Formulation and In-Vitro Evaluation of Ternary Solid Dispersion of Aceclofenac by 32 Factorial Design

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INTRODUCTION

1.1 HISTORICAL BACKGROUND OF SOLID DISPERSION TECHNOLOGY [1]

The effect of the particle size of the drugs on their dissolution rates and biological availability was reviewed comprehensively by Fincher. For drugs whose gastrointestinal absorption is rate limited by dissolution, reduction of the particle size generally increases the rate of absorption and or total bioavailability. This commonly occurs for drugs with poor water-solubility. For example, the therapeutic dose of griseofulvin was reduced to 50% by micronization and it also produced a more constant and reliable blood level. The commercial dose of spironolactone was also decreased to half by just a slight reduction of particle size. Such enhancement of drug absorption could further be increased several fold if a micronized product was used.  In 1961, a unique approach of solid dispersion to reduce the particle size and increase rates of dissolution and absorption was first demonstrated by Sekiguchi and Obi. They proposed the formation of a eutectic mixture of a poorly soluble drug such as sulfathiazole with a physiologically inert, easily soluble carrier such as urea.

 

The eutectic mixture was prepared by melting the physical mixture of the drug and the carrier, followed by a rapid solidification process. Upon exposure to aqueous fluids, the active drug was expected to be released into the fluids as fine, dispersed particles because of the fine dispersion of the drug in the solid eutectic mixture and the rapid dissolution of the soluble matrix. Chiou and Riegelman recently advocated the application of glass solution to increase dissolution rates. They used PEG 6000 as a dispersion carrier. It is believed that this relatively new field of pharmaceutical technique and principles will play an important role in increasing dissolution, absorption and therapeutic efficacy of drugs in future dosage forms.

Therefore, a thorough understanding of its fast release principles, methods of preparation, selection of suitable carriers, determination of physical properties, limitations and disadvantages will be essential in the practical and effective application of this approach.

In addition to absorption enhancement, the solid dispersion technique may have numerous pharmaceutical applications which remain to be further explored. It is possible that such a technique can be used to obtain a homogeneous distribution of a small amount of drug at solid state, to stabilize unstable drugs, to dispense liquid or gaseous compounds, to formulate a fast release priming dose in a sustained release dosage form, and to formulate sustained release regimens of soluble drugs by using poorly soluble or insoluble carriers.

1.2 INTRODUCTION TO SOLID DISPERSION TECHNOLOGY [2]: The enhancement of oral bioavailability of poorly water soluble drugs remains one of the most challenging aspects of drug development. Although salt formation, solubilization and particle size reduction have commonly been used to increase dissolution rate and thereby oral absorption and bioavailability of such drugs, there are practical limitations of these techniques. The salt formation is not feasible for neutral compounds and the synthesis of appropriate salt forms of drugs that are weakly acidic or weakly basic may often not be practical. Even when salts can be prepared, an increased dissolution rate in the GIT may not be achieved in many cases because of the reconversion of salts into aggregates of their respective acid or base forms. The solubilization of drugs in organic solvents or in aqueous media by the use of surfactants and cosolvents leads to liquid formulations that are usually undesirable from the viewpoints of patient acceptability and commercialization. Although particle size reduction is commonly used to increase dissolution rate, there is a practical limit to how much size reduction can be achieved by such commonly used methods as controlled crystallization, grinding, etc. The use of very fine powders in a dosage form may also be problematic because of handling difficulties and poor wettability.

In 1961, Sekiguchi and Obi developed a practical method whereby many of the limitations with the bioavailability enhancement of poorly water-soluble drugs can be overcome, which was termed as “Solid Dispersion”.

