0.6 0.5
Absorbance
0.4 0.3 0.2 0.1 0 0
5
10
15
Concentration (mcg/ml)
20
25
Formulation and In-Vitro Evaluation of Ternary Solid
Dispersion of Aceclofenac by 32 Factorial Design 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
Tablet / capsule
Dosage form
Disintegration
Large solid particle (usually 5-100 microns)
Solid Dispersion /solution
Disintegration
Drug in GI tract
Colloidal particles/ fine oily globules (Usually <1 microns)
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 5Âľm 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 agentâ&#x20AC;&#x2122;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: â&#x20AC;˘
Charging the bioactive material and suitable polymer into the autoclave.
â&#x20AC;˘
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 17β 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 bioavailability 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 â&#x20AC;&#x153;microenvironmentâ&#x20AC;?, 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
Shimadzu Corporation BL-220H
03
pH meter
Elico LI-122
05
Tablet dissolution tester
USP Apparatus - II
06
Digital Controlled Speed Stirrer
Remi Motors RQ 121/D
07
Mechanical Shaker
Remi Motor Instruments
08
IR-Spectrophotometer
Perkin Elmer 1600-Series FTIR
3.3 RAW MATERIALS CHARACTERIZATION DRUG PROFILE Drug: Aceclofenac [13] Chemical Name: 2-[(2, 6窶電ichlorophenylamino) phenyl] acetoxy acetic acid. Molecular formula: C16H13Cl2NO4 Molecular weight: 354.2
Chemical structure: ` Systematic (IUPAC) name [1]
2-[2-[2-[(2, 6-dichlorophenyl) amino] phenyl] acetyl] oxyacetic acid Description: A white or almost white crystalline powder. Physicochemical properties of Aceclofenac: Melting point: 149º to 150º Solubility: Practically insoluble in water, soluble in alcohol and methyl alcohol, freely soluble in acetone and dimethyl formamide. Standard: It contains not less than 99.0 percent and not more than the equivalent of 101.0 percent of 2-[[2–[2–[(2, 6–dichloro phenyl) amino] phenyl] acetyl] oxy] acetic acid, calculated with reference to the dried substance. Storage: Storage in a well-closed container, protected from light. Therapeutic category: Anti-inflammatory, analgesic. Pharmacological Profile: Aceclofenac is a non-steroidal agent with marked anti-inflammatory and analgesic properties. The mode of action of aceclofenac is largely based on the inhibition of prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclo-oxygenase which is involved in the production of prostaglandins [12]. Pharmacokinetics: After oral administration, aceclofenac is rapidly and completely absorbed as unchanged drug. Peak plasma concentrations are reached approximately 1.25 to 3.00 hours following ingestion. Aceclofenac penetrates into the synovial fluid, where the concentration reaches approximately 57% of those in plasma. The volume of distribution is approximately 25 L. The mean plasma elimination half-life is around 4 hours. Aceclofenac is highly protein bound >99%, aceclofenac circulates mainly as unchanged drug. 4-hydroxy aceclofenac is the main metabolite detected in plasma. Approximately twothirds of the administered dose is excreted via the urine, mainly as hydroxyl metabolite. No changes in the pharmacokinetics of aceclofenac have been detected in the elderly [1]. Adverse Effects: 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. Hypersensitivity: Leukocytoelastic vasculitis, a type-III hypersensitivity reaction with lung hemoptysis has been reported in patients following therapy with aceclofenac. Drug Interactions [2]: •
Enhancement of effects of oral anticoagulants.
•
Increased plasma concentrations of lithium, methotrexate and cardiac glycosides.
•
The risk of nephrotoxicity may be increased if given with ACE inhibitors, ciclosporin,
tacrolimus or diuretics.
•
Convulsions may occur due to an interaction with quinolones.
•
The risk of GIT bleeding and ulceration associated with NSAIDs is increased when used with
corticosteroids, the antiplatelets clopidogrel and ticlopidine. •
There may be increased risk of hemotoxicity during concomitant use of zidovudine and
NSAIDs. Uses and Administration: •
Aceclofenac, a phenyl acetic acid derivative is an NSAID. It is used in the management of
osteoarthritis rheumatoid arthritis and ankylosing spondylitis. •
The usual dose of aceclofenac is 100 mg given twice daily by mouth. The initial dose should
be reduced to 100 mg daily in patients with hepatic impairment [2].
