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.     

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

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.     

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.     

The Effect of the Wet Granulation Process on Drug Dissolution

Abstract

Wet granulation can be an important processing step for pharmaceutical solid dosage forms. In this investigation emphasis was directed towards the influence of a “simple” wet granulation process on drug release from granules and their resulting tablets. Direct compression blends of the same materials were used as controls. Binary mixtures containing a 5% level of either theophylline, hydrochlorothiazide or chlorpheniramine maleate in microcrystalline cellulose or lactose were granulated with water. Experimentally, the powders were dry blended in a planetary mixer, wet granulated, and subsequently wet milled and dried. No dry milling step was included. Granule characterization consisted of particle size, density, porosity, compression and dissolution testing. Dissolution results varied with the drug, as expected, and dissolution at 10 minutes ranged from 35 to 95 % release. In general, however, the results indicate that dissolution from granules and the corresponding direct compression blend are similar. Although differences in compressibility were observed in the systems studied, granulation was not found to be detrimental to drug release.     

Chitosan Formulations for Steroid Delivery: Effect of Formulation Variables on In Vitro Characteristics

ABSTRACT

Chitosan film formulations for steroid delivery after craniomaxillofacial surgery were formulated by using three different types of chitosan with respect to their molecular weight as low, medium and high. Film formulations were prepared by casting/solvent evaporation technique. In vitro characterization, film thickness, equilibrium swelling degree, in vitro release profiles and surface morphologies were investigated. For two different types of crosslinkings, the release of dexamethasone sodium phosphate (DSP) can be extended as the molecular weight increases. As a result, chitosan film formulations should be beneficial for steroid delivery for a certain time after craniomaxillofacial surgery.     

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 Process Variables on Drug Release from Microparticles Containing A Drug-Resin Complex

Abstract

Microparticles consisting of dextromethorphan-resin complex (resinate) coated with a cellulose derivative were prepared by a modified emulsion-solvent evaporation method. Adjustment of the release rate was achieved by varying resinate (core) to polymer (coat) ratio or by using additives. Higher ratios of resinate to polymer gave faster release of the drug. Polyethylene glycol (PEG) 4000 also increased the release rate. Increasing core to coat ratio also increased average particle size. Placing the emulsifying agent in different phases of the emulsion in the fabrication process also affected the particle size distribution. The microparticles showed good sustained release of the drug     

Polyglycolide: Degradation and drug release. Part II: Drug release

This paper considers drug release from a polyglycolide (PGA) matrix and is divided into two sections. The first investigates the effects on the degradation of the polymer of incorporating a model drug, theophylline, into the polymer. Small and wide angle X-ray scattering, and mass loss and water uptake measurements indicate that the presence of this drug does not affect the time scale of the degradation process. However, the dissolved theophylline molecules affect the extent to which the polymer crystallizes during degradation. In the second section, theophylline release profiles, obtained using UV-spectrophotometry, show that the erosion of the polymer controls the release of the drug. The drug release results add further evidence to support the four stage degradation process which was described in Part I. © 2001 Kluwer Academic Publishers     

Multiphase versus Single Pot Granulation Process: Influence of Process and Granulation Parameters on Granules Properties

ABSTRACT

High-shear wet granulation is widely used for the production of pharmaceutical dosage forms. Different equipment is available for high-shear granulation and drying. This review focuses on two main processes for granules production: multiphase consisting of high-shear granulation followed by drying in a separate apparatus, and single pot granulation/drying. At present, formulas are specifically developed with regard to the production equipment, which raises many problems when different industrial manufacturing equipment is used. Indeed, final granules properties are likely to depend on equipment design, process, and formulation parameters. Therefore, a good understanding of these parameters is essential to facilitate equipment changes.

The aim of this review is to present the influence of equipment, process, and formulation parameters on granules properties, considering both the granulation and the drying steps of multiphase and single pot processes.     

