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.     

Robustness Testing of a Tablet Formulation Using Multivariate Design

ABSTRACT

A total of 45 experiments were carried out to evaluate the robustness of two similar tablet formulations—a product of two strengths—with respect to normal batch-to-batch variation of the excipients and the active pharmaceutical ingredient. The formulations consist of 10 ingredients. Because of the differing amounts of active pharmaceutical ingredients, the two formulations also differ in the amounts of two of the diluents and one of the binders. The excipients and active pharmaceutical ingredient were characterized in terms of multiple variables, and principal properties were calculated with principal component analysis. A Plackett and Burman design was applied to the principal properties. The relationships between the design factors and two responses, mean disintegration time and mean crushing strength, were evaluated by using regression methods. Both formulations were found to be robust under controlled conditions.     

Optimization of Disintegration Time and Crushing Strength of a Tablet Formulation

Abstract

In an experiment with a factorial design, the following aspects were scrutinized: the impact on disintegration time and crushing strength caused by the loss-on-drying of the granulation; the granule-size distribution; the lubricant concentration; the compression force; and the pre-compression. Both with regard to disintegration time and crushing strength, these factors were found to have a significant influence: the loss-on-drying of the granulation; the fraction less than 0.150 mm; the concentration of magnesium stearate; and the compression force. A reduction of the tablet disintegration time was obtained by means of an increase of the granulation moisture; by an increase of the fine fraction; or by a reduction of the lubricant concentration or the compression force. The tablet crushing strength was increased by reducing the deviation of the granulation loss-on-drying from approximately 4.6 %; by a reduction of the fine fraction; by decreasing the lubricant concentration; or by increasing the compression force. The fraction larger than 0.300 mm had no significant influence; nor did the pre-compression. Further, there were no significant interactions.

By means of superimposing contour plots of disintegration time and crushing strength, a region was obtained where the requirements of disintegration time and crushing strength could be satisfied by controlling the processing variables.     

Optimization of Disintegration Time and Crushing Strength of a Tablet Formulation

In an experiment with a factorial design, the following aspects were scrutinized: the impact on disintegration time and crushing strength caused by the loss-on-drying of the granulation; the granule-size distribution; the lubricant concentration; the compression force; and the pre-compression. Both with regard to disintegration time and crushing strength, these factors were found to have a significant influence: the loss-on-drying of the granulation; the fraction less than 0.150 mm; the concentration of magnesium stearate; and the compression force. A reduction of the tablet disintegration time was obtained by means of an increase of the granulation moisture; by an increase of the fine fraction; or by a reduction of the lubricant concentration or the compression force. The tablet crushing strength was increased by reducing the deviation of the granulation loss-on-drying from approximately 4.6 %; by a reduction of the fine fraction; by decreasing the lubricant concentration; or by increasing the compression force. The fraction larger than 0.300 mm had no significant influence; nor did the pre-compression. Further, there were no significant interactions.

By means of superimposing contour plots of disintegration time and crushing strength, a region was obtained where the requirements of disintegration time and crushing strength could be satisfied by controlling the processing variables.     

Sustained Release Tablet Formulation for a New Iron Chelator

Sustained release tablet formulations for a new orally active iron chelator (1, 2, dimethyl-3-hydroxy-pyrid-4-one, DMHP or L1) have been developed. Coprecipitates containing DMHP and polymer were prepared and compressed into matrix-type tablets. The dissolution profiles as a function of (1) the type of polymer, and (2) polymer content, were determined. Both Eudragit types (RLPM and RSPM) and all hydroxypropylmethylcellulose (HPMC) grades (E4M, E10M, and K4M) exhibited significant sustained release activity. Above a certain ratio, increase in the polymer concentration did not provide any further decrease in the release rates. All grades of HPMC and both Eudragit RSPM and RLPM showed non-Fickian release kinetics. The role of HPMC and Eudragits in the formulation of a sustained release tablet of a water soluble drug is demonstrated.     

Sustained Release Tablet Formulation for a New Iron Chelator

Abstract

Sustained release tablet formulations for a new orally active iron chelator (1, 2, dimethyl-3-hydroxy-pyrid-4-one, DMHP or L1) have been developed. Coprecipitates containing DMHP and polymer were prepared and compressed into matrix-type tablets. The dissolution profiles as a function of (1) the type of polymer, and (2) polymer content, were determined. Both Eudragit types (RLPM and RSPM) and all hydroxypropylmethylcellulose (HPMC) grades (E4M, E10M, and K4M) exhibited significant sustained release activity. Above a certain ratio, increase in the polymer concentration did not provide any further decrease in the release rates. All grades of HPMC and both Eudragit RSPM and RLPM showed non-Fickian release kinetics. The role of HPMC and Eudragits in the formulation of a sustained release tablet of a water soluble drug is demonstrated.     

