Showing papers in "Drug Development and Industrial Pharmacy in 1993"

Bonding Surface area and Bonding Mechanism-Two Important Factors fir the Understanding of Powder Comparability

Abstract: Two factors could be regarded as primary factors for the compactability of powders: the dominating bond mechanism and the surface area over which these bonds are active. Owing to considerable experimental difficulties, these factors have not been evaluated in any detail for pharmaceutical materials. Instead, more indirect, secondary factors are normally studied and used for correlations with tablet strength. Such secondary factors are particle size, shape and surface texture. Also the importance of volume reduction mechanisms, i.e. elastic deformation, plastic deformation and particle fragmentation have been studied in detail.For the investigation of dominating bond mechanisms and estimation of the magnitude of the surface area of the solids involved in interparticulate attraction in compacts several pharmaceutical excipients representing both plastically deforming materials (sodium chloride, Avicel® PH 101, Sta-Rx 1500®, and sodium bicarbonate) and fragmenting materials (lactose, sucrose, paracet...

Mucoadhesive Drug Delivery Systems

Abstract: Pharmaceutical aspects of mucoadhesion have been the subject of great interest during recent years because mucoadhesion could be a solution for bioavailability problems that result from a too short length of stay of the pharmaceutical dosage form at the absorption site within the gastro-intestinal tract.This paper describes some aspects of bioadhesion such as mucus structure, stages of adhesion and the theories proposed that attempt to explain the adhesion mechanism. The factors that affect the bioadhesive power of a polymer, the methods that permit the evaluation of a bioadhesive system and the methods for surface characterization of biomaterials are discussed. Finally, the various polymers used and the bioadhesive systems designed for several therapeutic purposes are presented.

Comparative compaction properties of various Microcrystalline Cellulose types and Generic Products

Abstract: 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 performan...

Relationship Between Swelling and Drug Release in a Hydrophilic Matrix

Abstract: Hydroxypropylmethylcellulose (HPMC) is widely used for controlled-release preparations. The process of drug release is controlled by matrix swelling and polymer dissolution. This study examines the mechanism of behaviour of HPMC in a polymer-drug directly-compressed matrix. The results obtained show that the swelling of HPMC which can be described by first-order kinetics is affected by concentration and viscosity grade of the polymer. This swelling action of HPMC in turn is controlled by the rate of water uptake into the matrices. An inverse relationship exists between the drug release rate and matrix swelling rate. This implies that HPMC swelling is one of the factors affecting drug release. The swelling behaviour of HPMC is therefore useful in predicting drug release.

Evaluation of xanthan gum as a hydrophilic matrix for controlled-release dosage form preparations

Abstract: Xanthan gum was evaluated as hydrophilic matrix for controlled release preparations. Different parameters were considered: direct and wet granulation, gum concentration, effect of addition of binders, pH, ionic strength, rotation speed and surfactant. Suitable controlled release profile could be obtained. Practically no influence of the parameters studied was noted, with the exception of gum concentration, the rotation speed and presence of ion in the dissolution medium. The release rate profiles were evaluated by different kinetic equations: Zero order, First order, Higuchi equation and RRSBW equation and the data statistically analyzed with F-Ratio. Without binder, in aqueous medium, zero order kinetics were found from the origin of the release rate profile. With binder and dissolution media with electrolytes or buffer solutions, generally zero order kinetics were also found after an initial period of about half an hour. The release kinetics were independent of the method of preparation and comp...

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

Abstract: 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, Tg, 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.

Influence of Aging on the Physical-Mechanical Properties of Acrylic Resin Films Cast from Aqueous Dispersions and Organic Solutions

Abstract: The physical-mechanical properties of the enteric copolymers, poly(methacrylic acid, ethyl acrylate) Eudragit® L100-55, and Eudragit® L30D have been investigated. Free films of the copolymer containing varying levels of glyceryl triacetate (triacetin) and citrate ester (Citroflex®) plasticizers were prepared by both aqueous and solvent casting techniques. Conditioned films were stored at different humidities and temperatures for predetermined time periods prior to testing. Free films with plasticizer concentration ranging from 0 to 30% by weight of the polymer demonstrated that physical aging at room temperature resulted in physical-mechanical changes as the stress-strain curves indicated a decrease in the percent elongation with increases in the tensile strength. Films prepared from the aqueous latex approached a constant state of equilibrium at a faster rate than films prepared from isopropyl alcohol, where the mechanical properties approach a relatively constant value. Free films containing var...

