The Influence of Different Plasticizers and Polymers on the Mechanical and Thermal Properties,Porosity and Drug Permeability of Free Shellac Films

ABSTRACT

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.     

Investigation of the effect of various shellac coating compositions containing different water-soluble polymers on in vitro drug release

In this study drug pellets were coated with aqueous shellac coating formulations containing different amounts of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), and carbomer 940. The coating level needed for enteric coating was determined. The influence of different amounts of PVA, HPMC, and carbomer on drug release and mechanism; the porosity, and the stability of shellac coatings was investigated. The results show that the incorporation of different concentrations of HPMC into shellac coatings, due to the increasing of pores, could considerably increase the drug release from the pellets in purified water. Moreover, the swelling effect of carbomer 940 leads to much more diffusivity through shellac coatings in water. In addition, PVA results in small cracking in the films and much more diffusion of drug in water. Furthermore, all coating systems containing different hydrophilic polymers that were used in the present work could prevent the dissolution of drug in simulated gastric juice for 2 hours. On the other hand, a rapid and complete release of drug within 45 minutes was observed in simulated intestinal fluid. Drug release from shellac coated pellets and ones containing different amounts of carbomer was affected between 3-6 months, whereas shellac coatings containing different amounts of PVA or HPMC show the same dissolution profiles with small deviation after 12 months.     

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.     

Studies on Drug Release from a Carbomer Tablet Matrix

The purpose of this investigation was to study the drug release mechanisms for tablet matrices of carbomer. Carbomer is a polymer of acrylic acid which is cross-linked with polyalkenyl polyether. The drug and the carbomer were blended and directly compressed into tablets using a laboratory Carver press. The influence of the level of carbomer, the type of drug, and the pH of dissolution media were investigated by measuring drug release kinetics. In general, the release of a relatively neutral molecule (e.g. theophylline) in the pH 7.2 phosphate buffer solution appears to exhibit nearly zero-order kinetics via a diffusion-controlled mechanism for all polymer levels studied (10-85%).

The drug release process based on diffusion can be described by the general expression:

M_t = k₁t^1/2 + k₂t

where M, represents the amount of the drug released at time t, and k₁, k₂ are related to kinetic constants characteristic of the drug delivery systems. The release kinetics are modified when an ionic species, such as sodium salicylate, is incorporated into the tablet matrix.     

The effect of different plasticizer molecular weights and concentrations on mechanical and thermomechanical properties of free films

Plasticizers are usually added to improve the mechanical and conditional (thermomechanical) quality of film coatings. Different molecular weights and concentrations of polyethylene glycol were incorporated as plasticizers in hydroxypropylmethylcellulose (HPMC) films. Thermomechanical and mechanical properties of cast films were tested using tensile and dynamic mechanical thermal analysis (DMTA) testing, respectively.

The results, as expected, showed that addition of plasticizer caused a decrease in both mechanical and thermomechanical properties, but lower grades had more effect than higher molecular weights and concentrations.

The conclusion could be drawn that combining different grades of plasticizers to optimize mechanical and thermomechanical properties is more efficient than using different concentrations of plasticizers.     

Drug release from heat-treated polyvinyl alcohol films

Polyvinyl alcohol (PVA) films containing 10% w/w of a model drug, sulphathiazole, were cast from aqueous solutions and subjected to heat treatment at specific temperatures for known periods of time. Heat treatment at temperatures above the T_g of the PVA films slowed down the rate of drug release from the films. Increasing the temperature of heat treatment from 120°C to 160°C further decreased the rate of drug release. On the other hand, if the heat treatment were conducted at a temperature below the T_g e.g. at 80°C, there were insignificant differences between the release profile of sulphathiazole from heat-treated films and that from untreated films. The duration of heat treatment affected the rate of drug release to a smaller extent compared to the temperature of heat treatment. These results correlated with the heat induced changes in the morphology of, and in the extent of water uptake by the PVA films.     

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.     

In-vitro evaluation of sustained-release dyphylline tablets

Dyphylline tablets were prepared by direct compression of mixtures of the drug, emcompress and different ratios of hydroxypropyl methylcellulose (HPMC) or cellulose acetate phthalate (CAP). Physical properties of the prepared tablets and the drug release in 0.1 N HC1 and phosphate buffer, pH 7.4 were investigated.

All tablets were found to satisfy the USP requirements regarding content, weight uniformity and friability. Hardness was greatly enhanced and thickness was slightly increased by increasing the polymer ratio in tablet formulations. Disintegration time of the dyphylline tablets was delayed by the presence of either HPMC or CAP and there was a direct relationship between the polymer ratio and the disintegration time. Considerable retardation in the rate and extent of drug release from the prepared tablets in both dissolution liquids was observed. As the polymer ratio increased in the tablet formulations, the drug release was significantly inhibited.     

Design and evaluation in vitro of controlled release mucoadhesive tablets containing chlorhexidine

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity.

Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa.

Similar tests have also been carried out on a commercial product, Corsodyl gel^®, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.     

