Optimization of Direct Compression Tablet Formulations for Use in Tropical Countries

Abstract

With the aid of a combined mixture- and factorial- design, 2 standard tablet formulations were selected suitable for use in tropical countries. The formulations were based on native ingredients or ingredients that are available worldwide. The selection of the standard formulations was based on both the initial tablet properties of the formulations one day after preparation as well as the physical stability after storage under tropical conditions.

The selected formulations were evaluated by adding model drugs (diazepam, 2 mg per tablet or hydrochlorthiazide, 100 mg per tablet) and measuring tablet properties, not only one day after preparation, but also after storage under tropical conditions. Both selected tablet formulations were suitable standard formulations for tablets prepared by direct compression for use in tropical countries.     

The use of surface analysis techniques to determine the route of manufacture of tablet dosage forms

Analytical methods for determining the manufacturing process of tablet dosage forms have not been previously reported. The use of surface analysis techniques in particular X-ray Photoelectron Spectroscopy and Time of Flight Secondary Ionization Mass Spectrometry will be described and a model proposed which allows the prediction of the route of manufacture in calcium phosphate and cellulosic-based tablet formulations. Results of the application of this model to evaluate prototype tablet formulations prepared by wet granulation or direct compression will be reported. Strengths and limitations of the model will be discussed.     

An evaluation of starch obtained from pearl millet - Pennisetum typhoides. As a binder and disintegrant for compressed tablets

Abstract

The binding and disintegrant properties of millet starch obtained from Pearl Millet - Pennisteum typhoides (Staph. Burn, and Hubb.) Fam. Gramineae have been evaluated using tablet formulations of four drugs.

The results showed that Millet starch compared favourably with Maize starch with regards to most of the parameters used to evaluate the tablets. It can be safely concluded that millet starch is suitable for use as a binder and disintegrant in tablet formulations.     

Determination of precompression and compression force levels to minimize tablet friability using simplex

Abstract

Pilot simplex experiments for improving the tablet strength of three aspirin tablet formulations based on precompression and compression forces were presented. As each simplex moved towards the direction of the optimum, the friability was being minimized and the crushing strength was concomittantly being maximized. Because it followed a systematic direction, simplex process would locate a local optimum rapidly. The appropriate levels of precompression and compression forces that produced tablets with the desired strength were attained in five trials. By contrast, random search for this force combination required at least ten trials. Simplex technique is a cost and time effective means for determining the precompression and compression forces that will reduce the friability or increase the hardness of a tablet formulation. Results appeared to also indicate that crushing strength might be a more reliable measure of tablet strength than friability.     

Gastrointestinal Transit and Concomitant Absorption of Verapamil from a Single-Unit Sustained-Release Tablet

Abstract

A radiographic procedure is described for determining the position of a single-unit sustained-release tablet and the concomitant drug serum level. The results confirmed that, under fasting conditions, an essential part of the absorption of the model drug, verapamil, takes place in the colon. Food affected not only the gastrointestinal transit of the tablet but also the absorption rate of verapamil. With food the commencement of absorption was clearly more rapid than under fasting conditions. This is because the tablet is retained for a longer time by the food in the upper parts of the gastrointestinal tract, which favour drug absorption. It is concluded that absorption of verapamil from the colon is also effective and can be utilized in sustained release formulations. The ratio of AUC values of verapamil to those of norverapamil was markedly higher under fasting conditions, indicating enhanced bioavailability of verapamil from formulations which release most of the drug into the colon.     

A Mixture Experiment Approach for Controlling the Dissolution Rate of a Sustained-Release Tablet

Abstract

Several sustained-release tablet formulations with acceptable pharmacokinetic properties were found to be unstable because of the effects of lactose. Because the pharmacokinetic properties were acceptable, an attempt was made at developing stable formulations that reproduced the in vitro drug release characteristics of the unstable formulations. Through the use of a statistically designed mixture experiment, alternative formulations were generated and tested for dissolution. The dissolution data collected in the mixture experiment were used to develop a statistical regression model for identifying formulations with dissolution rates equal to those of the unstable formulations. The form of the regression model was based on the Higuchi equation. The data analysis indicated that it is possible to generate dissolution profiles that reproduce those of the original formulations by adjusting the ratios of Methocel® K4MCR Premium and Methocel KWOMCR Premium and by replacing the detrimental lactose with calcium phosphate dibasic anhydrous.     

