Release of a Low Dose Water Soluble Medicinal Agent from Inert Wax Matrix Tablets

Directly compressible wax matrix tablets have been developed for a low dose medicinal agent (Chloropheniramine maleate). A mixture of castor wax NF and Hydrogenated Vegetable Oil NF, was optimized in the ratio of 50:50 as matrix based on their bulk density and particle size distribution and compression properties The compression properties indicated that the increase in compression forces resulted in a tablet of higher hardness up to 8 Kp. However further increase in compression forces resulted in the decrease in hardness and capping was apparent.

The result of dissolution studies indicated no significant effect of hardness and tablet shape (Round and rectangular shaped) on the dissolution properties of wax matrix tablets. A plot of percent drug released various square root of time exhibited a linear relationship. The release rates of CPM from wax matrix tablets were found to be independent of the rotational speed of paddles between 50-75 RPM. From these results, the release mechanism of CPM from wax matrix tablets appears to be primarily diffusion controlled rather than matrix erosion.     

Talc functionality as lubricant: texture, mean diameter, and specific surface area influence

Talc is widely used as a glidant (flow regulator) for powders. This study highlights the characteristics that confer to talcs new end use properties in improving the lubrication function during compression. We studied the contribution of texture, mean diameter (D50), and specific surface area on the residual die pressure, the ejection pressure, the lubrication index, and the tablet hardness. Different textures were studied: microcrystalline, macrocrystalline, and moderately macrocrystalline talc grade. The compression parameters were improved according to the texture. D50 varies from 0.62 to 15 µm. As D50 decreases, the lubrication performance is improved. Finally, the specific surface area of talcs was studied. This last characteristic of talcs was shown as the most relevant parameter in determining lubrication ability.     

Optimization of Sotalol Floating and Bioadhesive Extended Release Tablet Formulations

A novel extended release sotalol HC1 tablet formulation which possesses a unique combination of floatation and bioadhesion for prolonged residence in the stomach has been developed. Tablets were produced by direct compression. A two-factor factorial, central, composite Box-Wilson experimental design was employed to develop and optimize the tablet formulation containing 240 mg sotalol HC1. The ratio of two major bioadhesive agents, sodium carboxymethylcellulose (NaCMC) to hydroxypropylmethylcellulose (HPMC), and the ratio of two direct compressible diluents, ethylcellulose (EC) to crosspovidone, were used as formulation variables (independent variables) for optimizing tablets response parameters, such as dissolution bioadhesive capability, tablet density and required compression force for producing 6 Kg hardness tablets. The data were also analyzed by means of quadratic response surface model. Response surfaces were generated as a function of formulation variables. An optimum direct compression, bioadhesive and floating tablet formulation of sotalol HCl was achieved by considering the dissolution characteristic as primary objective and using required compression force, bioadhesive capability as constraints within the experimental region. The surface model was validated for accurate prediction of response characteristics.     

Talc Functionality as Lubricant: Texture,Mean Diameter,and Specific Surface Area Influence

Abstract

Talc is widely used as a glidant (flow regulator) for powders. This study highlights the characteristics that confer to talcs new end use properties in improving the lubrication function during compression. We studied the contribution of texture, mean diameter (D50), and specific surface area on the residual die pressure, the ejection pressure, the lubrication index, and the tablet hardness. Different textures were studied: microcrystalline, macrocrystalline, and moderately macrocrystalline talc grade. The compression parameters were improved according to the texture. D50 varies from 0.62 to 15 µm. As D50 decreases, the lubrication performance is improved. Finally, the specific surface area of talcs was studied. This last characteristic of talcs was shown as the most relevant parameter in determining lubrication ability.     

Release of a Low Dose Water Soluble Medicinal Agent from Inert Wax Matrix Tablets

Abstract

Directly compressible wax matrix tablets have been developed for a low dose medicinal agent (Chloropheniramine maleate). A mixture of castor wax NF and Hydrogenated Vegetable Oil NF, was optimized in the ratio of 50:50 as matrix based on their bulk density and particle size distribution and compression properties The compression properties indicated that the increase in compression forces resulted in a tablet of higher hardness up to 8 Kp. However further increase in compression forces resulted in the decrease in hardness and capping was apparent.

The result of dissolution studies indicated no significant effect of hardness and tablet shape (Round and rectangular shaped) on the dissolution properties of wax matrix tablets. A plot of percent drug released various square root of time exhibited a linear relationship. The release rates of CPM from wax matrix tablets were found to be independent of the rotational speed of paddles between 50–75 RPM. From these results, the release mechanism of CPM from wax matrix tablets appears to be primarily diffusion controlled rather than matrix erosion.     

