Mechanics of tablet formation: a comparative evaluation of percolation theory with classical concepts.

The present study is based on the fundamentals of percolation theory and its application in understanding compression and compaction of powder materials. Four materials, i.e. carbamazepine, microcrystalline cellulose, crospovidone and croscarmellose sodium, with dissimilar deformation and compaction behavior were selected to validate the hypotheses of percolation phenomenon. The values of two percolation thresholds, i.e. bond and site, corresponding to the lower and intermediate compression pressures, were determined using Heckel equation. The compactibility of powder materials was evaluated using classical models as well as the power law equation. The values of percolation thresholds were found to better assess the deformation behavior of powder materials compared to the values of mean yield pressure. The power law equation demonstrated better prediction of compactibility of powder materials compared to the classical models. The value of the critical exponent, q, determined using power law equation by plotting tensile strength vs. normalized relative density of powder compacts was found to be closer to the theoretical value of 2.70. Furthermore, the theoretical knowledge of percolation thresholds of individual powder components in the binary mixture was found to be helpful in improving compaction properties of the poorly compactible material, i.e. carbamazepine. Thus percolation theory can be helpful in predicting compression and compaction behavior of powder materials and serve as a potent tool for the successful design of tablet formulations.

An integrated, quality by design (QbD) approach for design, development and optimization of orally disintegrating tablet formulation of carbamazepine.

The objective of the present study was to design and develop a formulation for orally disintegrating tablets (ODTs) of carbamazepine using quality by design principles. The target product profile (TPP) and quality target product profile (QTPP) of ODTs were identified. Risk assessment was carried out by leveraging prior knowledge and experience to define the criticality of factors based on their impact by Ishikawa fishbone diagram and preliminary hazard analysis tool. Box-Behnken response surface methodology was used to study the effect of critical factors on various attributes of ODTs. The independent factors selected were compression pressure (X1), concentration of sublimating agent (volatile material) (X2), disintegrant concentration (X3) and the responses were tablet crushing strength, tablet porosity, disintegration time, water absorption time, tablet friability and drug dissolution. ANOVA and lack of fit test illustrated that selected independent variables had significant effect on the response variables, and excellent correlation was observed between actual and predicted values. Optimization by desirability function indicated that compression pressure, X1 (1534 lbs), ammonium bicarbonate concentration, X2 (7.68%) and Kollidon® CL-SF concentration, X3 (6%) were optimum to prepare ODT formulation of carbamazepine of desired attributes complying with QTPP. Thus, in the present study, a high level of assurance was established for ODT product quality and performance.

Formulation, in vitro evaluation and study of variables on tri-layered gastro-retentive delivery system of diltiazem HCl.

CONTEXT: Tri-layered floating tablets using only one grade of polyethylene oxide (PEO) would enable easy manufacturing, reproducibility and controlled release for highly soluble drugs. OBJECTIVE: To evaluate the potential of PEO as a sole polymer for the controlled release and to study the effect of formulation variables on release and gastric retention of highly soluble Diltiazem hydrochloride (DTZ). METHODS: Tablets were compressed with middle layer consisting of drug and polymer while outer layers consisted of polymer with sodium bicarbonate. Design of formulation to obtain 12 h, zero-order release and rapid floatation was done by varying the grades, quantity of PEO and sodium bicarbonate. Dissolution data were fitted in drug release models and swelling/erosion studies were undertaken to verify the drug release mechanism. Effect of formulation variables and tablet surface morphology using scanning electron microscopy were studied. RESULTS AND DISCUSSION: The optimized formula passed the criteria of USP dissolution test I and exhibited floating lag-time of 3-4 min. Drug release was faster from low molecular weight (MW) PEO as compared to high MW. With an increase in the amount of sodium bicarbonate, faster buoyancy was achieved due to the increased CO2 gas formation. Drug release followed zero-order and gave a good fit to the Korsmeyer-Peppas model, which suggested that drug release was due to diffusion through polymer swelling. CONCLUSION: Zero-order, controlled release profile with the desired buoyancy can be achieved by using optimum formula quantities of sodium bicarbonate and polymer. The tri-layered system shows promising delivery of DTZ, and possibly other water-soluble drugs.

Material-Sparing Approach using Differential Scanning Calorimeter and Response Surface Methodology for Process Optimization of Hot-Melt Extrusion.

