Omar L. Sprockel

A melt-extrusion process for manufacturing matrix drug delivery systems

Abstract A novel melt-extrusion process was developed to prepare matrix drug delivery systems. The disks contained drugs suspended in various polymers or polymer/additive combinations. Theophylline was incorporated into polyethylene (PE), polycaprolactone (PC), polyvinyl acetate (PVA), and cellulose acetate butyrate (CAB) at a 50% drug loading. There was an 8-fold difference in the effective diffusion coefficient ( D e ) between the various polymers (from 1.17×10 −12 to 7.63×10 −12 cm 2 /h). Increasing the theophylline load from 50 to 70% in PC and PE disks increased the D e at least 10-fold. Disks with a solids content above 70% by weight could not be made. To modify the release, soluble particulate additives, that did not melt at the working temperature, were incorporated in the PE disks. The soluble, particulate additives reduced the D e significantly, and decreased the ease with which the melted mass could be extruded. To improve the ease of manufacture, the particulate additives were replaced with polyethylene glycols that melted at the working temperatures. The D e for the PC/PEG disks were approximately 10 times larger than those for the PC disks. In addition to theophylline, chlorpheniramine maleate and salicylic acid were also incorporated into PC disks. The release of the three drugs in water, a pH 1.2 buffer, and a pH 7.5 buffer was determined. The effects of drug type and media on the drug release rates were explained using the drugs solubility, mean particle size, and dissociation constant.

A controlled porosity drug delivery system

Abstract The relationship between the drug release rate constant (Ko) and the physicochemical properties of porosity modifiers incorporated in the polymer coat of a proposed compression coated drug delivery system was investigated. The effects of particle size, hygroscopicity, solubility, absolute density and powder specific surface area on Ko were related to their influence on the pore structure created. In general, porosity modifiers with larger particle sizes, smaller specific surface areas, greater hygroscopicity coefficients or higher solubilities caused faster drug release, by creating more conducting channels. The porosity modifier particle size and load were related to changes in the coat volume (Vcoat), coat porosity (efinal) and increased specific surface area (SSAd). The Vcoat decreased with an increased loading or particle size, promoting faster release. Ko increased very slowly until efinal and SSAd reached critical values (approximately 38% and 0.1 m2 g−1, respectively), after which Ko increased very rapidly. This information allows the selection of a porosity modifier with the appropriate characteristics to provide a delivery system with the desired release rate. Alternatively, one can specify the necessary coat characteristics after porosity modifier release that will yield the desired release rate.

Review of bilayer tablet technology.

Therapeutic strategies based on oral delivery of bilayer (and multilayer) tablets are gaining more acceptance among brand and generic products due to a confluence of factors including advanced delivery strategies, patient compliance and combination therapy. Successful manufacturing of these ever more complex systems needs to overcome a series of challenges from formulation design to tablet press monitoring and control. This article provides an overview of the state-of-the-art of bilayer tablet technology, highlighting the main benefits of this type of oral dosage forms while providing a description of current challenges and advances toward improving manufacturing practices and product quality. Several aspects relevant to bilayer tablet manufacturing are addressed including material properties, lubrication, layer ordering, layer thickness, layer weight control, as well as first and final compression forces. A section is also devoted to bilayer tablet characterization that present additional complexities associated with interfaces between layers. The available features of the manufacturing equipment for bilayer tablet production are also described indicating the different strategies for sensing and controls offered by bilayer tablet press manufacturers. Finally, a roadmap for bilayer tablet manufacturing is advanced as a guideline to formulation design and selection of process parameters and equipment.

Influence of compaction properties and interfacial topography on the performance of bilayer tablets.