Optimization of Sotalol Floating and Bioadhesive Extended Release Tablet Formulations

Abstract

A novel extended release sotalol HC1 tablet formulation which possesses a unique combination of floatation and bioadhesion for prolonged residence in the stomach has been developed. Tablets were produced by direct compression. A two-factor factorial, central, composite Box-Wilson experimental design was employed to develop and optimize the tablet formulation containing 240 mg sotalol HC1. The ratio of two major bioadhesive agents, sodium carboxymethylcellulose (NaCMC) to hydroxypropylmethylcellulose (HPMC), and the ratio of two direct compressible diluents, ethylcellulose (EC) to crosspovidone, were used as formulation variables (independent variables) for optimizing tablets response parameters, such as dissolution bioadhesive capability, tablet density and required compression force for producing 6 Kg hardness tablets. The data were also analyzed by means of quadratic response surface model. Response surfaces were generated as a function of formulation variables. An optimum direct compression, bioadhesive and floating tablet formulation of sotalol HCl was achieved by considering the dissolution characteristic as primary objective and using required compression force, bioadhesive capability as constraints within the experimental region. The surface model was validated for accurate prediction of response characteristics.     

Evaluation of Bilayer Tablet Machines—A Case Study

Four bilayer tablet compression machines were evaluated for their suitability for compression of a specific bilayer tablet formulation. Tablet machines evaluated were: Manesty (Model No. BB4), Manesty (Model No. Rotappress), Fette (Model No. P3102) and Kilian (Model No. 51AST-ZS) tablet presses. The tablet delamination tendency was the primary acceptance criteria for the evaluation of tablet press performance. The compression force on layer I was found to be the major factor influencing tablet delamination. It was found that the Kilian press was best suited for the compression of the model bilayer tablet formulation. The Kilian press is equipped with a special sampling device for layer I which allows additional compression force to be applied on layer I only at the time of weight sampling. The sampling device then returns to the original set points after sampling is completed. This feature maintains the compression force on layer I to a minimum during routine compression. Data indicated that the compression force on layer I and the compression zone in the die cavity of layer II were two factors needing to be controlled in order to yield bilayer tablets with acceptable physical characteristics.     

Characterization of excipient and tableting factors that influence folic acid dissolution, friability, and breaking strength of oil- and water-soluble multivitamin with minerals tablets

The goal of this study is to characterize the formulation and processing factors that influence folic acid dissolution from oil- and water-soluble multivitamin with minerals tablet formulations for direct compression. The following parameters were studied: bulk filler solubility, soluble to insoluble bulk filler ratio, triturating agent (preblending carrier) solubility, disintegrant usage, compression pressure, and folic acid particle size. Folic acid particle size was determined by using light microscopy, and surface area was measured by using BET adsorption. The tablets were compressed on an instrumented Stokes B2 tablet press, and the friability, weight variation, and dissolution were measured according to USP methods, along with tablet breaking strength. In summary, we found the following factors to be critical to folic acid dissolution: bulk filler solubility (soluble fillers, such as maltose, increase folic acid dissolution); disintegrant amount (levels less than 0.4% (w/w) are ineffectual, whereas levels greater than 1.2% (w/w) did not further increase dissolution); and compression force (generally, maltose produce harder tablets). In addition, folic acid dissolution was less affected by changes in compaction pressure when a “super” disintegrant and maltose, as a bulk filler, were used. It was determined that the trituration agent did not play a significant role in folic acid dissolution. In the range of parameters studied, statistical analysis found no significant interactions between the parameters studied, which means they act independently in an additive manner. The results also show that no one factor is completely responsible for dissolution failure. Thus, it is the combination of formulation factors and processing conditions that collectively add up to produce dissolution failure; however, the use of a disintegrant and a soluble filler such as maltose can make a formulation more robust to the inevitable changes that can occur during commercial production.     

Prediction of Tablet Properties by Compression Force-Time Profile Parameters

The compression force-time profile parameters proposed by Chilamkurti el al. (1) have proved to be no better than maximum compression force for prediction of the properties of three series of direct compression microcrystalline cellulose tablet formulations containing various proportions of prednisone, phenobarbital or isoniazide and punched under various compression forces. The usefulness of the Chilamkurti parameters is nevertheless not ruled in the case of formulations for which maximum compression force has little predictive value.     

Processing of alumina and zirconia nano-powders and compacts

Magnesia–doped alumina and yttria–doped zirconia nano-powders were synthesized using sucrose as a chelating agent and template material from the aqueous solutions of aluminium nitrate, magnesium nitrate, ytrrium nitrate and zirconyl nitrate, respectively. Synthesis parameters were optimized with varying sucrose to metal ion ratio, calcinations time, and temperature to produce these nano-powders. As-synthesized powders were characterized by room temperature X-ray diffraction, BET surface area analyzer and transmission electron microscopy. Y₂O₃–ZrO₂ nano-powders had particle size in the range of 80–200 nm with specific average surface area of 119 m²/g and for MgO–Al₂O₃ powders, particle sizes were 30–200 nm with the specific average surface area of 250 m²/g. Our results indicate that this synthesis method is a versatile one and can be applied to a variety of oxide-based materials to form nano-powders. Nano-powders were compacted uniaxially and densified in a muffle furnace. Sintered discs were used for hardness testing and density measurements, as well as for microstructural characterization.     