 

POORLY WATER

SOLUBLE DRUG

 

 

Solid

Dispersion /solution

 

 

Dosage form

 

 

Tablet / capsule

 

 

 

 

 

 

 

 

 

 

Disintegration

 

Large solid particle

(usually 5-100 microns)

 

 

Drug in GI tract

 

 

Colloidal particles/ fine oily globules

(Usually <1 microns)

 

 

Disintegration

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ABSORPTION INTO BODY SYSTEM

 

 

 

Lower dissolution rate Higher dissolution rate

 

1.2.1 Figure: A schematic representation of the bioavailability enhancement of a poorly water-soluble drug by solid dispersion compared with conventional tablet or capsule.

 

The advantage of solid dispersion compared with conventional capsule or tablet formulations is shown schematically in the above figure. From conventional capsules and tablets, the dissolution rate is limited by the size of the primary particles formed after the disintegration of dosage forms.

 In this case, an average particle size of 5µm is usually the lower limit, although higher particle sizes are preferred for ease of handling, formulation and manufacturing. On the other hand, if a solid dispersion or a solid solution is used, a portion of the drug dissolves immediately to saturate the gastrointestinal fluid, and the excess drug precipitates out as fine colloidal particle or oily globules of submicron size. Because of such easily promises in the bioavailability enhancement of poorly water-soluble drugs, solid dispersion has become one of the most active areas of research in the pharmaceutical field. [4]

 

 

1.3 DEFINITION AND TYPES OF SOLID DISPERSIONS:

Definition: Solid dispersion technology is the science of dispersing one or more active ingredients in an inert matrix in the solid stage in order to achieve increased dissolution rate, sustained release of drugs, altered solid state properties, and enhanced release of drugs from ointment and suppository bases, and improved solubility and stability.

TYPES OF SOLID DISPERSIONS:

a) Simple eutectic mixture: A eutectic mixture of a sparingly water soluble drug and a highly water soluble carrier may be regarded thermodynamically as an intimately blended physical mixture of its two crystalline component. The increase in surface area is mainly responsible for increased rate of dissolution. This led to a conclusion that the increase in dissolution was mainly due to decreased particle size.

b)  Solid solutions: Solid solutions consist of a solid solute dissolved in a solid solvent. A mixed crystal is formed because the two components crystallize together in a homogenous one-phase system. Hence, this system would be expected to yield much higher rates of dissolution than simple eutectic systems.

c)  Glass solution of suspension: A glass solution is a homogenous system in which a glassy or a vitreous of the carrier solubilizer drug molecules in its matrix. PVP dissolved in organic solvents undergoes a transition to a glassy state upon evaporation of the solvent.

d) Compound or complex formation: This system is characterized by complexation of two components in a binary system during solid dispersion preparation. The availability of the drug from the complex is dependent on the solubility dissociation constant and the intrinsic absorption rate of the complex.

e) Amorphous precipitation: Amorphous precipitation occurs when drug precipitates as an amorphous form in the inert carrier. The higher energy state of the drug in this system generally produces much greater dissolution rates than the corresponding crystalline forms of the drug [3].

 

1.4 METHODS OF PREPARING SOLID DISPERSIONS:

a) Fusion Method:

The fusion process is technically the less difficult method of preparing dispersions provided the drug and carrier are miscible in the molten state. Fusion was used by Sekiguchi and Obi, who melted a sulphathiazole-urea mixture of eutectic composition at above its eutectic temperature, solidified the dispersion on an ice bath and pulverized it, to a powder, since a super saturation of the drug can be obtained by quenching the melt rapidly (when the solute molecules are arrested in a solvent matrix by instantaneous solidification), rapid congealing is favoured. Consequently the solidification process is often affected on stainless-steel plates to favour rapid heat loss. A modification of the process involves spray congealing from a modified spray drier onto cold metal surfaces and has been used for dispersions containing mannitol or phenyl butazone urea. Decomposition should be avoided during fusion but is often composition dependent, and affected by fusion time and the rate of cooling. Therefore, to maintain decomposition at an acceptable level, fusion may be effected at a temperature only just in excess of that which completely melts both drug and carrier.

