The influence of different plasticizers and polymers on the mechanical and thermal properties, porosity and drug permeability of free shellac films

The effect of triethyl citrate (TEC) and different molecular weights and concentrations of polyethylene glycol (PEG), in addition to the effect of different water-soluble polymers and dispersions at different levels, hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), carbomer 940, polyvinyl alcohol (PVA), ethyl cellulose (EC), on the mechanical and thermal properties, drug permeability, and porosity of free shellac films were investigated. Shellac films were cast from aqueous solutions, and their mechanical properties were studied by tensile test. Thermal analyses were performed using differential scanning calorimetry (DSC).

The results showed that the addition of plasticizer caused a decrease in both elastic modulus and glass transition temperature (T_g) and an increase in elongation at break of free shellac films. This effect was related to the concentrations of plasticizers. Different molecular weights of PEGs have different plasticization mechanisms.

Moreover, the incorporation of different amounts of HPMC, MC, or carbomer in free shellac films caused an increase in the flexibility, decrease in T_g, and a marked increase in drug permeability of free shellac films, whereas the addition of PVA caused a decrease in flexibility and drug permeability and an increase in T_g. Addition of EC resulted in a slight decrease of the elasticity and a small decrease in drug permeability. However it does not show a considerable effect on the T_g. In addition, it was found that the drug permeability is directly related to the mechanical properties and T_g of shellac films.     

High-Viscosity HPMC as a Film-Coating Agent

The possibility of using high viscosity grades of hydroxypropylmethylcellulose (HPMC) as a film forming agent in a conventional coating process has been investigated. Ethanol/water mixtures having different weight ratios (5 to 18) and containing up to 5 % of HPMC revealed to be suitable.

The influence of some formulation additives (talc, PVP and plasticizers) on both the overall coating process and the in-vitro release profiles of ketoprofen containing coated tablets was also investigated and discussed.     

Research Papers: Preparation of Indobufen Pellets by Using Centrifugal Rotary Fluidized Bed Equipment Without Starting Seeds

ABSTRACT

Pellets containing Indobufen as model drug were prepared by using the centrifugal-rotary fluidized bed equipment without employing non-pareil seeds.

The influence of different amounts of spheronization enhancer (microcrystalline cellulose) and of different fillers (lactose, mannitol, calcium carbonate) on both processing and physical properties of the pellets were evaluated.

The preparation reproducibility was also investigated. The use of 30% w/w of microcrystalline cellulose was essential to produce a good quality pellets; the incorporation of filler decreased the qualitative characteristics of the pellets.

The water feeding rate proved to be an important parameter for the pellet growth.

Therefore, the results showed that this technology based on the rotary fluidized bed is a promising and alternative method in producing pellets.     

Carboxymethylstarches in Wet Granulation

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

The Mechanical and Adhesion Properties of Aqueous Based Hydroxypropyl Methylcellulose Coating Systems Containing Polydextrose and Titanium Dioxide

The effect of titanium dioxide and polydextrose on film adhesion to microcrystalline cellulose tablet surface and mechanical properties of aqueous-based hydroxypropyl methylcellulose free films were evaluated using a Lloyd LRX materials testing machine. The free films and the films applied to tablets were prepared by using a pneumatic spraying technique similar to that used in fluidized-bed coaters.

The film adhesion was found to increase with increasing concentrations of titanium dioxide and polydextrose in the film. The addition of polydextrose to the film increased only slightly the moisture permeation of coated tablets. This may be due to the hygroscopic nature of polydextrose. Over the range studied, the addition of polydextrose reduced the elongation and the tensile strength of the film, indicating decreased deformation capacity of the film and a risk of cracking.     

Crystal Engineering and Particle Design for the Powder Compaction Process

The historical background to the subject of crystal engineering of pharmaceuticals is briefly reviewed with reference to materials as diverse as insulin and direct compression tablet excipients. In the light of the limited scientific and practical information available on the topic two questions are posed -

Is it possible to prepare 'designer' materials with preferred processing, specifically compressive, properties giving optimised product characteristics?

How can such materials be efficiently manufactured?

In order to consider these questions, several important elements of data-base requirements are regarded as essential. These include knowledge of the crystalline phases of pharmaceutical solids, full understanding of the fundamental mechanical constants and moduli of particulate solids, and the relationships describing the influence of crystallographic structure on the mechanical properties of crystals and powders. At the same time the effects of preparation, pretreatment and processing effects on crystal structure, crystallinity and thermodynamic properties of powdered solids must be established.