3.4 POLYMERS USED IN SOLID DISPERSIONS: Polymers used in solid dispersions are as follows [13]
:
Polyethylene glycols (PEG): The term polyethylene glycols refer to compounds that are obtained by reacting ethylene glycol with ethylene oxide. PEGs whose molecular weight is above 300000 are commonly termed as polyethylene oxides [4]. Effect of PEG molecular weight: The dissolution rate of pure PEG decreases with increasing molecular weight. The dissolution rate of the drug in solid dispersion can be increased with an increase in molecular weight of PEG. In these cases, the rate at which the polymer dissolved dictated the rate at which the drug dissolved. Lower molecular weight PEGs melt at 37ºC in the dissolution medium prior to dissolution, further increasing the rate of dissolution. In some drug-PEG solid dispersion systems, the rate dissolution decreases with molecular weight up to a certain composition of the drug above which the trend becomes irregular [4]. Polymers and surface active agent combinations: The addition of surfactants to dissolution medium lowers the interfacial tension between the drug and the dissolution medium and promote the wetting of the drug thereby they enhance the solubility and dissolution of drugs. Ternary dispersion systems have higher dissolution rates than binary dispersion systems [13]. 3.5 CLASSIFICATION OF SURFACTANTS: Surfactant molecules may be classified based on the nature of the hydrophilic group within the molecule. The four main groups of surfactants are defined as follows:
1.
Anionic surfactants: Anionic surfactants, where the hydrophilic group carries a negative charge, such
as carboxyl (RCOO–) or sulphate.Examples of pharmaceutical importance include potassium laurate and sodium lauryl sulphate. 2.
Cationic surfactants: Cationic surfactants, where the hydrophilic group carries a positive charge (e.g.
quaternary ammonium halides,). Examples of pharmaceutical importance include cetrimide, a mixture consisting mainly of tetradecyl (Ca 68%), dodecyl (ca 22%), and hexadecyl trimethyl ammonium bromides (Ca 7%), as well as benzalkonium chloride. 3.
Ampholytic surfactants: Ampholytic surfactants (also called Zwitter ionic surfactants), where the
molecule contains, or can potentially contain, both a negative and a positive charge (e.g. the sulfobetaines, RN+ (CH3)2 CH2 CH2 SO3). Examples of pharmaceutical importance include N-dodecyl-N, N-dimethyl betaine, C12 H25 N+ (CH3)2 CH2COO–. 4.
Non-ionic surfactants: Non-ionic surfactants, where the hydrophile carries no charge but derives its
water solubility from highly polar groups such as hydroxyl or polyoxyethylene (OCH2 CH2O-) groups. Examples of pharmaceutical importance include polyoxy ethylated glycol mono-ethers (e.g., etomacrogol), sorbitan esters (spans) and polysorbates (Tweens). 3.6
USES OF SURFACTANTS [2]
Surface active agents (surfactants) are substances which at low concentrations, adsorb onto the surfaces or interfaces of a system and alter the surface or interfacial free energy and the surface or interfacial tension. Surface active agents have a characteristic structure, possessing both polar (hydrophilic) and non-polar (hydrophobic) regions in the same molecule. Thus, surfactants are said to be amphipathic in nature. Surfactants as Solubilizing Agents: Solubilization can be defined as “the preparation of a thermodynamically stable isotropic solution of a substance normally insoluble or very slightly soluble in a given solvent by the introduction of an additional amphiphilic component or components. The amphiphilic components (surfactants) must be introduced at a concentration at or above their critical micelle concentrations. Simple micellar systems as well as liquid crystalline phases and vesicles referred to above are all capable of solubilization. Surfactant uses in Pharmaceutical Preparations: 1. They are used in the formulation of liquid dosage forms like solutions, suspensions, emulsions, etc. 2. They are used in the preparation of aerosols and liposomes. 3. They are also employed in the preparation of some semisolid dosage forms. 4. They are used in the preparation of tablet dosage forms.