Effect of Sodium Lauryl Sulphate and TweenR80 on the Therapeutic Efficacy of Glibenclamide Tablet Formulations in Terms of BSL Lowering in Rabbits and Diabetic Human Volunteers

Abstract

Glibenclamide has limited gastrointestinal absorption. Therefore, different concentrations of sodium lauryl sulphate and tween^R80 were included into the tablet formulations to increase the absorption of the drug and hence, to enhance the BSL lowering in rabbits and human volunteers suffering from maturity onset diabetes mellitus. It was found that the surfactants had enhanced both the rate and extent of BSL lowering in rabbits as well as in diabetic patients in higher concentrations present in the tablet formulations.     

Pilot Study of Relative Bioavailability of Two Oral Formulations of Ketoprofen 25 mg in Healthy Subjects. A Fast-Dissolving Lyophilized Tablet as Compared to Immediate Release Tablet

ABSTRACT

The pharmacokinetics of ketoprofen from a fast-dissolving lyophilized tablet (LT), which need not be swallowed, as compared to an immediate release (IR) tablet as reference after single oral dose (25 mg) administration was determined in six healthy subjects aged between 25–40 years using a randomized crossover design. In this study, the rate and extent of absorption of ketoprofen were found to be very different after administration of the LT and the IR tablet. The rate of absorption of ketoprofen from LT was significantly faster than that of IR tablet and had significantly higher C_max (by about 50%) and earlier t_max (by 15 min), whereas the extent of absorption expressed by AUC was about 68% higher as compared to the IR tablet. The relative bioavailability (f_rel) of the LT compared with the IR tablet was 168%. The difference between the two formulations for half-life and MRT were statistically significant (p < 0.05). The tolerance of the two tested formulations was excellent. Ketoprofen LT remained physically and chemically stable for 12 months at 25°C and 60% relative humidity.     

Effect of Excipient and Processing Variables on Adhesive Properties and Release Profile of Pentoxifylline From Mucoadhesive Tablets

ABSTRACT

The bioavailability and onset of action of drugs with high first-pass metabolism can be significantly improved by administration via the sublingual route. The objective of this study was to evaluate the effect of polymer type and tablet compaction parameters on the adhesive properties and drug release profile from mucoadhesive sublingual tablet formulations. Pentoxifylline was selected as the model drug because it has poor oral bioavailability due to extensive first-pass metabolism. Two polymers known to possess mucoadhesive properties, carbomer and hydroxypropyl methyl cellulose (HPMC), were used to prepare the formulations. Tablets were prepared by using direct compression technique and evaluated for in vitro dissolution, drug-excipient interactions, and adhesive properties. In general, there was a decrease in the rate of drug release with an increase in the concentration of polymers. No drug-excipient interactions were evident from differential scanning calorimetry or high-performance liquid chromatography analysis. For the formulations containing HPMC, the force of mucoadhesion increased with an increase in the concentration of polymer; however, for carbomer formulations, no such correlation was observed. Force of mucoadhesion decreased as a function of hydration time in both of the polymers.     

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.     

Advantages of Impact Testing over Hardness Testing in Determining Physical Integrity of Tablets

Abstract

An investigation of four different tablet strength tests was carried out on four different placebo formulations (differing in Avicel: Pharmatose ratios). The results analysis compared fatigue failure, work of failure, and impact failure to diametrical compression measurements (hardness). The impact results clearly show how different formulations can have the same hardness, yet their impact resistance can vary by as much as 200%. The impact test used in this work and other tests described are useful in tablet development to understand, compare, and mitigate tablet breakage during subsequent unit operations.     

Measurement of the Thermal Energy Evolved upon Tablet Compression

Abstract

The increase in temperature that occurs when a granulation or powder is compressed into a tablet has long been of interest to pharmaceutical scientists. Not only can this rise in temperature be indicative of differences in formulations which affect their performance during the tabletting process, but it may also cause unforeseen changes in the final tablet. Exact measurements of this temperature rise and of the thermal energy released have proven to be elusive. The diversity in equipment used approximately equals the number of published studies. This is the first report in which an accurate temperature probe has successfully been placed within the powder bed being compacted. Using a measurement system of original design, both the temperature rise and thermal energy evolved have been measured for single component systems comprised of Avicel, calcium carbonate, Corn Starch USP, and sulfathiazole. Extension of this work will deal with reactive multicomponent systems     

Formulation of Griseofulvin Tablets

Abstract

Difficulties in the formulation of griseofulvin tablets are reviewed. A number of griseofulvin direct compression, pre-compression and polyvinylpyrrolidone granulated tablet formulation have been successfully produced and evaluated, in all cases a mixture of dicalcium phosphate dihydrate and calcium phosphato-carbonate complex was used as tablet matrix. Attempts to use other direct compression tablet matrices proved unsuccessful. The tablets produced have been compared with two commercially available products and the data obtained indicated that the formulations developed in this study have potential for further exploitation.     