 

b) Solvent Method:

Solid dispersion prepared by solvent removal process was termed by Bates et al as “coprecipitates”. They should more correctly, be designated as “coevaporates”, a term that has been recently adopted. The solvent process used organic solvents, the agent to intimately mix the drug and carrier molecules and was initially used by Tachibana and Nakamura when chloroform codissolved –carotene and polyvinylpyrrolidone. The choice of solvent and its removal rate are critical to the quality of the dispersion. Since the chosen carriers are generally hydrophilic and the drugs are hydrophobic, the selection of a common solvent is difficult and its complete removal, necessitated by its toxic nature, is imperative. Vacuo-evaporation may be used for solvent removal at low temperature and controlled rate. More rapid removal of the solvent may be accomplished by freeze-drying. Polyvinylpyrrolidone dispersions of Ketorpofen or dicoumarol were freeze-dried from their ammonical solutions.

The difficulties in selecting a solvent common to both drug and carrier may be overcome by using an azeotropic mixture of solvent in water. The bioavailability and stability of Nifedipine-enteric coating agent’s solid dispersion were studied, using hydroxy propylmethyl cellulose phthalate  and methacrylic methylester copolymer (Eudragit-L) as carriers. These result suggested that these solid dispersion systems might be useful for bioavailabiltiy enhancement and development of a sustained release preparation of nifedipine. The solid dispersion system was prepared by the solvent method. Nifedipine (3g) and a polymer (9g) were dissolved in about 90ml of mixed solvent (ethanol: dichloromethane 1:1) and then the solvent was evaporated off under reduced pressure. The residual solid was pulverized and the 32-80 mesh fractions were used. Solid dispersions of Griseofulvin-PVP, Sulfathiazole-PVP, have been obtained by this method.

 

c) Fusion Solvent Method:

This method consists of dissolving the drug in a suitable liquid solvent and incorporating the solution directly in the melt of PEG. If the carrier is capable of holding a certain proportion of liquid yet maintaining its solid properties and if the liquid is innocuous, the need for solvent removal is eliminated. This method is particularly useful for drugs that have high melting points or that are thermo-labile. Although there are advantages and disadvantages associated with all these methods, the choice of a method of preparation could affect the intended purpose of solid dispersion formulations.

d) Supercritical Fluid Method:

Supercritical CO2 is a good solvent for water insoluble as well as water soluble compounds under suitable conditions of temperature and pressure. Therefore, supercritical CO2 has potential as an alternative for conventional organic solvents used in solvent based processes for forming solid dispersions due to its favourable properties of being nontoxic and inexpensive.

 The process developed by Ferro Corporation consists of the following steps:

· Charging the bioactive material and suitable polymer into the autoclave.

· Addition of supercritical CO2 under precise conditions of temperature and pressure, that causes polymer to swell.

· Mechanical stirring in the autoclave and

· Rapid depressurization of the autoclave vessel through a computer controlled orifice to obtain desire particle size. The temperature conditions used in this process are fairly mild (35–75°C), which allows handling of heat sensitive biomolecules, such as enzymes and proteins.

· Solid dispersion of cabamazepine-PEG8000 has been obtained by this method.

1.5 METHODS OF DETERMINATION OF TYPES OF SOLID DISPERSION:

Various methods, which can contribute information regarding the physical nature of the solid dispersions, are thermo analytical methods such as Thermal Analysis, DSC, X-ray Diffraction Methods, Spectroscopic Methods and Microscopic Methods.

1.6 ADVANTAGES AND DISADVANTAGES OF SOLID DISPERSIONS:

Among the advantages of solid dispersions are the rapid dissolution rates that result in an increase in the rate and extent of the absorption of the drug, and a reduction in pre-systemic metabolism. This latter advantage may occur due to saturation of the enzyme responsible for biotransformation of the drug, as in the case of 17? estradiol; or inhibition of the enzyme by the carrier, as in the case of morphine-tristearin dispersion. Both can lead to the need for lower doses of the drug. Other advantages include transformation of the liquid form of the drug into a solid form (e.g., clofibrate and benzoyl benzoate can be incorporated into PEG 6000 to give a solid, avoidance of polymorphic changes and thereby bio-availability problems), as in the case of nabilone and PVP dispersion, and protection of certain drugs by PEGs (e.g., cardiac glycosides) against decomposition by saliva to allow buccal absorption.

