Instrumented Tablet Press Studies on the Effect of Some Formulation and Processing Variables on the Compaction Process

Abstract

Using an instrumented tablet press, compression force-time measurements were used to evaluate the effects of formulation and processing variables on the compaction process. The effects of tablet press speed, punch size, depth of upper punch penetration (into the die), and the setting of the overload spring mechanism were studied. The effects of tablet weight, particle size and amount of lubrication were also studied. Several direct compression materials which are believed to compact by different mechanisms were used in the study. The results indicate the sensitivity of the area under the compression force-time curve and the Area/Height ratio. Some of the changes seen in the area and A/H ratio were those which would be expected from a relatively simple model of compaction/compression. The results clearly show the usefulness of the instrumented tablet press as an analytical tool in the development of tablet formulations, the evaluation of processing requirements, and the remedy of tablet production problems.     

Effect of Formulation and Process Variables on the Dissolution Profile of Naproxen Sodium from Tablets

Results of this investigation revealed some important formulation characteristics of naproxen sodium. Tablets made from the granules, prepared by wet granulation method using water, showed a significant decrease in solution as compared to those made by dry blending method. During wet granulation, heat was evolved due to the hydration of naproxen sodium resulting in the retardation of dissolution. The pseudo-polymorphism and hydration is being investigated by Bansal et. al. (1). In addition, when polyvinyl pyrolidone (PVP K-90) was used instead of PVP K-30, the dissolution was further retarted. Addition of cross carmellose sodium (Ac-Di-Sol) did not change the dissolution behavior of these tablets. When naproxen sodium was granulated with water, a decrease in dissolution rate was observed as mixing time was increased from 5 minutes to 15 minutes. The increase in hardness of the tablet from 10 Kp to 18Kp did not alter the dissolution profile of naproxen sodium. When granulation was prepared using a low shear mixer (Planetary mixer) versus a high shear mixer (T.K. Fielder), the resultant tablets exhibited similar dissolution and physical chemical properties.     

Effect of Formulation and Process Variables on the Dissolution Profile of Naproxen Sodium from Tablets

Abstract

Results of this investigation revealed some important formulation characteristics of naproxen sodium. Tablets made from the granules, prepared by wet granulation method using water, showed a significant decrease in solution as compared to those made by dry blending method. During wet granulation, heat was evolved due to the hydration of naproxen sodium resulting in the retardation of dissolution. The pseudo-polymorphism and hydration is being investigated by Bansal et. al. (1). In addition, when polyvinyl pyrolidone (PVP K-90) was used instead of PVP K-30, the dissolution was further retarted. Addition of cross carmellose sodium (Ac-Di-Sol) did not change the dissolution behavior of these tablets. When naproxen sodium was granulated with water, a decrease in dissolution rate was observed as mixing time was increased from 5 minutes to 15 minutes. The increase in hardness of the tablet from 10 Kp to 18Kp did not alter the dissolution profile of naproxen sodium. When granulation was prepared using a low shear mixer (Planetary mixer) versus a high shear mixer (T.K. Fielder), the resultant tablets exhibited similar dissolution and physical chemical properties.     

Effect of Drug,Formulation, and Process Variables on Granulation and Compaction Characteristics of Heterogeneous Matrices: Part II. HPMC and PVP Systems

Abstract

A heterogeneous matrix comprising hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) at various ratios was granulated using acetaminophen and pseudoephedrine as model drugs. The effect of drug, polymer ratio, total polymer loading, and volume of the granulating fluid on granule growth, granule size distribution, compaction, and tablet properties of the matrix was studied. Formulations containing both acetaminophen and pseudoephedrine required less water to granulate than those containing only acetaminophen. Moreover, the particle sizes of granules prepared with acetaminophen and pseudoephedrine were smaller than those containing only acetaminophen. Tablet hardness increased and friability decreased considerably in all formulations containing pseudoephedrine. In general, the tablet hardness and tablet disintegration time varied with changes in total polymer loading, fraction of HPMC in the matrix, and composition of the model drug(s). All the matrix systems studied showed good flow characteristics at different polymer loadings or HPMC-PVP ratio for matrices formulated with either acetaminophen or both acetaminophen and pseudoephedrine. The results of this study indicate that the presence of drug and/or other excipient(s) in the formulation affects the hydration characteristics of the matrix polymer(s) and compression properties of the granules.     