Evaluation of Xanthan Gum in the Preparation of Sustained Release Matrix Tablets

Abstract: The objective of this study was to evaluate xanthan gum as a matrix former for the preparation of sustained release tablets. Preliminary experiments indicated that a fine particle sue of xanthan gum produced the slowest and most reproducible release profiles. Based on single surface experiments and tablet erosion studies, it was concluded that release of a soluble drug (chlorpheniramine maleate) and an insoluble drug (theophylline) from tablets containing low concentraions of xanthan gum was mainly via diffusion and erosion, respectively. Drug release from tablets containing xanthan gum was slightly faster in acidic media due to more rapid initial surface erosion than at higher pH. After hydration of the gum, drug release was essentially pH-independent. The amount released was directly proportional to the loading dose of drug and inversely proportional to gum concentration in tablets. Release profiles of chlorpheniramine maleate and theophylline remained unchanged after three months storage of the...

Effect of Penetration Enhancers on the in Vitro Transport of Ephedrine Through Rat Skin and Human Epidermis from Matrix Based Transdermal Formulations

Abstract: The potential of skin as a site for administration of systemically active Ephedrine HCl (EH) has been recognised. The effect of penetration enhancers, i.e., Dimethyl sulfoxide (DMSO), Dimethyl acetamide (DMA), Dimethyl formamide (DMF) and Azone on the in-vitro transport of EH from matrix based transdermal formulations through full thickness rat skin and human epidermis was investigated. The highest flux with minimum time lag through rat skin and human epidermis was observed from the batch containing Azone as penetration enhancer.

Study of the Influence of Spheronization and Drying Conditions on the Physico-Mechanical Properties of Neutral Spheroids Containing Avicel PH 101 and Lactose

Abstract: Beginning with binary Avicel-lactose (20/80) mixtures, the present study focuses on the influence of the spheronization speed and the drying process on the porousness, surface condition and the pressure resistance of neutral spheroids prepared by extrusion/ spheronization. Any increase in the spheronization speed provokes a decrease in the porousness and the average diameter of the pores, and gives a greater hardness and a smoother surface condition. In the final production phase, oven drying gives less porous and harder minigranules and a more homogenous surface than those dried by microwaves. In the experiment conditions, a negative correlation between porousness and hardness was established.

Formulation and Evaluation of Methotrexate Niosomes

Abstract: Methotrexate was encapsulated in niosomes prepared using Tweens and Spans. The size distribution, entrapment efficiency, pharmacokinetics and effect on tumour remission of mice transplanted with S-180 Sarcoma were evaluated. Niosomes prepared with Span 60 gave promising results.

Direct Compression Controlled Release Tablets Using Ethylcellulose Matrices

Abstract: Controlled release erodible matrix tablets were manufactured by a simple, direct compression process using ethylcellulose alone as the matrix former. Each of four different viscosity grades of ethylcellulose (10, 20, 45 and 100 cp) was dry mixed with either indomethacin or theophylline and a small amount of lubricant, then directly compressed into tablets. In initial trials, compression force was held constant, resulting in tablets of varying hardness. In a second study, the compression force was varied to produce tablets of equal hardness. Lower viscosity grades of ethylcellulose were more compressible than higher viscosity grades, allowing production of harder tablets for a given drug. Harder tablets resulted in controlled release of the drug over a longer time period. Dissolution studies indicated that tablet hardness is more important in determining dissolution rate than is the polymer viscosity grade. A mathematical model combining diffusion and erosion mechanisms was developed to describe dr...

Floating and swelling characteristics of various excipients used in controlled release technology

Abstract: During the past few years, great interest was developed in the subject of floating. In the present study, the floating and swelling characteristics of several excipients used controlled release technology were examined. The floating behavior was evaluated with resultant weight measurements, while a gravimetric method was employed for studying their swelling. The experiments were carried out in two different media, i.e. deionized water and simulated meal in order to monitor possible differences. The results indicated that higher molecular weight polymers and slower rates of polymer hydration are usually followed by enhanced floating behavior. The floating characteristics of all evaluated excipients were improved when simulated meal medium was used. Finally, the combination of resultant weight measurements and swelling experiments can be used to determine in vitro the buoyancy, weight and volume changes of orally administered dosage forms and to predict floating behavior.