Use of Surfactants in Solid Dispersion Systems
[11]
: The bioavailability of hydrophobic drugs can be
increased by strategies designed to enhance the dissolution rate of the drug. This has been achieved in many cases by forming a solid dispersion of the drug in a suitable carrier, often a hydrophilic polymer such as polyethylene glycol (PEG) or polyvinyl pyrrolidone. The drug is dispersed in the carrier by coprecipitation from a suitable solution containing both drug and carrier, by melting both components together, or by some other process involving a phase change. By using relatively high concentrations of carrier and a rapid precipitating process, the drug may form as an amorphous or molecularly dispersed high energy phase in the carrier. A number of workers have used surfactants as the carrier material to achieve this enhanced dissolution effect. Among the surfactants employed are poly oxyethylene stearate, Renex 650, poloxamer 188, texafor AIP deoxycholic acid, and tweens and spans. Surfactants have also been added to conventional drug-polymer solid dispersions to further improve drug release properties. Wetting agents speed up the penetration of gastric fluid in the tablets and hence, tablet disintegration. The effect, which is due to the lowering of contact angles and of surface and interfacial tensions of the aqueous medium by the surfactant, has been well documented. Aqueous solutions of surfactants exhibit a more or less abrupt change in their physical properties over a narrow concentration range. This distinct change in properties is generally accepted to be due to the formation of oriented aggregates or micelles. The narrow surfactant concentration range at which micelles begin to form is referred to as the critical concentration for micelle formation or CMC. Among the more interesting properties of micellar solutions is their ability to solubilize waterinsoluble materials. Micellar solubilization has been defined by McBain as “the spontaneous passage of solute molecules of a substance, insoluble in water, into an aqueous solution of a surfactant in which a thermodynamically stable solution is formed”. Micellar solubilization of a poorly water-soluble material can be treated as a process in which the poorly water-soluble material is partitioned between an aqueous phase and a micellar phase formed by the surfactant above its CMC [13]. 3.7 STANDARDIZATION OF DRUG AND POLYMER [8] Standardization of Drug: Tests were carried out on the sample of the drug to establish its identity and purity as per BP 2001 specifications. Standardization of Polymers: The polymers were tested as per pharmacopoeial or official manufacturer’s standards. Polyethylene glycol 6000: It was tested for compliance with IP 1996 specifications. Sodium lauryl sulphate: It was tested for compliance with IP 1996 specifications.
3.8 FACTORIAL DESIGN: It is well known that traditional experimentation involves a good deal of efforts and time especially when complex formulations are to be developed. It is desirable to develop an acceptable pharmaceutical formulation in the shortest period of time using minimum number of manhours and raw materials. In addition to the art of formulation, factorial design is an efficient method of indicating the relative significance of a number of variables and their interactions. Factorial design approach shows interactions between factors that a “one factor at a time” model cannot reveal. Following are the terms used in factorial design: 1. Factors: It is a variable, which has to be assigned such as rpm, drug-polymer ratio. The choice of factors to be included in an experiment depends on experimental objective and is predetermined. 2. Level: It takes into account the value beyond or below which a batch cannot be made effectively and are preselected high and low values of the variables. 3. Runs/trials: These compromises of factorial experiments, which consist of different combinations of all levels of all factors. 4. Effect of a factor: Is the change in response caused by varying the levels of the factor. 5. Interaction: Lack of additivity is known as interaction; either an antagonist or synergistic effect is observed. 3.9 ADVANTAGES OF FACTORIAL DESIGN [8]: 1. In absence of interaction, factorial designs have maximum efficiency in estimating main effects. 2. If interaction exists, factorial designs are necessary to reveal and identify interactions. 3. Maximum use of all data since main effects and interactions are calculated from all the data. 4. Factorial designs are orthogonal and all estimated effects and interactions are independent of the effects of other forms. 3.1O METHODS OF PREPARATION OF ACECLOFENAC SOLID DISPERSION SYSTEMS [9]: Preparation of Aceclofenac Solid Dispersions with PEG 6000 & SLS: Solid dispersions of aceclofenac in PEG 6000 and SLS were prepared using 3² factorial design with PEG 6000 and SLS as variables and maintaining the mount of aceclofenac (500 mg) constant in the following table. The method used for the preparation of this solid dispersion was fusion method as described for the preparation of aceclofenac solid dispersions with PEG 6000 and SLS. Independent variables