Effect of Drug, Formulation, and Process Variables on Granulation and Compaction Characteristics of Heterogeneous Matrices: Part II. HPMC and PVP Systems

A heterogeneous matrix comprising hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) at various ratios was granulated using acetaminophen and pseudoephedrine as model drugs. The effect of drug, polymer ratio, total polymer loading, and volume of the granulating fluid on granule growth, granule size distribution, compaction, and tablet properties of the matrix was studied. Formulations containing both acetaminophen and pseudoephedrine required less water to granulate than those containing only acetaminophen. Moreover, the particle sizes of granules prepared with acetaminophen and pseudoephedrine were smaller than those containing only acetaminophen. Tablet hardness increased and friability decreased considerably in all formulations containing pseudoephedrine. In general, the tablet hardness and tablet disintegration time varied with changes in total polymer loading, fraction of HPMC in the matrix, and composition of the model drug(s). All the matrix systems studied showed good flow characteristics at different polymer loadings or HPMC-PVP ratio for matrices formulated with either acetaminophen or both acetaminophen and pseudoephedrine. The results of this study indicate that the presence of drug and/or other excipient(s) in the formulation affects the hydration characteristics of the matrix polymer(s) and compression properties of the granules.     

Instrumented and Computer Interfaced Single Punch Tablet Press for the Rapid Evaluation of Compression and Lubrication Behaviour

A low cost instrumented and computer interfaced single punch tablet press was developed for the rapid data aquisition of compression and lubrication properties of powders arid processed materials.

A Manesty type F3 tablet machine has been modified to enable the fitting of piezo electric load cells to both upper and lower punch assemblies. The paper describes how the modifications permit interchangability of a range of punch sizes and shapes and yet ensure good accuracy and reproducibility of compression end lubrication data.

The instrumentation is interfaced with a dedicated A. I. M. 65 microcomputer for the rapid conversion of the instrumentation outputs into compression force units and for statistical evaluation. The computer software also incorporates a novel method for the evaluation of lubrication properties from a single or a series of pre-determined compression events, using the some sensitivity for force measurement from the lower punch lord cell.

The compression data and the physical properties of the compacts can be stored and retreived as fingerprints using a P. E. T. microcomputer and a digital plotter. A date bank may then be developed for the evaluation of raw materials, product development, monitoring of production performance and trouble shooting.

The paper further describes the evaluation of new lubricants in comparison with magnesium stearate using the instrumentation described.     

Instrumented and Computer Interfaced Single Punch Tablet Press for the Rapid Evaluation of Compression and Lubrication Behaviour

A low cost instrumented and computer interfaced single punch tablet press was developed for the rapid data aquisition of compression and lubrication properties of powders arid processed materials.

A Manesty type F3 tablet machine has been modified to enable the fitting of piezo electric load cells to both upper and lower punch assemblies. The paper describes how the modifications permit interchangability of a range of punch sizes and shapes and yet ensure good accuracy and reproducibility of compression end lubrication data.

The instrumentation is interfaced with a dedicated A. I. M. 65 microcomputer for the rapid conversion of the instrumentation outputs into compression force units and for statistical evaluation. The computer software also incorporates a novel method for the evaluation of lubrication properties from a single or a series of pre-determined compression events, using the some sensitivity for force measurement from the lower punch lord cell.

The compression data and the physical properties of the compacts can be stored and retreived as fingerprints using a P. E. T. microcomputer and a digital plotter. A date bank may then be developed for the evaluation of raw materials, product development, monitoring of production performance and trouble shooting.

The paper further describes the evaluation of new lubricants in comparison with magnesium stearate using the instrumentation described.     