The major disadvantages of solid dispersion are related to their instability. Several systems have shown changes in crystallinity and a decrease in dissolution rate with aging. The crystallization of ritonavir from the supersaturated solution in a solid dispersion system was responsible for the withdrawal of the ritonavir capsule (Norvir, Abboft) from the market. Moisture and temperature have more of a deteriorating effect on solid dispersions than on physical mixtures. Some solid dispersionS may not lend themselves to easy handling because of tackinesss [13].

1.7 MECHANISM OF INCREASED DISSOLUTION RATE: The enhancement in dissolution rate as a result of solid dispersion formulation, relative to pure drug varies from as high as 400 folds to less than two-fold. Corrigan reviewed the current understanding of the mechanism of release from solid dispersion. The increase in dissolution rate for solid dispersion can be attributed to a number of factors. It is very difficult to show experimentally that any one particular factor is more important than another. The main reasons for the improvements in dissolution rates are as follows [10]:

a) Reduction of particle size: In case of glass, solid solution and amorphous dispersions, particle size is reduced to a minimum level. This can result in an enhanced dissolution rate due to an increase in both the surface area solubilization.

b) Wettability and dispersibility: The carrier material may also have an enhancing effect on the wettability and dispersibility of the drug in the dissolution media. This should retard any agglomeration or aggregation of the particles, which can slow the dissolution process.

d) Metastable Forms: Formation of metastable dispersions with reduced lattice energy would result in faster dissolution rates. It was found that the activation energies for dissolution for furosemide were 17 K Cal per mol, whereas that for 1:2 furosemide: PVP coprecipitate was only 7.3 K Cal per mol [4].

1.8 INTRODUCTION TO SOLUBILIZATION [8]:  The solubility is defined as the concentration of the undissolved solid in a solvent under a given set of conditions. The solution becomes saturated and the dissolved solute is in equilibrium with the excess undissolved solute. Poorly water-soluble drugs are increasingly becoming a problem in terms of obtaining the satisfactory dissolution within the gastrointestinal tract that is necessary for good bioavailability.  It is not only existing drugs that cause problems but it is the challenge of medicinal chemists to ensure that new drugs are not only active pharmacologically but have enough solubility to ensure fast enough dissolution at the site of administration, often gastrointestinal tract.

Dissolution of solid dosage forms in gastrointestinal fluids is a prerequisite to the delivery of the drug to the systemic circulation following oral administration. Dissolution depends in parts on the solubility of the drug substance in the surrounding medium. Surface area of drug particle is another parameter that influences drug dissolution, and in turn drug absorption, particle size is a determinant of surface area.

The dissolution of a substance may be described by the modified Noye’s- Whitney equation;

 ……………. (1)

Where dc/dt is the rate of increase in concentration, the concentration of drug in a bulk solution in which dissolution of the solid particles is taking place; K is a proportionality constant; D is the diffusion coefficient of the drug in the solvent; S is the surface area of undissolved solid; V is the volume of the solution; h is the thickness of the diffusion layer around a particle; and Cs is the solubility of the drug in the solvent. If we consider a given drug under well-defined conditions (such as controlled liquid intake), we may assume that D, V and h are relatively constant values.  Thus we can write the equation (1) to:

………… (2)

Equation (2) shows that the two variables, which may be controlled by the formulation, are the surface area and the solubility of the drug. These two variables can be altered by the following techniques:

1. Control the solubility of a weak acid or base by buffering the entire dissolution medium, the “microenvironment”, or the diffusion layer surrounding a particle.

2. Control the solubility of the drug through choice of the physical state, such as crystal form, its hydrate and its amorphous form.