Effects of Plasticizers on Water Permeation and Mechanical Properties of Cellulose Acetate: Antiplasticization in Slightly Plasticized Polymer Film

The effects of plasticizers, triacetin and three different molecular weights of polyethylene glycol, on the water permeation and mechanical properties of cellulose acetate were investigated. At 37°C, the water permeability of cellulose acetate was found to decrease with increasing plasticizer to a minimum and then to increase with higher concentrations of plasticizer. Low plasticizer concentrations caused a decrease in water permeability by antiplasticization. Antiplasticization arose from an interaction between the polymer and the plasticizer molecules and decreases the molecular mobility of the polymer. This effect was confirmed by mechanical measurements of polymer free films at the same experimental temperature. However, when the temperature was raised above the glass transition temperature, T_g, of the polymer films, the polymer films contain enough energy to overcome the interaction between the polymer and plasticizer molecules, and the antiplasticization effect disappeared.     

Pharmaceutical Applications of Shellac: Moisture-Protective and Taste-Masking Coatings and Extended-Release Matrix Tablets

Abstract

Shellac is a natural polymer, which is used as enteric coating material in pharmaceutical applications. The major objective of the present study was to investigate the potential of shellac for other purposes, namely to provide moisture-protective and taste-masking coatings as well as extended-release matrix tablets. The efficiency of shellac to achieve moisture protection and taste masking was compared with that of hydroxypropyl methylcellulose (HPMC), which is most frequently used for these purposes. Shellac-coated tablets showed lower water uptake rates than HPMC-coated systems at the same coating level. The stability of acetylsalicylic acid was higher in tablets coated with shellac compared with HPMC-coated systems, irrespective of the storage humidity. Therefore, lower shellac coating levels were required to achieve the same degree of drug protection. Shellac coatings effectively masked the unpleasant taste of acetaminophen tablets. Compared to HPMC, again lower coating levels were required to achieve similar effects. The resulting drug release in simulated gastric fluid was not significantly altered by the thin shellac coatings, which rapidly ruptured due to the swelling of the coated tablet core. In addition, shellac was found to be a suitable matrix former for extended-release tablets. The latter could be prepared by direct compression or via wet granulation using ethanolic or ammoniated aqueous shellac binder solutions. The resulting drug-release patterns could effectively be altered by varying different formulation and processing parameters.     

Pharmaceutical applications of shellac: moisture-protective and taste-masking coatings and extended-release matrix tablets

Shellac is a natural polymer, which is used as enteric coating material in pharmaceutical applications. The major objective of the present study was to investigate the potential of shellac for other purposes, namely to provide moisture-protective and taste-masking coatings as well as extended-release matrix tablets. The efficiency of shellac to achieve moisture protection and taste masking was compared with that of hydroxypropyl methylcellulose (HPMC), which is most frequently used for these purposes. Shellac-coated tablets showed lower water uptake rates than HPMC-coated systems at the same coating level. The stability of acetylsalicylic acid was higher in tablets coated with shellac compared with HPMC-coated systems, irrespective of the storage humidity. Therefore, lower shellac coating levels were required to achieve the same degree of drug protection. Shellac coatings effectively masked the unpleasant taste of acetaminophen tablets. Compared to HPMC, again lower coating levels were required to achieve similar effects. The resulting drug release in simulated gastric fluid was not significantly altered by the thin shellac coatings, which rapidly ruptured due to the swelling of the coated tablet core. In addition, shellac was found to be a suitable matrix former for extended-release tablets. The latter could be prepared by direct compression or via wet granulation using ethanolic or ammoniated aqueous shellac binder solutions. The resulting drug-release patterns could effectively be altered by varying different formulation and processing parameters.     

Assessment of tailor-made HPMC-based matrix minitablets comprising a weakly basic drug compound

Tailor-made, pH-controlled matrix minitablets based on different HPMC types were developed comprising the weakly basic drug dipyridamole. The incorporation of pH modifiers, i.e., fumaric and succinic acid, enhanced the drug release at pH 6.8. Assessing the drug release, acid release, and the microenvironmental pH (pH_M) provided detailed understanding of pH-controlled mini-matrices.

The extent and duration of pH_M alteration was more pronounced in presence of fumaric acid. Minitablets based on the fast dissolving Methocel K100LV (≤ 100 cps) showed simultaneous release rates of dipyridamole and fumaric acid with a constant low average pH_M.     

Optical study of poly(vinyl alcohol)/hydroxypropyl methylcellulose blends

The proposal in this study was to evaluate the optical properties of different biopolymers films. The materials used were poly(vinyl alcohol) (PVA) and hydroxypropyl methylcellulose (HPMC). PVA/HPMC blends were prepared by casting technique. Variations in the group coordination in the infrared region were followed. The effects of HPMC concentrations on the optical properties of the PVA films were studied by near infrared, ultraviolet/visible, transmittance, and reflectance in the spectral region 200–2500 nm. Absorption, transmittance, and reflectance spectra were used for the determination of the optical constants. The study has been also extended to include the changes in the optical parameters including the band tail width and band gap energies and extinction coefficient for the investigated films. The results indicate that the optical band gap was derived from Tauc’s extrapolation and decreases with the HPMC contents. The obtained optical parameters were found to be strongly affected by HPMC contents.     