Effect of Particle Size on Deformation and Compaction Characteristics of Ascorbic acid and Potassium Chloride: Neat and Granulated Drug

Deformation and compaction characteristics of two soluble drugs, ascorbic acid and potassium chloride, were investigated. Five different particle size fractions of ascorbic acid with mean particle size (d₅₀) ranging from 30-300μm and four different particle size fractions of potassium chloride with d₅₀ ranging from 20-400 μm were selected in the study. The compaction behavior of the drug substances as neat drugs or as granulated drugs were evaluated on both a Carver press and an instrumented single-punch tablet press. The results clearly show that mean particle size of the drug substances plays an important role in their compactibility. Intrinsic compactibility of both drug substances was slightly improved with increased particle size. Granulations of the drugs with polyvinyl pyrrolidone significantly improved their compactibility. However, this effect was more pronounced in the drug substance with finer particle size. The Heckel plots indicate that deformation characteristics of both granulated drugs were related to their original mean particle sizes. The granulations prepared from the coarser particle size (d₅₀ 250 μm to 400 μm) underwent two stages of deformation, so-called “brittle fracture” and “plastic deformation”. While the granulations prepared from the finer particle size predoninantly underwent “plastic deformation”. The results indicated that the plastic deformation of both granulated drugs was progressively enhanced whilst fragmentation of particles was correspondingly reduced as the particle size of the drugs was decreased. Scanning electron photomicrographs indicated that the granulation process changed the surface morphology of the drug particles imparting more “microirregularities” or “defects”, thereby providing greater “interparticulate bonding” as compared with the neat drugs. Optimum particle size range of ascorbic acid and potassium chloride for satisfactory compactibility was found to be 30-40 μm and 20-40 μm, respectively. The present study demonstrates the importance of selecting the appropriate particle size of drug for the development of tablet dosage forms.     

Effect of Particle Size on Deformation and Compaction Characteristics of Ascorbic acid and Potassium Chloride: Neat and Granulated Drug

Abstract

Deformation and compaction characteristics of two soluble drugs, ascorbic acid and potassium chloride, were investigated. Five different particle size fractions of ascorbic acid with mean particle size (d₅₀) ranging from 30–300μm and four different particle size fractions of potassium chloride with d₅₀ ranging from 20–400 μm were selected in the study. The compaction behavior of the drug substances as neat drugs or as granulated drugs were evaluated on both a Carver press and an instrumented single-punch tablet press. The results clearly show that mean particle size of the drug substances plays an important role in their compactibility. Intrinsic compactibility of both drug substances was slightly improved with increased particle size. Granulations of the drugs with polyvinyl pyrrolidone significantly improved their compactibility. However, this effect was more pronounced in the drug substance with finer particle size. The Heckel plots indicate that deformation characteristics of both granulated drugs were related to their original mean particle sizes. The granulations prepared from the coarser particle size (d₅₀ 250 μm to 400 μm) underwent two stages of deformation, so-called “brittle fracture” and “plastic deformation”. While the granulations prepared from the finer particle size predoninantly underwent “plastic deformation”. The results indicated that the plastic deformation of both granulated drugs was progressively enhanced whilst fragmentation of particles was correspondingly reduced as the particle size of the drugs was decreased. Scanning electron photomicrographs indicated that the granulation process changed the surface morphology of the drug particles imparting more “microirregularities” or “defects”, thereby providing greater “interparticulate bonding” as compared with the neat drugs. Optimum particle size range of ascorbic acid and potassium chloride for satisfactory compactibility was found to be 30–40 μm and 20–40 μm, respectively. The present study demonstrates the importance of selecting the appropriate particle size of drug for the development of tablet dosage forms.     

The Quantitative Evaluation of a Granulation Milling Process II. Effect of Ouput Screen Size, Mill Speed and Impeller Shape

The processing variables associated with the comminution of pharmaceutical granulations were investigated. The three variables chosen were mill speed, output screen size and impeller shape. Experiments were performed on an aspirin granulation using proper techniques of experimental design. Analysis showed that the three mill variables cannot be considered independently but rather at the level of combinations. A complete characterization of the mill output according to particle size distribution is then possible based upon these combinations of mill variables.     