The topics of material based compaction problems, property groupings of pharmaceutical powders with particular emphasis on crystal structure and mechanical properties are discussed. The review then considers recent and current research work examining the compaction behaviour of modified or engineered materials, prepared using alternative crystallisation conditions and the incorporation of low level additives. Specific examples include modern direct compression excipients, 'spherical' drug particle production and high purity lubricant (magnesium stearate) powders.

In conclusion, the future potential of the concepts of crystal engineering and particle design is considered in terms of predicting mechanical and processing properties from fundamental molecular and structural information.     

Evaluation of sorghum starch as a tablet excipient

The suitability of sorghum starch as a binder and disintegrant at various concentrations in diverse tablet formulations have been investigated. Sodium bicarbonate and calcium carbonate were used as soluble and insoluble inorganic medicinal substances in various tablet formulations.

The effect of sorghum starch on the physical properties of the tablets were compared with those formulated with maize starch using the same concentrations of binder and disintegrant under the same experimental conditions.

The observations show that sorghum starch can be used as binder and disintegrant in tablet formulations. The indication is that the starch exhibit about twice the disintegrant power and about the same binding efficacy compared to maize starch.     

Technological Evaluation of three Enteric Coating Polymers I. With an Insoluble Drug

The enteric properties of a recent cellulose polymer, cellulose acetate trimellitate (CAT, EASTMAN KODAK) were evaluated on an insoluble substract for comparison, included in this paper are the properties of two other cellulose esters: cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose phthalate (HP55).

The physical properties and disintegration time at pH 1.2 and 6.5 were influenced by the level of coating solution. The gastroresistance was obtained more fastly with CAT and CAP than for HP55.

The influence of coating solution on drug release from tablet was investigated. The dissolution studies were made allowing the variation of pH in the dissolution medium during the kinetics.

Drug release from coated tablets was found to be dependent upon the type of polymers used to form film: higher release rates were obtained with CAT compared to CAP and HP55.     

Effect of Some Excipjents and Compression Pressure on the Adhesion of Aqueous-Based Hydroxypropyl Methylcellulose Film Coatings to Tablet Surface

The adhesion between aqueous-based hydroxypropyl methylcellulose (HPMC) films and tablet surface was evaluated using a Lloyd LRX materials testing machine. Special attention was paid to the effects of compression pressure and the excipients (microcrystalline cellulose, lactose and a commercial combination of lactose and cellulose (Cellactose^R)) on the adhesion properties of the film.

The adhesion of HPMC films was the lowest for the tablets containing lactose as a diluent and the highest for the tablets containing microcrystalline cellulose. The adhesion to Cellactose^R-based tablets increased with increasing compression pressure. With microcrystalline cellulose (MCC) and lactose, the effect of compression pressure on film adhesion was not so clear. The increase in concentration of a hydrophopic lubricant, magnesium stearate, decreased the adhesion between the films and tablets cores. The greatest decrease was observed with the MCC tablets.

Furthermore the results showed that, the film coating increased clearly the mechanical strength of the tablets, depending on the excipient, the compression pressure and amount of magnesium stearate.     

Technological Evaluation of Aqueous Enteric Coating Systems with and Without insoluble Additives

The most recent dispersible enteric polymers such as AQUATERIC, HPMCP HP 55 F, EUDRAGIT L 100 55 and cellulose acetate phthalate (micronized in our laboratory), were evaluated on two different physical and chemical substrates (soluble and insoluble). Four standard formulations were used with and without the most common solid additives such as talc and titanium dioxide.

A good distribution of all coatings was obtained on the both substrates previously studied.

The mechanical properties and the dissolution profile of gastric resistance showed clearly that the methacrylic copolymer-based product is a good alternative to esther celluloses manufactured with the most modern technologies.     

The Effect of Hygroscopic Formulation Ingredients on the Sorption Characteristics of Tablets

In order to examine the effect of hygroscopic ingredients on the sorption characteristics of tablets, three hygroscopic additives - citric acid anhydrous (CAA), sorbitol (SI) and maltodextrin (MA) - were added at concentrations of 10% and 20% to a standard tablet granulate formulation prepared with three different initial moisture contents. The additives chosen were intended to be representative of a range of active ingredients with varying hygroscopicity characteristics.

The granulate/additive mixtures, together with the corresponding additive-free mixtures, were then tabletted, and the sorption isotherms of the resulting tablets were determined. The sorption-related changes in hardness, thickness, diameter and disintegration time were also investigated.

Examination of the sorption isotherms showed that the position of the “ansor-ption point” - the point where the isotherm crosses the x-axis and thus the point at which the tablets start to adsorb water - was much more dependent on the initial moisture content of the tablets than on the presence of a hygroscopic additive. The presence of a hygroscopic additive had little or no effect.