Bilayer tablets are generating great interest recently as they can achieve controlled delivery of different drugs with pre-defined release profiles. However, the production of such tablets has been facing great challenges as the layered tablets are prone to delaminate or fracture in the individual layers due to insufficient bonding strength of layers and adhesion at the interfaces. This paper will provide an insight into the role of interfacial topography on the performance of the bilayer tablets. In this study, two widely used pharmaceutical excipients: microcrystalline cellulose and lactose were investigated. Bilayer tablets were manufactured with a range of first and second layer compression forces. A crack of known dimensions was introduced at the interface to investigate the crack propagation mechanisms upon axially loading the bilayer tablet, and to determine the stress intensity factor (K(I)) of the interface (will be discussed in a separate paper). The results indicated that a strong dependency of the strength of bilayer tablets and mode of crack propagation on the material and compaction properties. The results showed that the strength of bilayer tablets increased with the increase of interfacial roughness, and the first layer and second layer forces determined the magnitude of interfacial roughness for both plastic and brittle materials. Further, the results also indicated that layer sequence and compaction forces played a key role in influencing the strength of the bilayer tablets. For the same (first and second layer) force combination, interfacial strength is higher for the tablets made of brittle material in the first layer. It was observed that interfacial strength decreased with the increase of lubricant concentration. The studies showed that the effect of lubricant (i.e. reduction in compact strength with the increase of lubricant concentration) on the strength of compacts is higher for tablets made of plastic material as compared to the tablets made of brittle material.

Evaluation of the Performance Characteristics of Bilayer Tablets: Part I. Impact of Material Properties and Process Parameters on the Strength of Bilayer Tablets

Bilayer tableting technology has gained popularity in recent times, as bilayer tablets offer several advantages over conventional tablets. There is a dearth of knowledge on the impact of material properties and process conditions on the performance of bilayer tablets. This paper takes a statistical approach to develop a model that will determine the effect of the material properties and bilayer compression process parameters on the bonding strength and mode of breakage of bilayer tablets. Experiments were carried out at pilot scale to simulate the commercial manufacturing conditions. As part of this endeavor, a seven-factor half-fraction factorial (27−1) design was executed to study the effect of bilayer tablet compression process factors on the bonding strength of bilayer tablets. Factors studied in this work include: material properties (plastic and brittle), layer ratio, dwell time, layer sequence, first- and second-layer forces, and lubricant concentration. Bilayer tablets manufactured in this study were tested using the axial tester, as it considers both the interfacial and individual layer bonding strengths. Responses of the experiments were analyzed using PROC GLM of SAS (SAS Institute Inc, Cary, North Carolina). A model was fit using all the responses to determine the significant interactions (p < 0.05). The results of this study indicated that nature of materials played a critical role on the strength of bilayer compacts and also on mode of fracture. Bilayer tablets made with brittle materials in both the layers are strongest, and fracture occurred in the first layer indicating that interface is stronger than layers. Significant interactions were observed between the selected factors and these results will provide an insight into the interplay of material properties, process parameters, and lubricant concentration on the bonding strength and mode of breakage of bilayer tablets.

Instrumented roll technology for the design space development of roller compaction process.

Instrumented roll technology on Alexanderwerk WP120 roller compactor was developed and utilized successfully for the measurement of normal stress on ribbon during the process. The effects of process parameters such as roll speed (4-12 rpm), feed screw speed (19-53 rpm), and hydraulic roll pressure (40-70 bar) on normal stress and ribbon density were studied using placebo and active pre-blends. The placebo blend consisted of 1:1 ratio of microcrystalline cellulose PH102 and anhydrous lactose with sodium croscarmellose, colloidal silicon dioxide, and magnesium stearate. The active pre-blends were prepared using various combinations of one active ingredient (3-17%, w/w) and lubricant (0.1-0.9%, w/w) levels with remaining excipients same as placebo. Three force transducers (load cells) were installed linearly along the width of the roll, equidistant from each other with one transducer located in the center. Normal stress values recorded by side sensors and were lower than normal stress values recorded by middle sensor and showed greater variability than middle sensor. Normal stress was found to be directly proportional to hydraulic pressure and inversely to screw to roll speed ratio. For active pre-blends, normal stress was also a function of compressibility. For placebo pre-blends, ribbon density increased as normal stress increased. For active pre-blends, in addition to normal stress, ribbon density was also a function of gap. Models developed using placebo were found to predict ribbon densities of active blends with good accuracy and the prediction error decreased as the drug concentration of active blend decreased. Effective angle of internal friction and compressibility properties of active pre blend may be used as key indicators for predicting ribbon densities of active blend using placebo ribbon density model. Feasibility of on-line prediction of ribbon density during roller compaction was demonstrated using porosity-pressure data of pre-blend and normal stress measurements. Effect of vacuum to de-aerate pre blend prior to entering the nip zone was studied. Varying levels of vacuum for de-aeration of placebo pre blend did not affect the normal stress values. However, turning off vacuum completely caused an increase in normal stress with subsequent decrease in gap. Use of instrumented roll demonstrated potential to reduce the number of DOE runs by enhancing fundamental understanding of relationship between normal stress on ribbon and process parameters.