Avicel RC-591/Chitosan Beads by Extrusion-Spheronization Technology

Abstract: Beads were successfully prepared using the combination of Avicel RC-591 and chitosan using extrusion and spheronization technology. The effects of different viscosity grades of chitosan (SEACURE 142, 242, 342 and 442) on bead formation and on release profiles were examined using acetaminophen as a model drug. Incorporation of higher viscosity grades of chitosan yielded beads with rough surfaces and slower release characteristics. Seacure 342 was chosen for further studies using acetaminophen and theophylline as model drugs of different solubilities. Beads were prepared with varying proportions of Seacure 342 and Avicel RC-591 (20% drug loading). Drug release from the beads varied with the dissolution method used. Beads were swollen in 0.1 N HC1 while the bead structure remained intact. In water, the beads exhibited gel-like structures.

Pharmaceutical Quality of Glibenclamide Products A Multinational Postmarket Comparative Study

Abstract: A multinational postmarket comparative study of pharmaceutical quality of glibenclamide products was performed in cooperation with large number of laboratories and under anspices of the Section of Official Laboratories and Medicines Control Services of FIP and World Health Organization. 28 countries from Europe, Africa, North and South America, Asia and Australia participated in this study. Altogether 142 glibenclamide tablet formulations of the respective countries were investigated. The products were tested for identity, purity, content, uniformity of content and in-vitro dissolution properties. Most products tested fulfilled the pharmacoepial requirements concerning identity, purity and content (95–115%). Marked differences were recorded in respect of in-vitro dissolution behaviour. This applies not only to the products of different countries but also among products of the same country. It is anticipated that products, which are markedly differentiated in their in-vitro dissolution properties, ...

Phase Transformations in Sulfathiazole During Mechanical Activation

Abstract: The effect of mechanical treatment in a planetary ball mill on the transformations of polymorphs of sulfathiazole were studied by means of X-ray diffraction analysis, infrared spectroscopy and differential scanning calorimetry. It has been shown that mechanical treatment initiates transitions of sulfathiazole polymorphs III ⇄ I. In an initial period of mechanical treatment a part of the sulfathiazole was converted into a noncrystalline solid. Preliminary mechanical treatment of form III resulted in the reduction of III—I phase transition temperature by 20–30°C in the samples without form I and by 40–50°C in the samples where the part of the substance were transformed into form I during mechanical treatment.Single crystal thermomicroscopy studies showed that III → I phase transition proceeds via nucleation and a rapid advance of an interface through the crystal.It seems that deformation of crystals during mechanical treatment and formation of noncrystallirie solid with high extent of disordering ma...

Formulation and Evaluation of Oral and Transdermal Preparations of Flurbiprofen and Piroxicam Incorporated with Different Carriers

Abstract: Flurbiprofen and piroxicam were incorporated in carriers like niosomes, albumin microspheres and beta-cyclodextrin. The bioavailability and anti-inflammatory activity of drugs after oral and transdermal administration in rats were studied.

Liposomes for drug delivery to the respiratory tract

Abstract: This paper provides a review of the current literature pertaining to the pulmonary delivery of liposomes.The technological aspects of delivering liposomes to the lung are discussed, including the characterization of liposome-containing aerosols and the potential advantages and disadvantages of the various methods which have been employed for their generation.Studies have indicated that liposomes can be effectively deposited in the human respiratory tract, wherein they may remain for prolonged periods. A prolonged retention in the airways may markedly alter the pharmacokinetics of liposome associated materials; increasing local concentrations, whilst decreasing levels at sites distant from the lung. The future potential for such systems is discussed, including the possibilities for selective drug delivery to specific cell populations within the lung.

Prolonged release Matrix Pellets Prepared by Melt Pelletization I. Process Variables

Abstract: A melt pelletization process was investigated in an 8 litre laboratory scale high shear mixer using a formulation with paracetamol, glyceryl monostearate 40–50, and microcrystalline wax. The effects of jacket temperature, product temperature during massing, product load, massing time and impeller speed were investigated by means of factorially designed experiments. The maximum yield of pellets in the range of 500–1400μm was found to approx. 90%. For process conditions preventing deposition of moist mass, the process was found to be reproducible. Impeller speed and massing time were found to be important process variables. Remarkably low in vitro drug release rates were observed in USP-dissolution tests.