The influence of hydro-alcoholic media on hypromellose matrix systems

Hydrophilic matrices are widely used for extended release drug delivery, with hypromellose (HPMC) being a popular rate-controlling carrier. The FDA has recently issued an alert regarding the potential negative influence of alcohol on extended release dosage forms.

The aim of this study was to investigate the hydroalcoholic solution effect on hydration, gel formation and drug release from HPMC matrices. None of the investigated matrix formulations (felodipine, gliclazide, and metformin hydrochloride) resulted in dose-dumping when exposed to ethanol solutions.

HPMC compacts made of three different viscosity grades of Methocel showed consistent swelling and gel formation when exposed to hydroalcoholic media.     

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.     

The Release of an Ampholytic Drug from Acrylic Films

Benzyloxiamine was used as an ampholytic drug model to study the in vitro drug release from films in a function of pH. Two films based on commercial acrylic dispersions Scopacryl^R and Eudragit^R were used as drug carriers. The films investigated were produced by a solvent east technique. The pH into the films was adjusted at every experiment before cast

To understand the factors governing the release of the ampholytic drug its protonation/ionization macro and microconstants have been determined. The protonation macroconatants determined were log K₁= 7.80, log K₂ = 4.26 and log B₂= 12.06. The microconstants calculated were log K^f= 7.79, log K^a= 4.74, log K_a^f = 7.33 and log K_f^a = 4.29.

The release data could be interpreted by taking into account species concentrations calculated by use these constants on the one hand and the velocity and diffusion coefficients on the other.     

Synthesis of chemically cross-linked hydroxypropyl methyl cellulose hydrogels and their application in controlled release of 5-amino salicylic acid

The objective of this study was to achieve the colon-specific delivery of an anti-ulcerative colitis drug using hydroxypropyl methyl cellulose (HPMC) hydrogels. HPMC hydrogels containing poly ethylene glycol (PEG) as cross-links have been prepared by reacting HPMC sodium salt with polyethylene glycol dichloride.

The effect of cross-linking agent on swelling behavior of HPMC-PEG hydrogels, were investigated. Swelling parameters such as equilibrium degree of swelling, swelling ratio and network parameter such as molecular mass between cross-links (M_c) were determined. The cross-linking concentrations were 0.5%, 1%, 1.5%, and 2% (based on weight of HPMC). The equilibrium swelling ratio (Q) of cross-linked HPMC hydrogels increases from 13.2 to 27.1 as the cross-linker percentage increases from 0.5% to 2%. 5-Aminosalicylic acid (5-ASA) was used as a model of an anti-inflammatory drug. Cross-linked HPMC hydrogels were found to be a promising drug delivery system for the drugs to be delivered to the colon.     

Studies of Hie Effect of Powder Moisture Content on Drug Release from Hard Gelatin Capsules

The in vitro dissolution of model formulations from hard gelatin capsules containing drug: diluent powder mixtures at different moisture levels has been studied. The capsules were filled to a constant porosity of 50%. to contain either sodium barbitone or barbitone in 50:50 mixture with lactose or maize starch, the latter at one of three moisture levels. In addition, capsules containing drug alone were examined. The wettability and polarity indeces of the individual powders and binary mixtures, as well as the permeability and liquid penetration rates of powder beds were also determined.

The presence of either excipient was found to modify the time for 50% drug dissolution (t₅₀) compared with drug alone for all formulations examined, apart from the sodium barbitone: lactose capsules. The rate of drug dissolution was also dependent on the initial powder moisture content for the drug:starch formulations. Open storage of capsules at 20^%/75%. R.lt. generally increased t₅₀figures.

The findings are discussed in terms of the nature of the surfaces of the powder particles, moisture sorption phenomena and factors such as powder bed permeability and water penetitration lates.     

In vitro and in vivo adhesion testing of mucoadhesive drug delivery systems

Bioadhesive tablets were prepared by physical mixing of polymers and drug, then granulating and compressing into a tablet. The mucoadhesion was evaluated by shear stress measurement, detachment force measurement, and X-ray photography of the rabbit gastrointestinal tract. The strong interaction between the polymer and the mucous lining of the tissue helps increase contact time and permit localization. Polymers like hydroxypropyl methylcellulose K4M (HPMC K4M), hydroxypropyl methylcellulose 100 cps (HPMC 100 cps), carbopol-934, sodium carboxy methylcellulose (Na CMC), guar gum, and polyvinylpyrrolidone (PVP) were tested by shear stress measurement and detachment force measurement methods. HPMC K4M, showing maximum bioadhesion, was used in further studies. Adhesion was maximum between pH 5 and pH 6. Maximum adhesion was observed in the duodenum, followed by the jejunum and ileum. Barium sulfate (BaSO₄) matrix tablets containing polymer and drug were subjected to X-ray studies in rabbits, and it was found that the tablet was mucoadhesive even after 8 hr. Enteric coating did not show any effect on mucoadhesion after passing from the stomach.