Roller compaction process development and scale up using Johanson model calibrated with instrumented roll data

Roller compaction is a dry granulation process used to convert powder blends into free flowing agglomerates. During scale up or transfer of roller compaction process, it is critical to maintain comparable ribbon densities at each scale in order to achieve similar tensile strengths and subsequently similar particle size distribution of milled material. Similar ribbon densities can be reached by maintaining analogous normal stress applied by the rolls on ribbon for a given gap between rolls. Johanson (1965) developed a model to predict normal stress based on material properties and roll diameter. However, the practical application of Johanson model to estimate normal stress on the ribbon is limited due to its requirement of accurate estimate of nip pressure i.e. pressure at the nip angle. Another weakness of Johanson model is the assumption of a fixed angle of wall friction that leads to use of a fixed nip angle in the model. To overcome the above mentioned limitations, we developed a novel approach using roll force equations based on a modified Johanson model in which the requirement of pressure value at nip angle was eliminated. An instrumented roll on WP120 roller compactor was used to collect normal stress data measured at three locations across the width of a roll (P1, P2, P3), as well as gap and nip angle data on ribbon for placebo and various active blends along with corresponding process parameters. The nip angles were estimated directly using experimental pressure profile data of each run. The roll force equation of Johanson model was validated using normal stress, gap, and nip angle data of the placebo runs. The calculated roll force values compared well with those determined from the roll force equation provided for the Alexanderwerk(®) WP120 roller compactor. Subsequently, the calculation was reversed to estimate normal stress and corresponding ribbon densities as a function of gap and RFU (roll force per unit roll width). A placebo model was developed and calibrated using a subset of placebo run data obtained on WP120. The roll force values were calculated using vendor supplied equation. The nip angle was expressed as a function of gap and RFU. The nip angle, gap and RFU were used in a new roll force equation to estimate normal stress P2 at the center of the ribbon. Using ratios P1/P2 and P3/P2 from the calibration data set, P1 and P2 were estimated. The ribbon width over which P1, P2, and P3 are effective was determined by minimizing sum square error between the model predicted vs. experimental ribbon densities of the calibration set. The model predicted ribbon densities of the placebo runs compared well with the experimental data. The placebo model also predicted with reasonable accuracy the ribbon densities of active A, B, and C blends prepared at various combinations of process parameters. The placebo model was then used to calculate scale up parameters from WP120 to WP200 roller compactor. While WP120 has a single screw speed, WP200 is equipped with a twin feed screw system. A limited number of roller compaction runs on WP200 was used as a calibration set to determine normal stress profile across ribbon width. The nip angle equation derived from instrumented roll data collected on WP120 was applied to estimate nip angles on WP200 at various processing conditions. The roll force values calculated from vendor supplied equation and the nip angle values were used in roll force equation to estimate normal stress P2 at the tip of the feed screws. Based on feed screw design, it was assumed that the normal stress at the center of the ribbon was equal to those calculated at the tip of the feed screws. The ratio of normal stress at the edge of the ribbon Pe to the normal stress P2 at the feed screw tip was optimized to minimize sum square error between model predicted vs. experimental ribbon densities of the calibration set. The model predicted ribbon densities of the batches prepared on WP200 compared well with the experimental data thus indicating success of the scale up procedure. For the demonstration purpose, the model was also calibrated using instrumented roll data of active C batches. This would be applicable when sufficient amount of API is available or placebo model cannot predict ribbon density of active batches.