Chemically-Modified Celldlosic Polymers

Abstract: Chemically-modified celluloses are among the most commonly and widely used polymers in the food, cosmetic, and pharmaceutical industries today. Several products with widely different physicochemical properties are currently commercially available. Some of the major applications of these include their use as. i) tableting aids (binders, fillers, disintegrants); ii) viscosity imparting agents in the preparation of semi-solid, solution, and suspension formulations (eg, creams, gels, lotions, suspensions, shampoos, hair conditioners, food products, etc.); iii) taste and odor masking agents; iv) coating materials for tablets and other dosage forms; v) carriers for cosmetic and topical formulations; and vi) carriers including controlled- and/or sustained-release carriers for veterinary, agricultural, and pharmaceutical preparations. In this article, a general overview of various chemically-modified cellulosic products used in pharmaceutics, is presented.

Evaluation of Drug Layering and Coating: Effect of Process Mode and Binder Level

Abstract: Top-spray layering and Wurster coating are common techniques for layering and coating operations, respectively. In the present study, the efficiency of these techniques was compared with rotolayering and rotocoating in the Niro-Aeromatic MP-1 Rotoprocessor. Also, three different polymers were evaluated as binding agents in the layering procedure. A solution containing drug and a suitable binder was layered onto nonpareil seeds followed by coating with a water-insoluble polymer. The pellets were evaluated for physical properties, surface characteristics and drug content (assay). The process efficiency was evaluated from process time, assay, and SEM data of the pellets. Efficiency of layering was compared between toplayering and rotolayering processes while efficiency of coating was compared between Wurster coating and rotocoating processes. The physical properties of pellets were used to explain the influence of binder nature and level of use in the layering process.

Spray-Drying of liposomes for a Pulmonary Administration. I. Chemical Stability of Phospholipids

Abstract: Multilamellar vesicles constituted of soybean phosphatidyl-choline (SPC) and extruded through a 0.2 μm polycarbonate membrane were spray-dried in the presence of 10 % lactose. The particle mean diameter of the spray-dried product was about 7 μm when the liposomes were dispersed with a rotary atomizer. The dry residue can be resuspended in water to reconstitute liposomes without major change to the vesicle size distribution. Moreover, the chemical stability of the phospholipids was not significantly affected by this process, both in terms of hydrolysis and oxidation. It was concluded that spray-drying is a potentially interesting means to produce stable dried liposomes that could be administered to the lung by inhalation.

Effects of Environmental Temperature and Compression Energy on Polymorphic Transformation During Tabletting

Abstract: The effects of temperature on the polymorphic transformation and the compression of chlorpropamlde forms A and C during tabletting were investigated by X-ray diffractometry. The X-ray diffraction profiles of the sample powders deagglomerated after compression were recorded to calculate the degree of polymorphic transformation. A single punch eccentric tabletting machine equipped with two load cells (upper and lower punches) and with a noncontact displacement transducer was used to measure the compression stress, energy and distance between punches. A heater and a liquid nitrogen pool were mounted on the die of the tabletting machine, and the die temperature was controlled with a thermocontroller. Two types of compression methods, multi-tabletting at room temperature and single tabletting at 0–45°C, were used in the present study. In the first method, the stable form A or metastable form C was loaded in to the die and the sample was compressed with a compression stress of 196 MPa. Compression was r...

A Factorial Approach to High Dose Product Development by an Extrusion/Spheronization Process

Abstract: Extrusion/spheronization technology has been used for preparing high drug-loaded pellets. Typical formulations include 40-60% microcrystalline cellulose (MCC) to impart the plastic characteristics required for this process. Studies have suggested that pellets containing greater than 80% drug are difficult to process and require special grades of MCC. Most of these studies focused on either the process or formulation aspects of the product and failed to explore the interactions of process and product. Statistical experimental designs are well suited for exploring both process and product variables and their interactions with each other. This study addresses pelletization of a high dose drug with low density. A Nica® radial (basket-type) extruder was used in extrudate preparation, followed by spheronization on a serrated plate spheronizer. A Plackett-Burman screening design was employed to investigate product and process parameters affecting final pellet drug content, density and roundness. MCC type...