The objective of the present investigations was to demonstrate the applicability of DSC combined with response surface methodology as a material-sparing tool for determination of the processing conditions for HME during initial stages of development. Mefenamic acid (MFA) and Eudragit EPO (EPO) were used as a model drug and the polymeric carrier, respectively. Initial screening was performed using film-casting, polarized light microscopy, and TGA analysis to determine the levels for the experimental design. A Box-Behnken design was used to study the effect of the independent parameters, viz. drug loading, heating rate, and processing temperature, on the dependent parameters, viz. residual crystallinity and drug degradation. The results showed a quadratic relationship between independent and dependent parameters. Based on the design space, MFA-EPO dispersions with 20% drug loading were prepared using HME and vacuum compression molding (VCM). Both the HME and VCM samples did not show any signs of residual crystallinity. However, degradation of MFA was observed in VCM sample and the HME filaments processed at 100 rpm, but not at 150 rpm. The results demonstrate that DSC has potential to be a material-sparing tool to optimize drug loading and processing temperature for HME and will help product development using HME cost-effective.

Application of Thermodynamic Phase Diagrams and Gibbs Free Energy of Mixing for Screening of Polymers for Their Use in Amorphous Solid Dispersion Formulation of a Non-Glass-Forming Drug.

The objective of the present investigations was to assess the use of thermodynamic phase diagrams and the Gibbs free energy of mixing, ΔGmix, for the screening of the polymeric carriers by determining the ideal drug-loading for an amorphous solid dispersion formulation and optimum processing temperature for the hot-melt extrusion of a non-glass-forming drug. Mefenamic acid (MFA) was used as a model non-glass-forming drug and four chemically distinct polymers with close values of the solubility parameters, viz. Kollidon® VA64, Soluplus®, Pluronic® F68, and Eudragit® EPO, were used as carriers. The thermodynamic phase diagrams were constructed using the melting point depression data, Flory-Huggins theory, and Gordan-Taylor equation. The Gibbs free energy of mixing was estimated using the values of the drug-polymer interaction parameter, χ, and Flory-Huggins theory. The rank order miscibility of MFA in the four polymeric carriers estimated based on the difference in the values of their solubility parameters, Δδ, did not correlate well with the thermodynamic phase diagrams and Gibbs free energy plots. The study highlights the limitation of using the solubility parameter method in screening the polymeric carriers for poorly glass-forming drugs and reiterates the applicability of thermodynamic phase diagrams and Gibbs free energy plots in determining the ideal drug-loading and optimum processing temperature for hot-melt extrusion.

Comparative evaluation of rate of hydration and matrix erosion of HEC and HPC and study of drug release from their matrices.

Hydrophilic polymers, in contact with the dissolution medium, may swell and make a continuous gel layer, erode or undergo combination of the two. The swelling action of these polymers is controlled by the rate of their hydration in the dissolution medium. The extent of polymer swelling, relative mobilities of dissolution medium and drug, and matrix erosion dictate the kinetics as well as mechanism of drug release from the polymeric matrices. The objective of the present investigations was to study the rate of hydration and the rate of matrix erosion of two hydrophilic, non-ionic cellulose ethers, i.e., hydroxyethylcellulose (HEC) and hydroxypropylcellulose (HPC), and to compare the kinetics and mechanism of drug release from their matrices. Chlorpheniramine maleate was used as the model drug. Matrix tablets containing chlorpheniramine maleate, HEC or HPC and dicalcium phosphate were compressed at 156 MPa pressure. The rate of hydration of the polymer, rate of erosion of the matrices and in vitro drug release studies were carried out in phosphate buffer (pH 7.4). The hydration studies of the two polymers demonstrated that due to relatively larger water uptake, the degree of swelling of HEC matrices was considerably higher as compared to the HPC matrices. Also, HEC matrices exhibited relatively higher erosion as compared to HPC matrices. The drug release from HEC matrices occurred by non-Fickian transport, i.e., combination of drug diffusion and polymer swelling, while drug release from HPC matrices was controlled primarily by diffusion through pores and channels in the structure. The t(50%), time to reach 50% drug release, for HEC matrices was 4.8 h and that for HPC matrices was 6.5 h which indicates that a higher polymer level was needed in the case of HEC matrices to sustain the drug release for up to 12 h of dissolution as compared to HPC matrices due to relatively higher hydrophilicity of HEC.

Study of effect of excipient source variation on rheological behavior of diltiazem HCl-HPMC wet masses using a mixer torque rheometer.