3. Determine the surface area of the drug through control of particle size.

1.9 SOLUBILIZATION TECHNIQUES: Solubilization is the process by which the apparent solubility of a poorly water soluble substance is increased. Solubilization techniques include addition of a cosolvent, salt formation, prodrug design, complexation, particle size reduction, and the use of surface active agents. Use of solvate and hydrate, polymorphs, hydrotrophy, use of absorbents, pH adjustment, solubilizing vehicles, etc. are the some other physicochemical approaches to enhancing oral absorption of poorly water soluble drugs [10].

1.10 SELECTION OF A CARRIER [9].

The properties of the carrier have a major influence on the dissolution characteristics of the dispersed drug. A carrier should meet the following criteria to be suitable for increasing the dissolution rate of a drug.

1. Be freely water-soluble with intrinsic rapid dissolution properties.

2. Be non-toxic and pharmacologically inert.

3. Be heat stable with a low melting point for the melt method.

4. Be soluble in a variety of solvents and pass through a vitreous state upon solvent evaporation for the solvent method.

5. Be able to preferably increase the aqueous solubility of the drug and

6. Be chemically compatible with the drug and not form a strongly bonded complex with the drug.

OBJECTIVES

2.1 NEED FOR THE STUDY: By many estimates up to 40 percent of new chemical entities discovered by the pharmaceutical industry today are poorly soluble or lipophilic compounds. The solubility issues complicating the delivery of these new drugs also affect the delivery of many existing drugs. Aceclofenac is a NSAID. It is used in the management of osteoarthritis, rheumatoid arthritis and ankylozing spondylitis. Aceclofenac when taken orally shows gastrointestinal disturbances such as GI discomfort, nausea, and diarrhea. In some patients peptic ulceration and severe gastrointestinal bleeding may also occur. Solid dispersion technology can be used to improve the in vitro and in vivo dissolution properties of dissolution dependent poorly water soluble drugs. PEG and surfactant like SLS have been reported to be used for increasing the solubility of poorly soluble drugs. The usual dose of aceclofenac is 100 mg given twice daily by mouth. The initial dose should be reduced in patients with hepatic impairment. Its low solubility makes it a suitable candidate for solid dispersion systems [7].

2.2 OBJECTIVES OF THE STUDY: The objectives of the present study include:

· Evaluate the potential of polyvinyl pyrolidone, polyethylene glycol 6000 and sodium lauryl sulphate as suitable drug carrier systems for delivery of aceclofenac.

· Determine the effect of change in polymer and polymer composition and drug-polymer ratio on solubility of aceclofenac.

· Study of in vitro dissolution kinetics of aceclofenac from the formulated solid dispersion systems [6].

2.3 SCHEME OF WORK [5]:

PART-I: 1. Extensive literature survey.

2. Procurement of raw materials and drug

3. Standardization of raw materials and drugs.

 

PART-II: Preparation of solid dispersions employing 3² factorial designs, using different carrier systems by physical mixture, solvent evaporation method and fusion method.

Carrier Systems Used: PEG 6000 and SLS.

PART-III: Evaluation of Aceclofenac Solid Dispersions:

1. Physical appearance

2. Solubility study

3. Construction of standard calibration curve of aceclofenac in methanol and pH 6.48 phosphate buffer.

4. Drug-content uniformity.

PART-IV:

1. In vitro drug release studies.

2. Stability study.

 

PART-V: Statistical Analysis, Data Interpretation and Conclusions.

 

MATERIALS, METHODS AND EQUIPMENTS

3.1 Table: Materials and their source.

Sl. No.

Materials/ Chemicals

Source

01

Aceclofenac BP

Gift sample from Reneta Pharmaceutical Laboratories Ltd.

02

Polyethylene Glycol 6000

Gift sample from Reneta Pharmaceutical Laboratories Ltd.

03

Sodium lauryl sulphate

Gift sample from Reneta Pharmaceutical Laboratories Ltd.

 

3.2 Table: Equipments and their source.

Sl. No.

Equipment Name

Source

01

UV/Visible spectrophotometer

Shimadzu-1700

02

Electronic balance