Statistical Optimization of a Controlled Release Formulation Obtained by a Double Compression Process: Application of an Hadamard Matrix and a Factorial Design

Abstract

A formulation containing an antiinflammatory agent (diclofenac sodium), two inert matrices (ethylcellulose and polyvinyl chloride) and two lubricants (magnesium stearate and talc) was optimized by a double compression process

In a first stage, preliminary trials were performed in order to study the effect of lubricants added before and after precompression

An Hadamard matrix H(8) was applied to estimate the main effects of four parameters: applied force at the upper punch (UPF) during precompression, particle size range after grinding, UPF during the final compression and concentration of ethylcellulose added before the final compression

Following the Hadamard matrix, a factorial design 2² was built. The complete linear models were fitted by regression for each response reflecting the compression behaviour and dissolution kinetics

In an optimal point, the validation was carried out with the area under the dissolution curve, being the major response to be optimized

The dissolution curves were well fitted by the Weibull distribution     

Multivariate Analysis of Variance of Dissolution Data in the Development of Oral Sustained Release Formulations

A multivariate analysis of variance applied to polinomial interpretation of growth curves in used for the interpretation of dissolution curves of four experimental, sustained release, wax type theophylline tablets.

The factors under study were glyceril palmitic stearate, carboxypol imethylene contents and compression force. The tablets were formulated according an experimental design based on 4 × 4 Hadamard matrix. The USP type I apparatus for dissolution test and CHI 0.1 N plus O.1%. polysorbate 80 as dissolution medium was used.

The statistical interpretation of results showed: first, that dissolution rates were almost constant for the four formulations during 8 h; second, the main difference between formulation dissolution rates can be inputed to fat excipient content and in much lesser extent to carboxipolymethylene content; third, the theopylline release rate was unaffected by compression force.     

The changes in the Mechanic Properties of a direct tableting agent Microcrystalline Cellulose by Precompression

In the manufacturing of tablets, direct tableting agents are not only used in direct compression, but are also used in wet granulation and slugging methods. These agents are effective only if their particle size and form is appropriate. However, the precompression, milling and grinding which are applied in the slugging method changes the particular properties of these agents.

In this study, microcrystalline cellulose tablets were prepared both by direct compression and slugging. The consolidation, compressibility and flow properties of the two mixed powders were compared. Finally, it was observed that the compressibility of the mixed powder was influenced negatively by the slugging method.     

Influence of extrusion-spheronization processing on the physical properties of d-Indobufen pellets containing pH adjusters

d-Indobufen pellets containing pH adjusters (acids, buffer, salt) were prepared by extrusion-spheronization technology.

The interaction effect between some processing variables (feeding/agitator speeds of extruder, plate speed and residence time of spheronizer) was evaluated by comparing the basic formulation pellets with the pellets in which the soluble filler (lactose) was substituted by fumaric, tartaric and citric acids and also sodium citrate.

The criteria of formulation and process evaluation were the reproducibility of the particle size distribution, the density, the hardness and morphological properties, in addition to the reproducibility of the drug dissolution rates.

In all cases, the physical/technological characteristics were not influenced very much by pH adjuster incorporation, but the drug dissolution profiles showed some significant variations in the first hour. As a logical extension of this work, wet granulations with aqueous ethylcellulose and acrylic resin dispersions instead of only water were tested to evaluate the wetting effect of the release modifier inclusion. The results confirmed the validity of polymeric systems in the preparation of pellets and their ability to produce a further delay of d-Indobufen release.     

Preparation and Biological Evaluation of Ethylcellulose Microspheres Containing Tolmetin

Tolmetin microspheres were prepared by the coacervation process from the ethylcellulose. Microspheres were obtained both in presence and without protecting colloids, such as polyisobutilene (PIB) or ethyl-vinylacetate copolimers (EVA). The effect of these agents on the preparation, drug content, wall thickness, surface morphology, drug dissolution arid release from microspheres, were evaluated. The dissolution rate analysis was carried out also in the presence of a surfactant (Tween 80) at different pH values.

In addition, microspheres containing Tolmetin as a core material were submitted to biological tests, in comparison with the free drug, to evaluate upon experimental models the antipyretic activity and the gastric tolerability.     

The Effect of Recompression on the Dissolution of Wet Massed Tablets Containing 'Super' Disintegrants

The effect of recompression on the disintegration, and dissolution of tablets employing 'super' disintegrants within a wet-massed Avicel matrix is reported. Differences were found in the disintegration times of tablets containing intra-granular or extra-granular disintegrants (Polyplasdone XL, Explotab and Ac-di-sol), both between disintegrant type and within the same disintegrant system following rework.

In the case oE extra-granular disintegrant, reworked compacts dissolved faster than the first compression tablets, irrespective of disintegrant type. Thus, milling and dispersion of the drug during rework appear to dominate over the effects of impaired disintegration when 'super' disintegrants are present. The control compacts (no disintegrant), however, dissolved less quickly following rework, indicating that dissolution was controlled by disintegration.