Application of a Compaction Simulator to the Design of a High-Dose Tablet Formulation. Part I

The compaction properties of an investigational drug are studied by the use of a compaction simulator. The effects of punch velocity over the range of 30-640 mm^-1 on the compaction properties of the pure drug and a variety of formulas incorporating a high dose of the active compound have been investigated. The data were analyzed by applying the Heckel equation. The pure drug was found to have a high yield pressure at a relatively low punch velocity of 31 mm^-1. As the punch velocity was increased there was a decrease in crushing strength, primarily as a result of increasing yield pressure. These findings indicate that the pure drug predominantly consolidated by fragmentation and elastic deformation, with a slow plastically deforming component. The information obtained on the consolidation mechanism of the pure drug and, subsequently, on model formulas were instrumental in the design and selection of a robust formula and granulation process. The advantages of conducting dosage form design and characterization studies during the early phase of tablet formulation using means such as a compaction simulator are emphasized in this investigation.     

Application of a Compaction Simulator to the Design of a High-Dose Tablet Formulation. Part I

Abstract

The compaction properties of an investigational drug are studied by the use of a compaction simulator. The effects of punch velocity over the range of 30-640 mm^?1 on the compaction properties of the pure drug and a variety of formulas incorporating a high dose of the active compound have been investigated. The data were analyzed by applying the Heckel equation. The pure drug was found to have a high yield pressure at a relatively low punch velocity of 31 mm^?1. As the punch velocity was increased there was a decrease in crushing strength, primarily as a result of increasing yield pressure. These findings indicate that the pure drug predominantly consolidated by fragmentation and elastic deformation, with a slow plastically deforming component. The information obtained on the consolidation mechanism of the pure drug and, subsequently, on model formulas were instrumental in the design and selection of a robust formula and granulation process. The advantages of conducting dosage form design and characterization studies during the early phase of tablet formulation using means such as a compaction simulator are emphasized in this investigation.     

Formulation and Compaction of Microspheres

The factors affecting the tabletability of formulations containing uncoated and/or coated microspheres were discussed by presenting a case study. The size and shape, as well as surface properties of microspherical particles, the type and amount of coating agent, selection of the external additives, and the rate and magnitude of the pressure applied were found to be the most critical factors to be considered in order to obtain and maintain the desired drug release properties of the microspheres. It was found that microcrystalline cellulose was needed in order to produce satisfactory beads in terms of size, shape and surface characteristics. The microsphere formulations, which were found to be highly sensitive to lubrication, were more compressible than their powder forms, but produced much weaker tablets. When coated with Surelease, increasing the amount of coating on the pellets reduced the tensile strength of their compacts. Compaction of the microspheres at high velocities resulted in a decrease in the tensile strength values and an increase in the volumetric strain recovery values. Dissoultion studies revealed that, regardless of the amount of coating applied, the coated microspheres lost their sustained release properties during compaction.     

Formulation and Compaction of Microspheres

Abstract

The factors affecting the tabletability of formulations containing uncoated and/or coated microspheres were discussed by presenting a case study. The size and shape, as well as surface properties of microspherical particles, the type and amount of coating agent, selection of the external additives, and the rate and magnitude of the pressure applied were found to be the most critical factors to be considered in order to obtain and maintain the desired drug release properties of the microspheres. It was found that microcrystalline cellulose was needed in order to produce satisfactory beads in terms of size, shape and surface characteristics. The microsphere formulations, which were found to be highly sensitive to lubrication, were more compressible than their powder forms, but produced much weaker tablets. When coated with Surelease, increasing the amount of coating on the pellets reduced the tensile strength of their compacts. Compaction of the microspheres at high velocities resulted in a decrease in the tensile strength values and an increase in the volumetric strain recovery values. Dissoultion studies revealed that, regardless of the amount of coating applied, the coated microspheres lost their sustained release properties during compaction.     

Micromeritic and Packing Properties of Diclofenac Pellets and Effects of Some Formulation Variables

The effects of two common diluents (microcrystalline cellulose and calcium phosphate dihydrate), two binding agents (gelatin and methacrylic polymer), and spheronization on the micromeritic (size, shape, density), flow, and packing properties of sodium diclofenac pellets were examined. The shape was assessed as the aspect ratio and was correlated to the flow rate and to the deviation of the tapped porosity from the value of 26%, which corresponds to the ideal rhombohedral packing of spheres. It was found that porosity deviation decreased greatly with spheronization, but it increased with binder addition. Porosity deviation was proportional to the aspect ratio, while flow rate decreased logarithmically with porosity deviation. Porosity deviation may be a useful index for monitoring the quality of pellets, similar to the aspect ratio, as a successful, simple, and indirect indication of sphericity and of surface roughness as well.     