Effect of Cryogrinding on Physico-Chemical Properties of Drugs. II. Cortisone Acetate: Particles Sizes and Polymorphic Transition

The low temperature grinding (at 78 K) of cortisone acetate was carried out. From electron microscopy data, there were determined a form, mean linear sizes of particles and then specific surface was calculated. From X-ray data, a part of microcrystalline fraction in cryogrinded samples was calculated. As was indicated by X-ray data, the mechano-induced phase transition from “monoclinic” phase (form F_I) to “orthorhombic” one (form F_II) takes place as a result of I0-min grinding. The transition is confirmed by IR-spectroscopy results too. The local pressures induced by the mechanical stress seems to be the main cause of the phase transition observed.     

Determination of a Relationship Between Force-Displacement and Force-Time Compression Curves

A series of experiments were conducted to evaluate and compare force-displacement and force-time compression curves. A Stokes B-2 sixteen station rotary tablet press was instrumented with piezoelectric transducers to monitor compression and ejection forces (in addition to punch proximity) and interfaced with a microcomputer. Processing and material variables were examined for their effects on the direct parameters (ie. height and area) and derived parameters (ie. area:height ratio and maximum s1ope:height ratio) of the force-time compression curve. Upper punch displacement was estimated and force-displacement curves were plotted. The force-time curve was then divided into three segments pertaining to the three stages of upper punch movement: compression, relaxation, and decompression. The “relaxation” stage was defined as the portion of the compression force-time curve corresponding to the interval when the upper punch displacement was held constant. The total, net and elastic works of compaction were calculated and their relationships with the areas of the individual phases of the force-time compression curve were examined. It appears that the area under the cornpression force-time curve can be related satisfactorily to the work of compaction.     

Process Considerations in Reducing Tablet Friability and Their Effect on in vitro Dissolution

The tablet friability resulting from manufacturing process variations was studied for two differently sized tablets using the same formulation. Granulations containing lower moisture contents required higher compression and ejection forces to manufacture a tablet at a given hardness, although this did not influence friability. Increased tablet hardness (and to a lesser extent decreased tablet thickness) decreased the tablet friability of the larger tablet. An increase in the quantity of granulating fluid increased the granulation particle size and slightly improved compactibility without significantly affecting friability. Tablet dissolution increased as the quantity of granulating fluid was decreased. There was a strong interaction, with respect to dissolution, between moisture content and the amount of granulating fluid. Tablet hardness did not significantly influence dissolution. Doubling the quantity of magnesium stearate in the granulation in one tablet strength decreased the maximum tablet hardness that could be obtained, and for the other tablet strength increased friability. It also resulted in slower tablet dissolution.     

Development of sildenafil-loaded orally disintegrating tablet with new lactate salt

To develop a sildenafil lactate-loaded orally disintegrating tablet with a faster drug effect onset and immediate action of erection, the orally disintegrating tablets were prepared with various amounts of menthol and colloidal silica using the direct compression technique followed by vacuum drying. Their tablet properties such as friability, hardness, wetting time and disintegration time were investigated. The oral bioavailability of sildenafil in the orally disintegrating tablet was then compared with the sildenafil citrate-loaded commercial tablet (Viagra(?)) in rabbits. Sildenafil lactate was a new salt form with more improved solubility and alleviated bitterness compared with commercial salt, sildenafil citrate. As the amount of menthol in the orally disintegrating tablet increased, the friability increased and hardness decreased, resulting in a shorter wetting time and disintegration time. Colloidal silica did the opposite. The sildenafil lactate-loaded orally disintegrating tablet prepared with 45 mg/tab of menthol and 1.5 mg/tab of colloidal silica gave a hardness of 3-4 KP, friability less than 0.5% and disintegration time less than 30 s, suggesting that it was a practical and commercial product with good tablet property and excellent efficacy. Furthermore, it gave higher AUC and C(max), and shorter T(max) values than did the commercial tablet, indicating that it improved the oral bioavailability of sildenafil in rabbits compared with the commercial tablet. Thus, the sildenafil lactate-loaded orally disintegrating tablet might induce a fast onset of action and immediate erection compared with the sildenafil citrate-loaded commercial tablet.     