Levels
(–1) Lower
(0) Middle
(+1) Upper
PEG 6000 (X1) mg
1250
1500
1750
SLS (X2) mg
125
250
375
Amount of aceclofenac 500 mg was maintained constant in all the preparations. 3.10.1 FACTOEIAL DESIGN 3²: 3.10.2 Table: Factor & Levels in the Design of Aceclofenac Solid Dispersions with PEG 6000 and SLS. Run No. 01 02 03 04
X1 -1 -1 -1 0
X2 -1 0 +1 -1
05 06 07 08 09
0 0 +1 +1 +1
0 +1 -1 0 +1
3.11 EVALUATION OF ACECLOFENAC SOLID DISPERSION SYSTEMS [5]: Physical Appearance: All the batches of aceclofenac solid dispersions were evaluated for colour and appearance. Solubility of Aceclofenac: The solubility of aceclofenac in various carriers was carried out and the solubility was determined. Phase solubility studies on aceclofenac with different carriers like PEG 6000SLS (80:20) was performed by the method described by Higuchi and Connors. Excess amount of aceclofenac (10 mg) was added to 25 ml of distilled water containing various concentrations of carriers (0, 0.25, 0.50, 0.75, 1.00 and 1.25% w/v). The suspension were shaken for 3 hours on a rotary flask at 37±1ºC and filtered through a whatman No. 1 filter paper. The filtrate so obtained was analyzed spectrophotometrically at 275 nm and corresponding concentrations of the drug were computed from the standard curve [9]. 3.12 CONSTRUCTION OF CALIBRATION CURVE [8]: a) Calibration Curve of Aceclofenac in Methanol: A standard solution containing 1 mg/ ml of aceclofenac was prepared in methanol by dissolving 50 mg of pure aceclofenac in 50 ml of methanol. From this solution, working standard solutions of concentrations 0 to 20 µg/ml of aceclofenac was prepared by dilution with methanol. The absorbance of the solutions was measured at 275 nm against reagent blank. Calibration curve was prepared.
b) Calibration Curve of Aceclofenac in Phosphate Buffer pH 6.8: An accurately weighed amount of aceclofenac equivalent to 100 mg was dissolved in small volume of methanol, in 100 ml volumetric flask and the volume was adjusted to 100 ml with 6.8 phosphate buffer and further dilutions were made with 6.8 pH phosphate buffer. A series of standard solution containing 2 to 20 µg/ml of aceclofenac were prepared and absorbance was measured at 275 nm against reagent blank. All spectral absorbance measurements were made on Shimadzu-1700 UV-visible spectrophotometer. 3.13 IN-VITRO DISSOLUTION: The dissolution study was carried out using USP XXIII apparatus type-II. The dissolution medium was 900 ml 6.8 pH phosphate buffer kept at 37±5ºC. The drug or physical mixture or solid dispersions was taken in a muslin cloth and tied to the rotating paddle kept in the basket of dissolution apparatus, the basket was rotated at 50 rpm. Samples of 5 ml were withdrawn at specified time intervals and analyzed spectrophotometrically at 275 nm using Shimadzu-1700 UV-visible spectrophotometer; the samples withdrawn were replaced by fresh buffer solutions. Each preparation was tested in triplicate and then means values were calculated [7]. 3.14 INFRARED SPECTROSCOPY [8]: The infrared spectra (IR) of aceclofenac, PEG 6000 and SLS and some selected preparations were obtained using FTIR (Perkin Elmer 1600 Series). The IR spectra were carried by KBr pellet method. RESULTS AND DISCUSSION 4.1 DETERMINATION OF ACECLOFENAC CONENT
[3]
: An accurately weighed amount of each
preparation was dissolved in small volume of methanol and further diluted with methanol. The content of aceclofenac was determined spectrophotometrically at 275 nm using Shimadzu UV-visible spectrophotometer. Table: Amount of drug content in each formulation. SI. NO.
Formulation code
% of drug content
01
AFGS-1
98.33
02
AFGS-2
98.65
03
AFGS-3
98.45
04
AFGS-4
98.68
05
AFGS-5
98.89
06
AFGS-6
99.12
07
AFGS-7
99.14
08
AFGS-8
89.34
09
AFGS-9
99.15
From the above table it was seen that the amount of drug content in each formulation in a considerable label.
4.2 FTI-R STUDIES OF DRUG, POLYMER AND FORMULATION Figure: IR Spectra of pure Aceclofenac. Figure: IR Spectra of PEG 6000.