Fixed-point iteration to nonlinear finite element analysis. Part II: Formulation and implementation

The finite element formulation and implementation of the Fixed-Point Iteration (FPI) to linear/nonlinear structural static or dynamic analysis are developed. The direct and tangent formulations are presented and compared with the Newton–Raphson method (NRM). ‘Modified’ FPI algorithms have also been derived. A graphical interpretation of the method is introduced and suggested to call the FPI ‘the Saw method’. Mixing both the FPI and NRM is shown to be possible and may be useful in some applications. The overall strategies, iterative algorithms, and the appropriate norm convergence criteria necessary to implant the FPI into existing finite element programs are also included in the development. The superiority of the FPI over the NRM as seen from the development and the formulation lies in three major factors. First, the existing assembly process of element matrices is eliminated completely from the nonlinear finite element analysis. Secondly, the Gauss elimination or Crout's method is also eliminated. In the finite element terminology, this means that nonlinear structural static or dynamic responses can he obtained without recourse to the inverse of the structural stiffness matrix. Thirdly, the FPI can also be applied equally to linear structural analysis. Hence, the assembly process and the programming and storage associated with it can be removed from the existing finite element programs. While the FPI can solve problems that the NRM can, it will also be able to handle some engineering problems where the latter cannot. Buckling problems and problems where the force–displacement curve changes curvature are examples where the FPI is expected to be efficient.     

Fibrin-Based Drug Delivery Systems. II. The Preparation and Characterization of Microbeads

An emulsion method was employed to prepare fibrin beads having different sizes in this study. The oil phase of emulsion system was consisted of mineral oil with various amount of oleic acid as surfactant. Fibrin was converted from fibrinogen with thrombin in Tris buffer solution, then the mixture was emulsified into the oil phase forming droplets. After curing for one hour, 400 ul of glutaraldehyde solution (0.5% v/v) was added to minimize coagulation. The recovery of fibrin beads was simply done by decanting the oil phase and washing the residual with diethyl ether once and then with a mixture of isopropanol and n-hexane (1:3) containing 0.2% w/v Tween 80 twice. As expected, increasing the amount of oleic acid in the oil phase decreased the size of fibrin beads. It is due to the decrease of interfacial tension with increasing oleic acid amount. The presence of macromolecules showed no interference on the formation of fibrin beads except lysozyme. The diffusion characteristics of fibrin beads was evaluated using macromolecules of different molecular weight as model. The size of fibrin beads affected the penetration rate, whereas the effect of molecular weight of macromolecules was inconclusive. An exponential equation was able to approximate the penetration of macromolecules into fibrin beads during the late-time period. The possibility of using fibrin beads as the carrier to deliver protein drugs was appreciated.     

Interpolymer Complexation and its Effect on Bioadhesive Strength 6 Dissolution Characteristics of Buccal Drug Delivery Systems

During the process of development of mucoadhesive buccal delivery systems, interpolymer complex formation between carboxy vinyl polymer, which is similar to polyacrylic acid and other polymers as hydroxypropyl cellulose, carbopol-934, sodium carboxymethyl cellulose and polyvinyl pyrrolidone was studied as a function of pH. It was observed that carbopol-934 shows strong complexation with polyvinyl pyrrolidone and hydroxypropyl cellulose, but very little with sodium carboxymethyl cellulose. The degree of complexation is higher at acidic pH and decreases with an increase in pH. In further studies, when mucoadhesive buccal tablets were prepared using these polymer combinations, it was observed that the degree of complexation between the two polymers affected the rate and extent of drug release and also the bioadhesive strength of the tablets.     

Aqueous-Based Cellulose Acetate Butyrate Dispersion: Screening of Process and Formulation Variables to Obtain Verapamil HCl-Controlled Release Beads