Tablets with intra-granular Polyplasdone XL and Ac-di-sol dissolved less quickly following rework. Both disintegrants have poor intra-granular rework efficiencies. However, for Explotab, which has better rework intra-granular efficiency, reworked tablets dissolved faster than first compression compacts.     

In Vitro and in vivo Availability of Spironolactone from Various Oral Preparations

The dissolution rates in vitro and the bioavailability in humans were determined for 6 preparations containing 25 mg spironolactone and 5 preparations containing 100 mg spironolactone. Linear relationships were obtained by pairwise correlation of in vitro parameters with in vivo parameters. The following parameters were used.

In vitro parameters of dissolution:

1. The area under the dissolution-time-curve up to 1 h

2. The fraction of active ingredient dissolved within 20 min.

3. The slope of the dissolution-time-curve at 50 % dissolution

4. The dissolution rate constant

5. The time up to 50 % dissolution of the substance

6. The maximum slope of the dissolution-time-curve

In vivo parameters of bioavailability:

1. The time of maximum plasmaconcentration

2. The area under the plasmaconcentration-time-curve up to 1 h and 2 h after application

3. The quantities of active ingredient excreted in the urine up to 2 h after application

The highest correlation coefficient was found between the areas beneath the dissolution-time-curve and the plasmaconcentration-time-curve up to 1 h each.

No significant correlations were found between the within 1 h dissolved substance and maximum plasma-concentration, the area under the plasmaconcentration-time-curve up to 4 h and 24 h and quantities of active ingredient excreted in the urine up to 4 h after application.     

Factors Affecting Rate of Dissolution of Prednisone from Tablets

A study was carried out to evaluate some parameters which may have an effect on the dissolution rate of prednisone from tablets. The parameters examined involving formulation were: diluent proportion (Lactose-starch), dissintegrant type (starch, explotab (sodium starch glycolate) type of binder (starch paste, gelatine water solution and PVP alcoholic solution), lubricant, and dye concentration. The Manufacturing variables studied were: method of manufacture (wet granulation, direct compression and double compression), granule size in wet granulation and tablet hardness. dissolution profiles of tablets storaged 2 months at 45°C were compared with those of fresh samples. Tablets prepared with prednisone five years old, tablets with fresh active ingredient and tablets with two different prednisone concentrations (5 and 50 mg per tablet) were used for other evaluations.

In all cases micronized prednisone was used and all batches were physically and chemically evaluated before studying their dissolution following the USP basket method.

The parameters studied that affected significatively dissolution rate of prednisone were: type of binder, lubricant concentration, method of manufacture, active ingredient, age and prednisone concentration.     

Release of a Low Dose Water Soluble Medicinal Agent from Inert Wax Matrix Tablets

Directly compressible wax matrix tablets have been developed for a low dose medicinal agent (Chloropheniramine maleate). A mixture of castor wax NF and Hydrogenated Vegetable Oil NF, was optimized in the ratio of 50:50 as matrix based on their bulk density and particle size distribution and compression properties The compression properties indicated that the increase in compression forces resulted in a tablet of higher hardness up to 8 Kp. However further increase in compression forces resulted in the decrease in hardness and capping was apparent.

The result of dissolution studies indicated no significant effect of hardness and tablet shape (Round and rectangular shaped) on the dissolution properties of wax matrix tablets. A plot of percent drug released various square root of time exhibited a linear relationship. The release rates of CPM from wax matrix tablets were found to be independent of the rotational speed of paddles between 50-75 RPM. From these results, the release mechanism of CPM from wax matrix tablets appears to be primarily diffusion controlled rather than matrix erosion.     

Hydroxypropylmethylcellulose sustained release technology

The use of polymers in controlling the release of drugs has become important in the formulation of pharmaceuticals. Watersoluble polymers such as polyethylene glycol and polyvinylpyrrolidone may be used to increase the dissolution rates of poorly soluble drugs (Ford)¹ and slowly soluble, biodegradable polymers such as polylactic acid may be used for controlled release implants (Rak et a1.²), Hydrogels provide the basis for implantation, transdermal and oral-controlled release systems. Hydroxypropylmethylcellulose (HPMC) are cellulose ethers which may be used as the basic for hydrophilic matrices for controlled release oral delivery.

In tablet matrix systems the tablet is in the form of compressed compact containing an active ingredient, lubricant, excipient, filler or binder. The matrix may be tabletted from wet-massed granules or by direct compression.

This review article examines a previously published series of work and concentrates on the following aspects of the subject; the relationship between release rate and quantity of polymers, such consideration allow a certain predicability in release rates to be made. Also the effect of drug particle size, tablet shape and the presence of additional diluents in the formula are examined.     

Development of a New Tablet Formulation of Theophylline: In Vitro and in Vivo Studies

The preparation of a new scored 250 mg theophylline tablet is described, for which effects of particle size of the active principle, aspects of granulation and changes in tabletting settings were investigated.

In vitro studies showed the dissolution rate from tablets prepared from theophylline of commercial quality (50 μm) or of selected particle size (30 μm) to be faster than that from tablets prepared from micronized theophylline (10 μm). In vivo studies in dog showed that only the tablet from theophylline of selected particle size has the same bioavailability as an aqueous solution.