Evaluation of Cefmetazole Rectal Suppository Formulation(s)

The objective of this study was to determine formulation parameters necessary to develop a cefmetazole suppository. Three 1 gram cefmetazole rectal suppository formulations were compared using in-vitro testing of melting behavior, dissolution times and fracture weight; and in-vivo dog studies of the three suppository formulations compared to IM single dose. The in-vivo study compared the dosage forms in four dogs by a cross-over design. The formulation containing one gram of sodium 5-methoxysalicylate as adjuvant gave a relative bioavailability of 29.4%, while the suppository containing sodium salicylate as adjuvant gave 17.5% relative bioavailability. The formulation which did not contain adjuvant neither dissolved properly in-vitro nor produced observable plasma levels during the in-vivo dog study. Despite the relatively large size (4.9 grams), the suppositories were easily inserted and no leakage occurred from medium-sized dogs. Proctoscopic examinations were performed following blood collection for each dose period. The suppositories were well tolerated as administered in this study. No clinical signs or symptoms of inflammation or irritation of the colon of the dogs dosed once weekly for four weeks with the suppository were noted. Blood levels obtained from the 1 g cefmetazole rectal suppositories are sufficient to be effective against many infectious diseases caused by certain pathogens. The data from the present investigation warrants further studies of the tolerance and pharmacokinetics of the 1 gram cefmetazole rectal suppository in man.     

Tablet Formulation : Genichi Taguchi's Approach

In this paper the Taguchi Method for studying a large number of factors and interactions with only a few experiments is shortly presented and applied to the development of a tablet formulation.     

Tablet Formulation : Genichi Taguchi's Approach

Abstract

In this paper the Taguchi Method for studying a large number of factors and interactions with only a few experiments is shortly presented and applied to the development of a tablet formulation.     

Solutol and Cremophor Products as New Additives in Suppository Formulation

ABSTRACT

Our research has a double purpose. On the one hand, doctors have expressed the need to formulate a rectal suppository dosage form from diuretic ethacrynic acid, which would add to the choice of treatment methods and thereby increase the possibilities of individual cure. On the other hand, the liberation and thereby the bioavailability of poorly-soluble ethacrynic acid needs to be enhanced, and for this purpose solubility-increasing additives new to rectal therapy were used. Solutol HS 15, Cremophor RH 40, and Cremophor RH 60 were used as additives in concentrations of 1, 3, 5, and 10%. The quantity of drug released changed as a function of additive concentration. Depending on the acceptor phase, the best results were achieved with an additive concentration of 1–3%, which is related to the optimal additive quantity accumulated on the boundary surface.     

Optimization of a Slow-Release Tablet Formulation Containing Sodium Sulfathiazole and a Montmorillonite Clay

Abstract

A slow-release tablet formulation containing high levels of a montomorillonite clay, Veegum F®, was initially developed by trial and error. The present study was undertaken to utilize an approach involving statistics with the aid of computer science to develop a formula with desired characteristics. An experimental design for five factors was employed. The five factors consisted of levels of various components and the amount of compressional force applied while tableting. The response or dependent variables included tablet weight uniformity, hardness and friability; and percent drug in solution after 3 hours of dissolution testing. The response variables were fitted to a second-order polynomial with the five formulation factors as the independent variables. The resulting equations were used to optimize the formulation with respect to the response variables. The results indicated that a formulation with the desired characteristics could be predicted by the technique.     

Optimization of a Slow-Release Tablet Formulation Containing Sodium Sulfathiazole and a Montmorillonite Clay

A slow-release tablet formulation containing high levels of a montomorillonite clay, Veegum F®, was initially developed by trial and error. The present study was undertaken to utilize an approach involving statistics with the aid of computer science to develop a formula with desired characteristics. An experimental design for five factors was employed. The five factors consisted of levels of various components and the amount of compressional force applied while tableting. The response or dependent variables included tablet weight uniformity, hardness and friability; and percent drug in solution after 3 hours of dissolution testing. The response variables were fitted to a second-order polynomial with the five formulation factors as the independent variables. The resulting equations were used to optimize the formulation with respect to the response variables. The results indicated that a formulation with the desired characteristics could be predicted by the technique.     

Oral Sustained-Release Bioadhesive Tablet Formulation of Didanosine

The objective of this study was to formulate a hydrogel-forming bioadhesive drug delivery system for oral administration of didanosine (ddI). The aim of this tablet dosage form is to improve the oral absorption of ddI by delivering it in small doses over an extended period and localizing it in the intestine by bioadhesion. Compressed tablets of ddI using Polyox® WSRN-303, Carbopol® 974P-NF, and Methocel® K4M as the bioadhesive release rate-controlling polymers were prepared. The effect of polymer concentration on the release profile and in vitro bioadhesion of the matrix tablets was studied. Tablet formulations with Polyox WSRN-303 (10%) and Methocel K4M (30%) showed 93 and 90% drug release, respectively, after 12 h. The drug release was found to be linear when fitted in the Higuchi equation (square-root time equation), suggesting zero-order release. Carbopol 974-P-NF was found to inhibit the complete release of ddI because of drug-polymer interaction; hence, is not suitable for formulation of ddI. Drug diffusion and swelling of the polymer (anomalous Fickian release) was found dominant in ddI release. In general, in vitro bioadhesion increased with an increase in polymer concentration. Tablets containing a single polymer can be designed to form hydrogels serving the dual purpose of bioadhesion and sustained release.     