The additives did not begin to have any marked effects on the sorption isotherms of the finished tablets until the relative humidity level reached 62%. Above 62%, however, the differences in the hygroscopicity characteristics of the individual additives had a direct impact on the sorption profiles of the tablets.

As increasing amounts of moisture were adsorbed, tablet hardness fell whilst tablet thickness and diameter increased. The increases in thickness were in all cases greater than the increases in diameter. These findings applied to all tablets irrespective of their initial moisture content.

The sorption-related changes in disintegration time did not exhibit any consistent pattern and have therefore not been interpreted.

A comparison of the areas under the adsorption isotherms yielded the following results:

• The three additives adsorbed differently. Their adsorption, however, was always greater than that of any of the tablet variants.

• The areas under the adsorption isotherms of the additive-containing tablets were in all cases greater than the areas under the adsorption isotherms of the corresponding additive-free tablets. However, the differences were not always directly related to the concentration of the additive or to the area under the adsorption isotherm of that additive.

The relevance of these findings for routine pharmaceutical practice is discussed.     

Comparative compaction properties of various Microcrystalline Cellulose types and Generic Products

The purpose of this review is to compare the tableting properties of conventional microcrystalline cellulose (MCC) with those of other common direct compression diluents and of the numerous new MCC grades and brands recently made available. After a brief discussion of the mechanisms of consolidation involved in the formation of MCC tablets, the first section deals with the basic mechanical properties of powders important for compression. Values of parameters describing ductility, brittleness, elasticity and viscoelasticity are presented and discussed in relation with the degree of polymerization, the crystallinity, the moisture content and the morphological properties of the materials.

The tableting properties of the powders during the compression process (densification behavior, work of compression) and the mechanical strength of the finished products (compactibility) are examined. Special attention is given to the effects of moisture content, lubricants and other added substances on the performances of MCC products. Comparative tablet weight variation data are provided for several MCC types from different supplies.

Finally, aging of the MCC compacts is discussed in relation to environmental conditions, before warning the user in the conclusion on the considerable variability of MCC products currently available on the market.     

Fast- and slow-release tablets for oral administration of flavonoids: rutin and quercetin

Many derivatives of rutin (Rt) and its metabolite quercetin (Q) are employed in clinics for cardiovascular chronic pathology, and are also known for their antiulcer behavior in vivo and antiproliferative and antimutagenic activity in vitro. Unfortunately, the absorption of quercetin and rutin from the gastrointestinal tract is slow and irregular, probably due to their very slight solubility in water and slow dissolution rate.

In this work the dissolution rate of the drugs from oral formulations has been improved using some enhancers such as cross-linked sodium carboxymethylcellulose (CMC-XL), sodium carboxymethylstarch (E), and cross-linked polyvinylpyrrolidone (P). The drugs were loaded on the hydrophilic carriers by different techniques such as mixing or co-milling. The in vitro dissolution profiles of the mixed or co-milled drug/polymer systems, obtained in various media with different pH, were compared. The results show that the drug dissolution rate from the co-milled drug/carrier systems is faster than that from mixed systems, and CMC-XL and sodium carboxymethylstarch systems are able to enhance the dissolution rate. For this reason, these co-milled drug/carrier systems were used for the production of both fast- and slow-release tablets. The co-milled drug/CMC-XL system was used for the preparation of fast-release tablets containing rutin, while three different fast-release tablets were formulated and tested using respectively Q/CMC-XL, Q/E, and Q/P co-milled systems.

The effect of the presence of sodium lauryl sulfate in the aqueous medium on the dissolution profile of flavonoids alone was also studied.

The prolonged-release formulations have been developed using hydroxypropylmethylcellulose (HPMC) of different viscosity grades as retarding polymer. An extended release of the drugs for times ranging from 6 to 14 hr could be obtained, depending on the type and viscosity of the HPMC used.     

Habit Modifications of Nitrofurantion Crystallized from Formic Acid Mixtures

The crystal size and the length to width ratio of Nitrofurantoin, an anti-bacterial urinary tract drug, can be controlled using an appropriate mixture of solvents and suitable crystallization conditions.

Some solvents will form undesirable complexes with the drug (INF) while with others no crystal structure modification or complexation was detected (HCO₂H).

The length (y) to width (x) ratio of the Nitrofurantoin varies from 2.5 to 1.5 when crystallized from pure formic acid or in a mixture with water or ethanol.

The y/x values correspond to the solvent interactions and super saturation (S).

The crystal growth regularity is ascribed to the solvent power and thus when more regular crystals will precipitate bioavailability and solubilization of the drug will increase. Best results were obtained when mixture of formic acid-ethanol solution was used as crystallization media yielding large tabular crystals.     