The objectives of the present investigation were to evaluate the possibility of using a custom-designed cellulose acetate butyrate (CAB) pseudolatex dispersion on Verapamil HCl-loaded beads for sustained release of the drug. Excipient compatibility was studied by thermal analysis, X-ray diffraction, and content analysis. Inert beads (Nupareil) were loaded with verapamil HCl and subsequently coated with CAB pseudolatex dispersion. Process and formulation factors were screened by Plackett-Burman screening design in order to identify the most important factors affecting the amount of verapamil HCl released in 12 hours. X-ray diffraction pattern and content analysis showed no degradation of verapamil HCl and suggested absence of any interaction. However, thermal analysis indicated an interaction between verapamil HCl and excipient. A polynomial equation was developed to show the relationship between dependent and independent variables. The mathematical model fitted the data and explained 98.05 % of variability in the response. The difference between observed and predicated values of any given run did not exceed 6 % of maximum cumulative release at 12 hours. Plackett-Burman screening design identified coating weight gain, duration of curing, and amount of plasticizer as the most important factors determining cumulative percent released in 12 hours. Amount of Polydextrose/HPMC (Opadry II), spray rate, fluid bed coater outlet temperature, and atomizing pressure had no statistically significant (p < 0.05) influence on the response.     

Effect of Formulation Variables on Dissolution Profile of Diclofenac Sodium from Ethyl- and Hydroxypropylmethyl Cellulose Tablets

Abstract

The effects of formulation variables on the release profile of diclofenac sodium from ethyl cellulose (EC) and hydroxypropylmethyl cellulose (HPMC) matrix tablets were investigated. With increase in viscosity of ethyl cellulose used in nonaqueous granulation, a decrease in drug release from the tablets was observed, while the percentage of fines articles passed through 60 mesh) in the granulation had a significant effect on the dissolution profile. Granules containing 15% fines exhibited slow release of the drug in comparison to those containing 30% fines with EC matrices. An analysis of kinetics of drug release from hydrophobic EC matrix showed Fickian diffusion regulated dissolution. Drug release from HPMC tablets followed an apparent zero-order kinetics.     

Effect of Formulation Variables on Dissolution Profile of Diclofenac Sodium from Ethyl- and Hydroxypropylmethyl Cellulose Tablets

The effects of formulation variables on the release profile of diclofenac sodium from ethyl cellulose (EC) and hydroxypropylmethyl cellulose (HPMC) matrix tablets were investigated. With increase in viscosity of ethyl cellulose used in nonaqueous granulation, a decrease in drug release from the tablets was observed, while the percentage of fines articles passed through 60 mesh) in the granulation had a significant effect on the dissolution profile. Granules containing 15% fines exhibited slow release of the drug in comparison to those containing 30% fines with EC matrices. An analysis of kinetics of drug release from hydrophobic EC matrix showed Fickian diffusion regulated dissolution. Drug release from HPMC tablets followed an apparent zero-order kinetics.     

Tableting of Eudragit RS and Propranolol Hydrochloride Solid Dispersion: Effect of Particle Size,Compaction Force,and Plasticizer Addition on Drug Release

The application of a solid dispersion (SD) system of propranolol HCl and Eudragit RS was evaluated in the preparation of prolonged release tablets. The effects of SD size fraction, compaction force, and inclusion of plasticizers [namely diethylphtalate (DEP) and triethylcitrate (TEC)] on crushing strengths of matrices and release profile of drug were also investigated. The results showed that when compressed as a tablet, the SD system was more efficient in prolonging drug release than physical mixture. This effect was due to formation of much harder tablets of the SD system (crushing strength 8.5 kg) compared with those of physical mixtures (crushing strength 2.7 kg). All matrices of the SD system showed release rate patterns that were best described by the Higuchi equation. It was also shown that the rate of drug release decreased from 19.8% to 9.13% min^??1/2 as the SD size fraction decreased from 300–350 to 125–250 µm. However, further reduction of size fraction did not significantly affect tablet crushing strength and drug release rate. Increase in compaction force from 5 to 30 kN increased the crushing strength of matrices from 2.9 to 13.6 kg. However, the rate of drug release remained nearly unchanged beyond compaction pressure of 10 kN, indicating that crushing strength of matrices in the range of 8.5–13.6 kg did not affect drug release rate. The addition of 5% or 10% of either plasticizer (DEP or TEC) led to an increase in crushing strength of matrices and more retardation of drug release. This effect was more pronounced for higher concentrations of plasticizers. This effect was probably due to more plastic deformation of matrices under the compaction force, which helped matrices to retain their shape throughout the dissolution test.