Film-Coated Enteric Tablet Formulation of Ketorolac Tromethamine

Abstract

A great majority of polymers used for pharmaceutical film-coating purposes have been derivatives of cellulose or methacrylate copolymers (Eudragit series) in most recent studies. The type and frequency of the ester substituents in the chemical structure of these polymers determines their water permeability and pH-solubility characteristics; therefore, different members of the series may be employed for taste-masking or as enteric-coating agents or dissolution rate-controlling membranes in sustained-release dosage forms. Ketorolac tromethamine (KT) is a non-steroidal drug with potent analgesic and anti-inflammatory activity and is absorbed rapidly (T_max < 1.0 hr) with an efficiency of > 87% following oral and intramuscular administration. The most frequent adverse effects occurring with KT are gastrointestinal disturbances such as peptic ulceration and gastrointestinal bleeding. For this reason, enteric-coated film tablets of KT were prepared in this study by the spray technique. Eudragit S-100 and L-100 were selected as coating materials. Polyethylene glycol (PEG) 4000 was used as a plastifying agent. Core tablets of KT were prepared by the direct compression technique. Tablet specifications were determined and evaluated statistically.     

Formulation of a Fast-Dissolving Ketoprofen Tablet Using Freeze-Drying in Blisters Technique

ABSTRACT

The aim of this work was to develop a ketoprofen tablet which dissolve-rapidly in the mouth, therefore, needing not be swallowed. The solubility and dissolution rate of poorly water-soluble ketoprofen was improved by preparing a lyophilized tablet (LT) of ketoprofen using freeze-drying technique. The LT was prepared by dispersing the drug in an aqueous solution of highly water-soluble carrier materials consisting of gelatin, glycine, and sorbitol. The mixture was dosed into the pockets of blister packs and then was subjected to freezing and lyophilization. The saturation solubility and dissolution characteristics of ketoprofen from the LT were investigated and compared to the plain drug and the physical mixture (PM). Results obtained showed that the increase in solubility of ketoprofen from LT matrix, nearly three times greater than the solubility of the plain drug, was due to supersaturation generated by amorphous form of the drug. Results obtained from dissolution studies showed that LT of ketoprofen significantly improved the dissolution rate of the drug compared with the PM and the plain drug. More than 95% of ketoprofen in LT dissolved within 5 min compared to only 45% of ketoprofen plain drug dissolved during 60 min. Initial dissolution rate of ketoprofen in LT was almost tenfold higher than that of ketoprofen powder alone. Crystalline state evaluation of ketoprofen in LT was conducted through differential scanning calorimetry (DCS) and x-ray powder diffraction (XRPD) to denote eventual transformation to amorphous state during the process. Scanning electron microscopic (SEM) analysis was performed and results suggest reduction in ketoprofen particle size.     

Improved Bioavailability of a Micronized Megestrol Acetate Tablet Formulation in Humans

Megestrol acetate, a progestogen widely used in the palliative treatment of endometrial carcinoma and breast cancer, is currently administered orally as a solid dosage form. Bioavailability of the drug following oral administration is closely related to the effectiveness and safety profile of the drug in formulation. Improved immediate-release formulations should allow improved drug delivery into the systemic circulation and, at the end, to the site of action. The micronization of drugs is one of the technological procedures to achieve such a purpose. This paper reports the design and results obtained in an in vivo study of the bioavailability of a micronized megestrol acetate tablet formulation compared to a conventional form. A significant increase in the drug bioavailability was observed, in either the rate or the extent of absorption. In vitro dissolution data of the two study formulations reflected the in vivo findings.     

The Stability of Aspirin in a Moisture Containing Direct Compression Tablet Formulation

Abstract

Studies were conducted on the stability of a direct compression tablet formulation containing aspirin as a model hydrolabile drug. Emdex^R (a mixed-sugar diluent containing approximately 8 percent moisture) and stearic acid (a lubricant) made up the remainder of the formulation. Both tablets and uncompressed powder blend were manufactured, packaged in storage containers and placed on stability at different storage temperatures. Stability samples were assayed for aspirin and salicylic acid using a stability indicating analytical method. Analysis of the stability data showed that the rate of aspirin decomposition accelerated with time. Also, the aspirin decomposition rate increased with temperature. The data were fit to the empirical equation y = 100 – ktⁿ, where y is the percent aspirin remaining, t is time, and k and n are constants. The formulation showed good stability, with less than one percent decomposition occuring after 1.75 years of storage at room temperature. This result indicates that although the aspirin formulation contained approximately 8 percent moisture, at room temperature the majority of the moisture present in the formulation is not available to react with the aspirin. The apparent activation energy of the solid-state aspirin decomposition was 46 kcal/mole, which is higher than expected. This result may be due to a temperature dependent release of moisture from the Emdex^R. Further studies are needed to verify this explanation.