“In Vitro” - “In Vivo” Correlations of Eight Nitrofurantion Tablet Formulations: Effect of Various Technological Factors

Abstract

The bioavailability of eight nitrofurantoin tablet formulations differing in technological respects has been evaluated and correlated with de dissolution curves obtained using USP XXI Ed methods I and II. Method I was found incapable of predicting bioavailability of formulations when Carbopol 934 is used as binder. The influence of the technological factors varied is discussed.     

Optimization and Evaluation of Time-Dependent Tablets Comprising an Immediate and Sustained Release Profile Using Artificial Neural Network

The aim of this work was to optimize time-dependent tablets using artificial neural network (ANN). The time-dependent tablet consisted of a tablet core, which contained sustained release pellets (70% isosorbide-5-mononitrate [5-ISMN]), immediate release granules (30% 5-ISMN), superdisintegrating agent (sodium carboxymethylstarch, CMS-Na), and other excipients, surrounded by a coating layer composed of a water-insoluble ethylcellulose and a water-soluble channeling agent. The chosen independent variables, i.e., X₁ coating level of tablets, X₂ coating level of pellets, and X₃ CMS-Na level, were optimized with a three-factor, three-level Box-Behnken design. Data were analyzed for modeling and optimizing the release profile using ANN. Response surface plots were used to relate the dependent and the independent variables. The optimized values for the factors X₁–X₃ were 4.1, 14.1, and 29.8%, respectively. Optimized formulations were prepared according to the factor combinations dictated by ANN. In each case, the observed drug release data of the optimized formulations were close to the predicted release pattern. An in vitro model for predicting the effect of food on release behavior of optimized products was used in this study. It was concluded that neural network technique could be particularly suitable in the pharmaceutical technology of time-dependent dosage forms where systems were complex and nonlinear relationships often existed between the independent and the dependent variables.     

Influence of Surfactants on the In-Vitro release and Permeation of Lorazepam from Tablets

Abstract

Sodium lauryl sulfate, tween 80, sodium taurocholate and sodium tauroglycocholate were included into lorazepam tablet formulations to increase the dissolution and permeation of the drug. The increasing concentration of the surfactants has increased the dissolution and permeation of the drug. The fractional quantity remained to be permeated versus time plots show the exponential decay.     

Plasma Levels of lormetazepam after Sublingual and Oral Administration of 1 MG to Humans

Abstract

A new galenical formulation containing 1 mg lormeta-zepam (LMZ) for sublingual administration (“sleeping wafer”, see Figure 1) has been developed. In an open-cross over design the plasma lormetazepam levels were monitored radioimmunologically in 16 volunteers. Subjects received the sublingual formulation and an oral tablet (Noctamid^R-1) in a randomized sequence at weekly intervals. After sublingual administration the mean plasma lormetazepam levels were significantly higher between 7.5 and 25 minutes than after administration of the tablet. The earlier rise in plasma LMZ levels is also reflected in partial areas under the plasma level curve up to 45 minutes. LMZ was completely absorbed from both formulations as shown in total AUCs.

It is anticipated that sublingual administration of the new formulation will lead to a 40 - 50 % reduction of sleep latency. Possibilities for therapeutic application of the new formulation are discussed.     

Sucralfate as a Bioadhesive Gastric Intestinal Retention system: Preliminary Evaluation

Abstract

A prototype formulation of a gastric intestinal retention system was successfully developed. A matrix tablet containing sucralfate, Methocel E4M and the appropriate type of drug powder, granules or pellets was prepared using the Carver Press. Three different formulations were evaluated using three different drug entities, namely; theophylline sustained release pellets, aspirin granules and antacid powder. Tablets of these three different formulations showed remarkable adhesive characteristics onto the glass vessel in acidic medium up to at least eight hours. In addition, all three different formulations exhibited sustained release in-vitro dissolution profiles. These data imply that this gastric intestinal retention system can be used to prepare sustained release formulations.     

Prelimnaky Evaluation of Cissus Root Gum as a Binder in Sodium Salicylate Tablet Formulations

Abstract

Cissus root gum was processed and evaluated as a binder in lactose-based tablets each containing 100 mg of sodium salicylate as the active ingredient. Acacia binder was used as basis for comparison. Tablet hardness, friability, disintegration time and dissolution rate were the parameters investigated. The cissus gum gave hard and non-friable tablets at 1 - 3% w/w concentration of the tablet formula. Tablets containing above 2% w/w of the cissus gum gave high disintegration time values and the pattern of dissolution of the incorporated drug suggests that the gum may be useful in prolonged release tablet formulations. No significant changes in the tablet properties was observed after storage at 30°C for 16 weeks.