as a controlling tool to compensate for excessive moisture content in the granulation process.

Effect of fluidisation activity on end-point detection of a fluid bed drying process.

The influence of inlet air humidity variations on fluid bed drying end-point detection was the primary focus here. Various drying end-point criteria based on temperature and humidity measurements were compared. Seasonally changing inlet air humidity affects the moisture content of the finished granules, as long as the drying process remains unchanged. However, a specific moisture content of the finished granules is commonly desired after fluid bed drying. When experimental batches of varying inlet air humidity were compared at the beginning of the drying phase, the temperature of the granules increased linearly as the humidity of the inlet air increased. This effect causes variation in moisture contents of the final granules of different batches when the fixed temperature of the mass is used as an end-point criterion. With varying inlet air humidity, the often used DeltaT temperature difference method resulted in more precise estimation of the drying end-point than the constant temperature criterion. In this study new insights were found into the correlation between moisture content and temperature of the fluidising mass. Fluidisation activity greatly affected detection of drying end-point. Use of the DeltaT criterion requires proper fluidisation throughout the process.

Interdependence of particle properties and bulk powder behavior of indomethacin in quench-cooled molten two-phase solid dispersions.

Solid dispersions (SDs) hold a proven potential in formulating poorly water-soluble drugs. The present paper investigates the interfacial phenomena associated with the bulk powder flow, water sorption, wetting and dissolution of the SDs prepared by a modified melt and quench-cooling (QC) method. Poorly water-soluble indomethacin (IND) was QC molten with solubilizing graft copolymer (Soluplus®) or polyol sugar alcohol (xylitol, XYL). The interfacial interactions of SDs with air/water were found to be reliant on the type (amorphous/crystalline) and amount of the carrier material used. The final SDs were composed of fused agglomerates (SOL) or large jagged particles (XYL) with good wetting and powder flow properties. The initial dissolution of IND was accelerated by both carrier materials studied. The QC molten SDs with amorphous Soluplus® significantly improved the dissolution rate of IND at pH 6.8 (79.9 ±â€¯0.2% at 30 min) compared to that of pure crystalline drug. The substantial improvement in the dissolution rate of IND was in connection with the amorphous state of the drug being stabilized by Soluplus® in the QC molten SDs. However, it is evident that a strong H-bond formation between the components in some regions of the QC molten SDs can limit the dissolution of IND. The QC molten two-phase SDs with a polyol carrier (XYL) showed rapid and continuous drug release without reaching a plateau.

Introducing a novel gravitation-based high-velocity compaction analysis method for pharmaceutical powders.

With modern tableting machines large amounts of tablets are produced with high output. Consequently, methods to examine powder compression in a high-velocity setting are in demand. In the present study, a novel gravitation-based method was developed to examine powder compression. A steel bar is dropped on a punch to compress microcrystalline cellulose and starch samples inside the die. The distance of the bar is being read by a high-accuracy laser displacement sensor which provides a reliable distance-time plot for the bar movement. In-die height and density of the compact can be seen directly from this data, which can be examined further to obtain information on velocity, acceleration and energy distribution during compression. The energy consumed in compact formation could also be seen. Despite the high vertical compression speed, the method was proven to be cost-efficient, accurate and reproducible.

Physical solid-state properties and dissolution of sustained-release matrices of polyvinylacetate.

Solid-state compatibility and in vitro dissolution of direct-compressed sustained-release matrices of polyvinylacetate (PVAc) and polyvinylpyrrolidone (PVP) containing ibuprofen as a model drug were studied. Polyvinylalcohol (PVA) was used as an alternative water-soluble polymer to PVP. Differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) were used for characterizing solid-state polymer-polymer and drug-polymer interactions. The mechanical treatment for preparing physical mixtures of polyvinyl polymers and the drug (i.e. simple blending or stressed cogrinding) was shown not to affect the physical state of the drug and the polymers. With the drug-polymer mixtures the endothermic effect due to drug melting was always evident, but a considerable modification of the melting point of the drug in physical binary mixtures (drug:PVP) was observed, suggesting some interaction between the two. On the other hand, the lack of a significant shift of the melting endothermic peak of the drug in physical tertiary drug-polymer mixtures revealed no evidence of solid-state interaction between the drug and the present polymers. Sustained-release dissolution profiles were achieved from the direct-compressed matrices made from powder mixtures of the drug and PVAc combined with PVP, and the proportion of PVAc in the mixture clearly altered the drug release profiles in vitro. The drug release from the present matrix systems is controlled by both diffusion of the drug through the hydrate matrix and the erosion of the matrix itself.

Non-destructive assessment of mechanical properties of microcrystalline cellulose compacts.

In the present study the mechanical properties of microcrystalline cellulose compacts compressed were studied. The resistance to crushing was tested using diametral compression testing and apparent Young's modulus was determined using consecutive uniaxial compression of the full cross-sectional area of single tablets. As non-elastic deformation during the first compression cycle and reverse plasticity were discovered, the loading phase of the second compression cycle was used to determine Young's modulus. The relative standard deviation of 10 consecutive measurements was 3.6%. The results indicate a direct correlation between crushing strength and Young's modulus, which found further support when comparing surface roughness data and radial recovery of the tablets to Young's modulus. The extrapolated elastic modulus at zero-porosity was found to be 1.80±0.08 GPa, which is slightly lower than previously reported values, confirming the complexity of measuring the elastic properties of microcrystalline cellulose compacts. The method can be used for non-destructive assessment of mechanical properties of powder compacts for example during storage studies.

Formation and characterization of three-component-sorbitan monoester surfactant, oil and water-creams.

The effect of molecular structure of four sorbitan monoester surfactants (sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate and sorbitan monooleate) on the formation of simple three-component creams is presented. Interfacial properties of the surfactants were determined using a du Nouy tensiometer and rheological properties of selected creams with oscillation stress sweep, creep recovery and viscosity tests. Depending on the composition, sorbitan monolaurate and sorbitan monooleate formed both o/w creams and w/o creams, while sorbitan monopalmitate and sorbitan monostearate formed only o/w creams. Sorbitan monostearate and sorbitan monopalmitate had the smallest cmc and A(cmc) values and they were the most effective surfactants in lowering the interfacial tension. These surfactants formed the most stable and elastic creams with clear linear viscoelastic regions and small compliance values. Sorbitan monolaurate and sorbitan monooleate formed viscous creams without elastic properties.