The scale up study showed that the characteristics of the tablets, including dissolution rate, are independent of the formulation factors.     

Dissolution Study of Prolonged Release Morphine Tablets Using Hydrophilic Matrices

This study presents the results of “in vitro” dissolution of prolonged release morphine tablets using hydroxypropylmethylcellulose. Tablets with four different doses were elaborated and the liberation from these formulated tablets was compared with that of the only commercial pharmaceutical preparation of this type registered in the Spanish Pharmaceutical Market.

The results of the dissolution tests show that the drug was gradually released in all cases and tablets had released from 60 to 90% of its contents after 8 hours.

In the comparative study, the commercial tablets showed the fastest release. In both cases the release rate was lower when artificial intestinal fluids were used as the dissolution medium.     

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     

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.     

Drug Dissolution Testing: Today and Tomorrow

This article discusses the present role of dissolution tests both in terms of current compendial requirements and the use of such tests by the pharmaceutical industry.

Insofar as future use is concerned, the suggestion is made that the compendia clearly distinguish between those monographs where dissolution tests have been shown to be of biological significance (i.e., Digoxin Tablets) and those which are simply acting as physical quality control procedures. Logically, a dissolution test should be applied to all solid dosage forms, although from a logistical point of view it might be appropriate to confine this requirement, at least initially, to those drugs having an aqueous solubility of 0.5 per cent or less.

In the future, the pharmaceutical industry should expand its use of dissolution testing both in formulation development and production control, with a view to establishing, in as many instances as possible, dissolution tests having biological significance, i.e., where reliable in vitro - in vivo correlations have been established.     

Selection of Optimum Dissolution Test Methods in Dosage Form Design

The rate limiting factors involved in release of a drug from a tablet are generally accepted to be the disintegration of the tablet followed by the subsequent dissolution of the drug from the dispersed granules.

The development of new potencies of an existing tabletted product by weight multiplication was found to result in non-conformance to established specifications for the product not formulation related.

In addition to a study of the rate limiting factors mentioned above compendial dissolution tests were also compared. Apparatus II was shown to produce more rapid and consistent results than Apparatus I in this investigation and this test is recommended as the one of choice where large volume compacts are involved.     

Granulation in a Fluidized Bed II Effect of Binder Amount on the Final Granules

There are many parameters affecting the properties of the final granules prepared in a fluidized bed. In this study one of the product parameters, quantity of the binder, has been studied for its effect on the final granule size, size distribution and friability

Determination of granule size change as a function of binder quantity leaded us to study the growth mechanisms during fluidized bed granulation. Two mechanisms are suggested;

1) Snowballing of primary granules (nuclei)

2) Agglomeration of primary granules

It has been shown that there is a critical amount of binder at which the formation of the primary granules comes to an end if more binder is added to the system. Then granule growth occurs by agglomeration of the primary granules. The physical properties of the granules formed before and after this critical binder concentration varies significantly     

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.     

The Effect of Indomethacim Microcapsules on Intestinal Ulceration in the Rat

The absorption of indomethacin in the rat was studied following a single oral dose of indomethacin in the form of the powdered drug or microcapsules.

Serum levels of unmetabolized drug were measured and gastrointestinal ulceration was assessed 72 hours after dosing by measuring the tensile strength of the intestine after its removal from the animal and by counting the number of ulcers present on the intestinal wall.

In vitro dissolution of the powdered drug and microcapsules was carried out in water, in Polyethylene Glycol solution and in 40mM sodium cholate solution for a comparison with the in vivo results.

Both in vitro and in vivo results for the microcapsules were similar to those of the powdered drug and therefore encapsulation of indomethacin offered no advantage over conventional dosage forms.     

Development of Diclofenac Sodium Controlled Release Solid Dispersions by Spray Drying Using Optimization Strategy I. Powder Formulation

Diclofenac sodium (DS) controlled release solid dispersions were prepared by spray drying using ethylcellulose (EC), methacrylic acid copolymer (Eudragit), chitosan, hydroxypropyl methylcellulose (HPMC), and carbomer as single carriers and EC-chitosan as combined carriers. Among solid dispersions of 3:1 drugsingle carrier, the system containing chitosan exhibited the slowest dissolution followed by the systems containing Eudragit, EC, HPMC, and carbomer, respectively. Combined carriers of EC-chitosan exhibited more dissolution retarding effect than single carrier of EC or chitosan. An Hadamard matrix H[8] was employed to estimate the main effects of four parameters: spray feeding volume and contents of absolute ethanol, EC, and chitosan. Optimization strategy using multiple linear regression and a feasibility computer program was utilized to obtain the optimum quantities of the four parameters that would result in a required DS controlled release solid dispersion. The validation of the optimum DS solid dispersion was confirmed by statistical analysis. The optimized 10: (2.5+0.02) DS:(EC+chitosan) controlled release solid dispersion exhibited a dissolution profile that was well fitted to Higuchi model.