4.2.3 Figure: IR Spectra of Sodium Lauryl Sulphate. 4.2.4 Figure: IR Spectra of formulation (AFGS-4).
4.2.5 Figure: IR Spectra of formulation (AFGS-5).
4.2.6 Figure: IR Spectra of formulation (AFGS-6)
From the above FTI-R studies it was seen that there is no significant chemical reaction between drug and polymer in the formulations. So FTI-R studies showed no chemical change between drug and polymer and aceclofenac is homogeneously distributed in an amorphous state within the carrier and no aceclofenac crystallized out of the dispersions. The formulations studied were found to be stable.
4.3 CALIBRATION CURVE OF ACECLOFENAC 4.3.1 Table: Standard Calibration Curve of Aceclofenac in Methanol. Calibration curve for
Aceclofenac.
Solvent
Methanol.
Wavelength
275 nm.
Unit for concentration Sl. No. 01 02 03 04 05 06
mcg/ml.
Concentration mcg/ml 0 4 8 12 16 20
Average Absorbance 0.000 0.132 0.280 0.411 0.555 0.692
4.3.2 Figure: Standard Calibration Curve of Aceclofenac in Methanol.
4.3.3 Table: Standard Calibration Curve of Aceclofenac in pH 6.8 phosphate buffer. Calibration curve for
Aceclofenac
Solvent
Phosphate buffer pH 6.8
Wavelength
275 nm
Unit for concentration
mcg/ml
Sl.
Concentration mcg/ml
Average Absorbance
No. 01 02 03 04 05
( X-values) 0 4 8 12 16
( Y-values) 0.000 0.116 0.221 0.328 0.429
06
20
0.526
4.3.5 Figure: Calibration curve of Aceclofenac in Phosphate Buffer pH 6.8
4.4 PERCENT RELEASE OF DRUG FROM THE FORMULATIONS 4.4.1 Table: Percent Release of Aceclofenac from Solid Dispersions containing PEG 6000 and SLS. Time(m in) 0 10 20 30 40 50 60
AFGS1 0 17.628 29.644 44.604 55.536 58.718 62.13
AFGS2 0 16.395 29.021 43.361 54.286 56.434 61.059
AFGS3 0 15.765 26.89 37.554 46.543 66.576 72.5
AFGS4 0 20.917 32.536 45.56 54.342 61.217 65.556
AFGS5 0 19.887 31.734 43.56 51.89 60.54 66.123
AFGS6 0 19.678 30.678 41.534 52.89 62.89 72.69
AFGS7 0 21.978 39.326 55.573 63.277 66.502 67.76
AFGS8 0 21.532 35.214 51.438 62.818 65.424 68.043
AFGS9 0 21.532 35.876 49.567 60.546 64.456 73.124
4.4.2 Figure: Percent Release of Aceclofenac from Solid Dispersions containing PEG 6000 and SLS 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60
70
Time (min) AFGS1 AFGS2 AFGS3 AFGS4 AFGS5 AFGS6 AFGS7 AFGS8 AFGS9 % of Drug release
The above table and figure showed that the percent release of drug is proportional to the polymer concentration in the formulation. The general trend indicated that there was an increase in dissolution rate for solid dispersions prepared with large quantity of SLS. The much use of SLS in formulation, the greater the dissolution rate. The dissolution rate of SLS is greater than PEG. CONCLUSION In the present study it can be concluded that the percent release of drug was proportional to the polymer concentration in the formulation. Solid dispersion of Aceclofenac by using 3² factorial designs with SLS is more than PEG because dissolution rate of SLS is more. So the greater the concentration of SLS in the formulation, the more the rate of drug release. Finally it may be concluded that, dissolution rate of aceclofenac can be increased by solid dispersion technique, which may be due to increased hydrophilic nature of carrier and also possibly due to reduction in drug crystallinity. REFERENCES: [1] Parfitt K. Analgesics Anti-inflammatory and Antipyretics, In Raynolds, J.E.F., (ed.) Martindale: The complete drug reference, 32nd Ed, Massachusetts; 1999: 2-12. [2] Kay AE, Alldred A. Rheumatoid arthritis and Osteoarthritis, In Walker R., Edwards C., Clinical Pharmacy and Therapeutics, 3rd Ed, Churchill Livingstone, London; 2003; 791-807.
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