ESTIMATION OF THE AVERAGE ASPECT RATIO OF LAMELLAE-SHAPED PARTICLES BY LASER DIFFRACTOMETRY

Reinforcing properties for polymers and elastomers, rheological properties of high density aqueous slurries, hidding power, lubricating properties of platey particles strongly depend on their size distribution and shape factor or aspect ratio (A.R.).

Determinations of A.R. of fine particles by conventional methods are time-consuming and require sophisticated equipment. A method based upon later light diffractometry has been developed to meet control requirements in industry, the average A.R. can be determined within 5 to 10 minutes, depending upon the number of measurements made using a commercial laser granulometer.

The method relies on:

a cylindrical model (disc) of platey particles.

determinations of the projected area of particles in dilute suspensions of controlled solids concentrations.

calibration of the instrument, using isodiametric particles

simple material balance to derive the average thickness h of the platey particles from projected area measurements and volume of the solid.

A.R. is defined as d50(S)/h. where d50(S) is the mean projected area diameter and h the average thickness attributed to all particles occurring in the sample.     

The Solubility of Allopurinol in Aqueous Solutions of Polyvinylpyrrolidone

Saturation solubilities of allopurinol have been determined in aqueous solutions at pH 1.0 containing different molecular weight fractions of polyvinylpyrrolidone (P.V.P.). The P.V.P. was characterized using light scattering techniques.

Over the temperature range 15-40° the solubilities increased linearly with concentration of P.V.P. For equal concentrations of different P.V.P. species the lower the molecular weight the greater is the increase in solubility of allopurinol. Solubility increases were never more than a twofold increase for any polymer species at any temperature. Binding ratios indicated a low affinity of allopurinol to all the P.V.P. species with the greatest affinity being for the lower molecular weight fraction.

The solubility data has been used to calculate enthalpy, free energy and entropy values for allopurinol/P.V.P. systems. Changes in these thermodynamic parameters did not suggest complex formation between allopurinol and P.V.P.     

Investigation of Prolonged Drug Release from Matrix Formulations of Chitosan

A hydrocolloidal matrix system containing complexes of chitosan was investigated for preparation of sustained release tablets and examined in-vitro.

Theophylline tablets using chitosan as a sustained release base were evaluated. It was found that when chitosan is used in a concentration of more than 50% of tablet weight, an insoluble non-erosion type matrix was formed. Tablets prepared with a chitosan concentration of less than 33% were fast releasing.

Chitosan used in a concentration of about 10% acted as a disintegrant and the drug was dissolved within an hour.

Citric acid slowed down the release rates of chitosan based theophylline tablets. Theophylline tablets using carbomer-934P as a sustained release base were evaluated. Carbomer-934P in lower concentrations forms an erosion type matrix. In order to produce a twenty-four (24) hour sustained release tablet, more than 10% concentration of carbomer-934P is needed. Combination with chitosan and carbomer-934P produced slower releasing tablets.

A hydrocolloidal erosion type matrix was formulated using chitosan, carbomer-934Pand citric acid. Only 10% of chitosan was needed to prepare theophylline sustained release tablets in these mixtures.

The dose dumping potential of chitosan tablets due to rapid disintegration in alkaline media was eliminated by preparing hydrated erosion type matrix systems.     

The Effect of Partice and Power Proterties on the Mechnical Properties of Directly Compressed Cellulose Tablets

The inherent material properties of four cellulose powers were evaluated and the effect of these properties on the mechnical strenght and surface hardness of direct compression tablest was studied. Two of the materials studied were the other two were experimental cellulose powers, and agglomerated cellulose and a deploymerized cellulose.

The agglomerated cellulose powder formed the strongest as well as the hardest tablets. Also both microcrystalline celluloses formed clearly stronger tablets than depolymerized cellulose, but surface hardness of the tablets compressed using these three cellulose powders was, however, quits similar.

The most important material property affecting the breaking strength of tablets was the suesific surface area of the starting material. No correlaiton between cystallinity, particle size or particule shape starting material and the strength of tablets was observed.

The surface hardness of tablets showed no simple correlation with the breaking strenth of tablets or with any single material property of cellulose powders. It is obvious, compacion could affect markeldy the hardbness of the compact surface, thus possibly masking the effect of a single material property.     

Dissolution Characteristics of Pharmaceutical Equivalents

The in-vitro release of diltiazem from pharmaceutical equivalents of sustained release tablets, commercially available in Italy, was studied.

The in-vitro release profiles were determined by means of different methods and apparatus. Paddle, basket, Poole, Diffutest and Stricker methods were compared.

The absorption rates in artificial gastric and enteric juices by means of lipid barriers were calculated.

Some preparations showed a diffusion mechanism, some a first-order release.

The differences among the dissolution profiles of the formulations were enhanced with the Strieker method.