Evolution of the microstructure during the process of consolidation and bonding in soft granular solids.

The evolution of microstructure during powder compaction process was investigated using a discrete particle modeling, which accounts for particle size distribution and material properties, such as plasticity, elasticity, and inter-particle bonding. The material properties were calibrated based on powder compaction experiments and validated based on tensile strength test experiments for lactose monohydrate and microcrystalline cellulose, which are commonly used excipient in pharmaceutical industry. The probability distribution function and the orientation of contact forces were used to study the evolution of the microstructure during the application of compaction pressure, unloading, and ejection of the compact from the die. The probability distribution function reveals that the compression contact forces increase as the compaction force increases (or the relative density increases), while the maximum value of the tensile contact forces remains the same. During unloading of the compaction pressure, the distribution approaches a normal distribution with a mean value of zero. As the contact forces evolve, the anisotropy of the powder bed also changes. Particularly, during loading, the compression contact forces are aligned along the direction of the compaction pressure, whereas the tensile contact forces are oriented perpendicular to direction of the compaction pressure. After ejection, the contact forces become isotropic.

Solubilization of entecavir by povidone to overcome content uniformity challenges for low-dose tablet formulations

Development of 0.1, 0.5, and 1.0 mg entecavir tablet formulations for the treatment of hepatitis B virus was challenging for content uniformity. Entecavir with pKa of 2.8 and 9.8 does not have sufficient solubility in acidic or alkaline medium or in common pharmaceutical solvents such as ethanol to dissolve the drug in granulating fluid to prepare the homogeneous granulation. Povidone (PVP), a commonly used binder, was found to increase entecavir solubility depending on the PVP concentration and temperature of the solution. At 15% w/w PVP concentration, entecavir solubility increased from 2 mg/mL to about 8 mg/mL at room temperature. When the PVP solution was heated to 50°C or 70°C, the solubility was increased to about 23 or 33 mg/mL, respectively. Based on Raman spectra of entecavir in PVP solution, the increase in entecavir solubility in the presence of PVP may not be due to any molecular interactions between them. Solubilization of entecavir in PVP and eventual granulation did not change the polymorphic form of the drug based on the powder X-ray and differential scanning calorimetric (DSC), and thermo-gravimetric analysis (TGA) of neat entecavir re-crystallized from the PVP solution. The enhancement in the solubility of entecavir by PVP was sufficient to keep the amount of solution, which was used for granulation, to be about 20% w/w of the batch size like the traditional aqueous granulation. The granulation manufactured using this approach provided better tablet content uniformity than one using micronized entecavir.

Discrete particle modeling and micromechanical characterization of bilayer tablet compaction

A mechanistic particle scale model is proposed for bilayer tablet compaction. Making bilayer tablets involves the application of first layer compaction pressure on the first layer powder and a second layer compaction pressure on entire powder bed. The bonding formed between the first layer and the second layer particles is crucial for the mechanical strength of the bilayer tablet. The bonding and the contact forces between particles of the first layer and second layer are affected by the deformation and rearrangement of particles due to the compaction pressures. Our model takes into consideration the elastic and plastic deformations of the first layer particles due to the first layer compaction pressure, in addition to the mechanical and physical properties of the particles. Using this model, bilayer tablets with layers of the same material and different materials, which are commonly used pharmaceutical powders, are tested. The simulations show that the strength of the layer interface becomes weaker than the strength of the two layers as the first layer compaction pressure is increased. The reduction of strength at the layer interface is related to reduction of the first layer surface roughness. The reduced roughness decreases the available bonding area and hence reduces the mechanical strength at the interface. In addition, the simulations show that at higher first layer compaction pressure the bonding area is significantly less than the total contact area at the layer interface. At the interface itself, there is a non-monotonic relationship between the bonding area and first layer force. The bonding area at the interface first increases and then decreases as the first layer pressure is increased. These results are in agreement with findings of previous experimental studies.