Moisture, Hardness, Disintegration and Dissolution Interrelationships in Compressed Tablets Prepared by the Wet Granulation Process

Interrelationships among moisture, hardness, disintegration and dissolution in compressed tablets were studied by compressing tablets from granulations prepared by the wet granulation process containing low moisture levels. Hardness, disintegration and dissolution of these tablets did not change on exposure to ambient room conditions. After equilibration under high humidities, a decrease in tablet hardness occurred which depended linearly on tablet hardnesses at the time of compression. After overnight exposure to ambient room conditions, the softened tablets increased in hardness and this increase greatly exceeded the initial hardnesses. The magnitude of hardness increase was independent of the hardnesses at the time of compression. Increased tablet hardnesses resulted in an increase in the disintegration time, although in vitro dissolution of the drug remained unaffected. The results suggest that moisture gain and subsequent loss on storage under varying humidity conditions could account for major increases in hardness of compressed tablets in storage.     

Optimization of Tablet Formulations Containing

An optimized direct compression tablet formulation of a conventional theophylline tablet was developed using the technique of response surface methodology and successive quadratic programming (SQP). The response surfaces were obtained from fitting data generated from a secondorder uniformprecision rotatable hexagonal experimental design. The tablet formulation was optimized for mean in vitro dissolution time using disintegration time, ejection force, friability and hardness, as constraints within the experimental region by the SQP technique. The response surface model was validated by preparing and evaluating the predicted formulation. The characteristics of the tablet formulation were analyzed by principal component analysis. Sensitivity analysis for the optimal solution was performed for each constraint, while all remaining constraints were held constant. The robustness of the response surface model was evaluated by simulation for error in the compression force values.     

Tablet Properties and Dissolution Characteristics of Compressed Cellulose Acetate Butyrate Microcapsules Containing Succinyl Sulfathiazole

Cellulose acetate butyrate microcapsules of succinyl sulfathiazole were prepared by a modified emulsion-solvent evaporation method and formulated for compression with microcrystalline cellulose and carboxymethyl starch. Tablet hardness decreased and friability increased as microcapsule content increased. Formulations containing up to 50% microcapsules produced satisfactory tablets, but at 70% microcapsules, the tablets were unacceptably fragile. Variation of microcapsule size fraction from 75 μm up to 428 μm had only a small effect on tablet properties when formulated at the 40% level. Tablet hardness increased with increasing compression pressure from 1.9 kg at 17.6 MPa to 14.9 kg at 210.7 MPa. Dissolution properties of the microcapsules were essentially unchanged at compression pressures up to 351 MPa with T_50% values ranging from 121 to 132 minutes. Uncompressed microcapsules had a T_50% value of 130 minutes.     

Optimization of Tablet Formulations Containing

Abstract

An optimized direct compression tablet formulation of a conventional theophylline tablet was developed using the technique of response surface methodology and successive quadratic programming (SQP). The response surfaces were obtained from fitting data generated from a secondorder uniformprecision rotatable hexagonal experimental design. The tablet formulation was optimized for mean in vitro dissolution time using disintegration time, ejection force, friability and hardness, as constraints within the experimental region by the SQP technique. The response surface model was validated by preparing and evaluating the predicted formulation. The characteristics of the tablet formulation were analyzed by principal component analysis. Sensitivity analysis for the optimal solution was performed for each constraint, while all remaining constraints were held constant. The robustness of the response surface model was evaluated by simulation for error in the compression force values.     

Formulation factors affecting drug release from poly(lactic acid) (PLA) microcapsule tablets

A sustained-release (SR) formulation of phenobarbital (PB) microcapsule tablet was prepared using low molecular weight (MW) DL- and high MW L-poly(lactic acid) (PLA) polymer. Microencapsulation of PB showed a unimodal size distribution (375 to 550 microns) of the microcapsules with high loading capacity (> 84%). Drug release from the microcapsule was influenced by the polymer ratios and increased with an increase in L-PLA amount. Microcapsules and physical mixtures of PB and the PLA were directly compressed independently to form microcapsule and matrix tablets, respectively. Drug release from the microcapsule tablets was significantly lowered (p < .001) compared to matrix tablets or free microcapsule (free microcapsule > matrices > microcapsule tablets). We also investigated the effect of tablet adjuvants, compression pressures, and microcapsule loading on the tablet performance in terms of friability, hardness, porosity, tensile strength, and the release kinetics of PB. The drug release rate increased with increasing compression pressure in the case of Emcompress or lactose, but not Avicel. The drug release rate was three- to fivefold increased with sodium starch glycolate compared to tablets without a disintegrant. With an increase in microcapsule loading, a decrease in the drug release rate was observed; however, the tablet performance remained satisfactory. The morphology of the microcapsules was monitored microscopically after the dissolution and the disintegration of tablets. The drug release accelerated with compression pressures and microcapsule loading from the tablets due to mechanical destruction of the microcapsule wall, which was more clearly seen after disintegration and dissolution of the tablets. Our data suggest that the PLA microcapsule can be tableted to make a SR product without significantly affecting its release kinetics.     

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.