Development and in-vitro evaluation of a multiparticulate sustained release theophylline formulation

Abstract: A multiparticulate sustained release formulation of theophylline was developed and evaluated in-vitro. The formulation comprised spherical pellets of high drug loading, coated with a rate controlling membrane. The pellets were prepared using an extrusion spheronisation method, whilst coating was performed with an aqueous dispersion of ethylcellulose using a fluidized bed coating technique. When ethylcellulose was used alone as the coating polymer, the drug release profile was unsatisfactory, but could be improved by incorporating a coating additive. Several additives were evaluated and methylcellulose of high Viscosity grade was found most satisfactory. The in-vitro theophylline release was relatively linear and pH independent, and could be varied in a predictable manner by manipulating the coat thickness. In addition, when the coated pellets were subjected to additional thermal treatment, the drug release was stable after storage for one year.

A screening study of lubricants in wet powder masses suitable for extrusion-spheronization

Abstract: Fourteen different substances were evaluated for their usefulness in reducing surface defects, heat due to friction and energy consumption in an instrumented extruder. The materials include several common lubricants and glidants, surface active agents, humectants, polyethylene glycol and a binder in a simple binary system with high drug loading. The substances under study were evaluated at two concentrations in a matrix composed of acetaminophen, Avicel PH-101 (70:30) and water. Maximum screen temperature, peak amperage draw, surface morphology of the extrudate, resistance to applied force, resistance to abrasion, surface morphology of the spheres, sphericity and size analysis were determined for each substance/concentration combination. High HLB surfactants, particularly SLS, performed best at levels as low as 0.125%, keeping heat and amperage draw to a minimum and greatly reducing surface defects.

The Effects of Formulation Variables on Iontophoretic Transdermal Delivery of Leuprolide to Humans

Abstract: Feasibility of applying iontophoresis to facilitate the transdermal permeation of leuprolide acetate was investigated. Because of the complexity of the factors involved in the process of iontophoresis, theoretical predictions of the combination effects from formulation variables are difficult. This study incorporated the formulation variables, drug levels and buffer concentrations, in a device prepared by Drug Delivery System, Inc., to assess the feasibility for leuprolide delivery.Steady state serum leuprolide concentrations were achieved within 30 minutes of patch application, and were maintained for the duration of the study period. An increase in LH levels was observed for each formulation. The serum leuprolide concentrations were higher with lower drug concentration and more dilute buffer solutions. Increasing drug concentration in the patch appeared to inhibit delivery of leuprolide. A mean steady state serum concentration, 0.8 ng/ml, was achieved by a formulation composed of 10 mg/ml leupro...

Effect of Hydrotropic Substances on the Complexation of Clotrimazole with β-Cyclodextrin

Abstract: The phase diagrams of clotrimazole/β-cyclodextrin (β-CD) in phosphate buffer, pH = 7.1, containing 0.5 M of various hydrotropic agents were constructed. The water structure disruptors, urea and nicotinamide, increased the intrinsic solubility of the antimycotic drug clotrimazole while the water structure forming agents, sorbitol and fructose, decreased the solubility. Concerning the complex constant between clotrimazole and β-CD, it was the other way around. The connection between the slopes of the phase diagrams, the intrinsic solubility of clotrimazole and the complex constant was discussed. Nicothamide decreased the solubility of β-CD in the buffer solution. The results reported in this study are in disagreement with the claim that addition of water structure forming agents to cyclodextrin solutions can be used to increase the total solubility of drugs

Comparison of Diffusion Studies of Hydrocortisone Between the Franz Cell and the Enhancer Cell

Abstract: The Franz diffusion cell remains a popular method to study diffusion of transdermal drug delivery systems through membranes. Recently, VanKel Industries, Inc., (Edison, NJ) developed the “Enhancer Cell,” a new device for in vitro transdermal drug diffusion testing. The purpose of this study was to evaluate the enhancer cell for in vitro transdermal diffusion of hydrocortisone from an ointment using a synthetic membrane and a biological membrane and compare it to the traditionally employed Franz cell. The Enhancer cell utilizes existing USP dissolution equipment (USP Apparatus II). Results show a higher cumulative release from the Enhancer cell as compared to the Franz cell. The Enhancer cell demonstrated more durability and was easier to use during experimentation and after completion of the experiment no apparent change was observed in the condition of the ointment or the skin when compared to the Franz cell.