In the wet massing of powders and powder blends, the rheological behavior of the wet powder masses not only plays a critical role in the unit process but also influences the attributes of the product. The physical properties of the powder excipients, such as particle size and size distribution, shape, surface area, bulk and tapped density and surface morphology, are a major source of variability in the rheological behavior of wet powder masses and the quality attributes of the final product. The objective of the present investigations was to study the rheological behavior of wet masses containing hydroxypropyl methylcellulose (HPMC) obtained from two sources (Methocel from Dow and Pharmacoat from Shin-Etsu) using a mixer torque rheometer. In order to simulate a real formulation, diltiazem HCl (DTZ) (40% loading) was used as part of the substrate powder mass. Hydroxypropyl cellulose (HPC) was used as the binder. Since HPMC is water-soluble, isopropyl alcohol (IPA) was used as the wet massing liquid. The rheological behavior of the wet powder masses was studied as a function of mixing time and amount of wet massing liquid (IPA). The rheological profiles obtained for DTZ-Methocel and DTZ-Pharmacoat exhibited same magnitude for mean torque, however, for DTZ-Pharmacoat the peak was more extended than that for DTZ-Methocel. The extended peak for DTZ-Pharmacoat indicated that the wet mass will stay suitable during the process for larger quantities of the wet massing liquid before turning into paste and becoming unsuitable for the process as compared with the DTZ-Methocel system. The mixing kinetics of the two powder systems appeared to be quite different. These differences in the rheological behavior of the wet masses may be attributed to the difference in the particulate and surface properties of the two HPMCs. Some of the properties of the two HPMCs, such as particle size and size distribution, surface area, surface morphology and DSC thermograms, explain the difference observed in their rheological behavior. The difference in the rheological profiles of the two DTZ-HPMC systems indicated superiority of Pharmacoat over Methocel considering their wet massing behavior.

Influence of plasticizer type and coat level on Surelease film properties.

Two commercially available formulations of aqueous ethylcellulose dispersion differing in their plasticizer, i.e., Surelease/E-7-7050 containing dibutyl sebacate (DBS) and Surelease/E-7-7060 containing glyceryl tricaprylate/caprate (GTC), were evaluated and compared for their film properties as a function of polymeric coat level. Ibuprofen tablets were coated at 1, 2, 3, and 5% w/w levels using each Surelease formulation, and the coated tablets were evaluated for their drug release characteristics, coat reflectivity (gloss), surface texture, Brinell hardness, and elastic modulus. The drug release was dependent on the coat level and followed Hixson-Crowell cube-root model at 1% coat level. However, at > or = 2% coat levels, the release from tablets coated with GTC plasticized formulation appeared to be best described by non-Fickian release mechanism and that from tablets coated with DBS plasticized formulation appeared to follow apparent zero-order release mechanism. At equal coat levels, tablets coated with GTC plasticized Surelease yielded lower drug release rates, higher reflectivity (gloss), lower surface roughness, higher Brinell hardness, and lower elastic modulus than those coated with DBS plasticized formulation. A good correlation was observed between the drug release rates and the reflectivity and surface texture of the coated tablets. The film-coats of GTC plasticized formulation were harder and more elastic than those of DBS plasticized formulation indicating better mechanical integrity.

Influence of type and level of water-soluble additives on drug release and surface and mechanical properties of Surelease films.

Ethylcellulose in combination with water-soluble additives has been used in the development of microporous membrane-coated dosage forms. In the present study, application of three types of water-soluble additives, namely polyethylene glycols (PEG 400, 3350, and 8000), maltodextrins (Maltrin M150, M100, and M040 in the order of lower to higher average polymer size and molecular weight; dextrose equivalence 16.9, 11.1, and 4.8, respectively), and xylitol, as porosity modifiers in the films of a commercially available aqueous ethylcellulose dispersion (Surelease/E-7-7060 plasticized with glyceryl tricaprylate/caprate) was investigated. The effect of type and level of these additives on drug release characteristics and surface and mechanical properties of the polymeric films was studied. Each additive was incorporated at 20 and 30% levels in the polymeric dispersion based on its solids content. Ibuprofen tablets were coated using the polymeric dispersion with and without additive at 3% w/w coat level in a fluid-bed equipment. The coated tablets were evaluated for their drug release rate, coat reflectivity (gloss), Brinell hardness, and elastic modulus. Differential scanning calorimetric analysis of the films was performed to determine the physico-chemical changes in the applied film-coats. The rate of drug release, hence film porosity, was observed to be dependent on the type and level of the additive added. The molecular weight of the additive and its concentration in the polymeric dispersion had significant influence on the rate of drug release, hardness, and elasticity of the film-coats.