Effect of Processing Variables on the Structural Evolution of Silica Gels

Constant shear rate and dynamic rheological measurements have been used to investigate the effect of shear on the processes controlling the structural evolution (size and volume fraction of clusters and the extent of cluster–cluster cross-linking) during the gelation of colloidal silica sols. In the absence of shear, the storage and loss moduli (G and G, respectively) initially increase slowly prior to gelation, indicating that cluster growth and network formation are initially proceeding slowly, but then the system evolves rapidly, with cluster growth occurring at a slightly faster rate than network formation. In contrast, sols presheared for 4 h prior to gelation exhibit rapid increases in both G and G immediately after cessation of the applied shear, reflecting significant differences in the evolution of the gel structure. On aging, the viscoelastic properties of the unsheared and presheared samples are similar, indicating that their structures are comparable on the length scales (several microns) being probed by the frequency range used here. However, their chemical and microstructural properties differ significantly, due to differences in the intercluster bonds. The effect of shear rate, initial pH, colloid particle size, and volume fraction on the structure of the resulting sols and gels is discussed.     

Optimizing the Friability of a Tablet Formulation

Abstract

The impact on tablet friability caused by the loss-on-drying of the granulation, the granule-size distribution, the lubricant concentration, the compression force, and the pre-compression was scrutinized in a factorially designed experiment. A reduction of friability was obtained by reducing the deviation of the granulation loss-on-drying from approximately 4.6%; by decreasing the lubricant concentration; or by increasing the compression force.     

Optimizing the Friability of a Tablet Formulation

The impact on tablet friability caused by the loss-on-drying of the granulation, the granule-size distribution, the lubricant concentration, the compression force, and the pre-compression was scrutinized in a factorially designed experiment. A reduction of friability was obtained by reducing the deviation of the granulation loss-on-drying from approximately 4.6%; by decreasing the lubricant concentration; or by increasing the compression force.     

Effect of Formulation Composition on the Properties of Controlled Release Tablets Prepared by Roller Compaction

This study discusses the effect of formulation composition on the physical characteristics and drug release behavior of controlled‐release formulations made by roller compaction. The authors used mixture experimental design to study the effect of formulation components using diclofenac sodium as the model drug substance and varying relative amounts of microcrystalline cellulose (Avicel), hydroxypropyl methylcellulose (HPMC), and glyceryl behenate (Compritol). Dissolution studies revealed very little variability in drug release. The t₇₀ values for the 13 formulations were found to vary between 260 and 550 min. A reduced cubic model was found to best fit the t₇₀ data and gave an adjusted r‐square of 0.9406. Each of the linear terms, the interaction terms between Compritol and Avicel and between all three of the tested factors were found to be significant. The longest release times were observed for formulations having higher concentrations of HPMC or Compritol. Tablets with higher concentrations of Avicel showed reduced ability to retard the release of the drug from the tablet matrix. Crushing strength showed systematic dependence on the formulation factors and could be modeled using a reduced quadratic model. The crushing strength values were highest at high concentrations of Avicel, while tablets with a high level of Compritol showed the lowest values. A predicted optimum formulation was derived by a numerical, multiresponse optimization technique. The validity of the model for predicting physical attributes of the product was also verified by experiment. The observed responses from the calculated optimum formulation were in very close agreement with values predicted by the model. The utility of a mixture experimental design for selecting formulation components of a roller compacted product was demonstrated. These simple statistical tools can allow a formulator to rationally select levels of various components in a formulation, improve the quality of products, and develop more robust processes.     

Development of a New Tablet Formulation of Theophylline: In Vitro and in Vivo Studies

The preparation of a new scored 250 mg theophylline tablet is described, for which effects of particle size of the active principle, aspects of granulation and changes in tabletting settings were investigated.

In vitro studies showed the dissolution rate from tablets prepared from theophylline of commercial quality (50 μm) or of selected particle size (30 μm) to be faster than that from tablets prepared from micronized theophylline (10 μm). In vivo studies in dog showed that only the tablet from theophylline of selected particle size has the same bioavailability as an aqueous solution.

The scale up study showed that the characteristics of the tablets, including dissolution rate, are independent of the formulation factors.