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SOLID DISPERSION AS AN APPROACH FOR SOLUBILITY AND DISSOLUTION ENHANCEMENT OF IBUPROFEN AND PIROXICAM


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ABSTRACT

 

The aim of this study was to enhance the solubility and hence dissolution rate of two poorly

 

soluble         drugs:        ibuprofen         and        piroxicam         using         Eudragit        RS        100         and

 

hydroxymethylpropylcellulose (HPMC) as carriers, by solid dispersion technique and to evaluate the effect of trona (sodium sesquicarbonate) on the dispersions . Solid dispersions of ibuprofen and piroxicam were prepared using HPMC or Eudragit RS 100 and their combinations by the solvent evaporation method. The prepared dispersions were characterized with respect to drug content, production yield, moisture sorption and desorption, Fourier Transform Infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC). The solubilities of the pure drug, solid dispersions and their physical mixtures were studied using standard method. In vitro drug release of ibuprofen and piroxicam from the solid dispersions was evaluated in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes in a sequential fashion. Anti-inflammatory effects of the solid dispersions were investigated in comparison to the pure drug using the egg albumin induced paw odema in rats. Stability studies at 75% relative humidity and room temperature (28oC) was carried out on the prepared solid dispersions. Results indicate that the solid dispersions with HPMC entrapped greater amount of drug in comparison to those with Eudragit RS 100. Moisture sorption studies indicate the amorphous state of drugs in the solid dispersions. Solubility studies revealed marked increase in solubility of drugs from solid dispersions when compared to pure drugs and physical mixtures. Solid dispersions of ibuprofen with HPMC containing 1:2 drug : polymer ratio had 8 fold increase in solubility when compared to pure drug . Solid dispersions of piroxicam with Eudragit and HPMC (ratio 0.1:1:1) gave a 3 fold increase in solubility when compared to the pure drug. Solid dispersion of the drugs with HPMC gave a faster drug release in simulated gastric fluid while Eudragit RS 100 based solid dispersions exhibited a delayed release of ibuprofen in the fluid. Solid dispersions of piroxicam incorporating trona showed enhanced solubility and dissolution when compared to dispersions without it, but trona was seen to decrease solubility and dissolution of ibuprofen. The FT-IR spectroscopic studies revealed that there was no chemical interaction between the drug and the polymers, while the DSC scans showed changes from crystalline to amorphous form of the drug. Solid dispersions were seen to have enhanced anti-inflammatory effect relative to the pure drug. Stability studies of these solid dispersions revealed that the formulations were stable.

CHAPTER ONE

1.0       INTRODUCTION

The oral route of drug administration is the most common and preferred method of delivery owing to convenience and ease of ingestion (Kumar et al., 2012). From a patient‘s perspective, swallowing a dosage form is a comfortable and a familiar means of taking medication. As a result, patient compliance and hence drug treatment is typically more effective with orally administered medications when compared with other routes of administration, for example, parenteral (Dhirendra et al., 2009). Although the oral route of administration is preferred, for many drugs it can be a problematic and inefficient mode of delivery for a number of reasons. Limited drug absorption resulting in poor bioavailability is paramount amongst the potential problems that can be encountered when delivering an active agent via the oral route. Drug absorption from the gastrointestinal (GI) tract can be limited by a variety of factors with the most significant contributors being poor aqueous solubility and/or poor membrane permeability of the drug molecule. When delivering an active agent orally, it must first dissolve in the gastric and/or intestinal fluids before it can then permeate the membranes of the GI tract to reach systemic circulation. The poor dissolution of water insoluble drugs is a substantial problem confronting the pharmaceutical industry. A poorly water soluble drug, more recently, has been defined in general terms as a drug which requires more time to dissolve in the gastrointestinal fluid than it may take to get absorbed in the gastrointestinal tract (Reena and Vandana, 2012). The absorption rate of a poorly water –soluble drug formulated as an orally administered solid dosage form, is controlled by its dissolution rate in the fluid at the absorption site. The dissolution rate is often the rate determining step in drug absorption. Therefore, the solubility and dissolution behavior of a drug are the key determinants of the oral bioavailability (Kumar et al., 2012). A drug with poor aqueous solubility will typically exhibit dissolution rate limited absorption, and a drug with poor membrane permeability will typically exhibit permeation rate-limited absorption. With recent advances in molecular screening methods for identifying potential drug candidates, an increasing number of poorly water-soluble drugs are being identified as potential therapeutic agents. In fact, it has been estimated that 40% of new chemical entities currently being discovered are poorly water-soluble (Lipinski, 2001). Unfortunately, many of these potential drugs are abandoned in the early stages of development owing to solubility concerns. One of the major current challenges of the pharmaceutical industry is related to strategies that improve the water solubility of drugs (Ueda et al., 2006). It is therefore becoming increasingly more important that methods for overcoming solubility limitations be identified and applied commercially such that the potential therapeutic benefits of these active molecules can be realized. Various approaches available to improve drug solubility as well as drug dissolution of poorly aqueous soluble drugs include micronisation, formation of inclusion complexes with cyclodextrins, formation of amorphous drugs, and formulation of solid dispersions of drugs using various hydrophilic carriers. Among them, formulation of solid dispersions is one of the most successful strategies to improve drug release of poorly water- soluble drugs (Hasnain and Nayak, 2012). In the Biopharmaceutics Classification System (BCS), drugs with low aqueous solubility and high membrane permeability are categorized as class II drugs. Solid dispersions technologies are particularly promising for improving the oral absorption and bioavailability of BCS class II drugs (Dhirendra et al., 2009)

1.1      Solubility

Solubility is defined as the amount of a substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution (Behera et al., 2010). Thermodynamically, it is the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion. Of the various states of matter that exist and the corresponding solutions that they can possibly form, the solutions of solids in liquids are the most frequently encountered type in pharmaceutical formulations. The solubility of a solid in an ideal solution depends upon a number of factors such as the temperature of the system, nature of the solvent, the melting point of the solid and the molar heat of fusion.

Solubility is an intrinsic material property that can be altered only by chemical modification of the molecule, in contrast to dissolution which is an extrinsic material property that can be influenced by various chemical, physical or crystallographic means such as complexation, particle size and surface properties ( Florence and Attwood, 1998).

1.1.1    Importance of solubility

The major challenge with the design of oral dosage forms lies with their poor bioavailability. Oral bioavailability depends on several factors including aqueous solubility, drug permeability, dissolution rate, first-pass metabolism, presystemic metabolism, and susceptibility to efflux mechanisms. The most frequent causes of low oral bioavailability are attributed to poor solubility and low permeability. Solubility also plays a major role for other dosage forms like parenteral formulations as well (Edward and Li, 2008). Drug absorption, sufficient and reproducible bioavailability, pharmacokinetic profile of orally administered drug substances are highly dependent on solubility of that compound in aqueous medium. Solubility is one of the most important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response (Vemula et al., 2010). Poorly water soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration which may lead to increased side effects. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as generic development. For any drug to be absorbed, it must be present in the form of an aqueous solution at the site of absorption. Water is the solvent of choice for liquid pharmaceutical formulations. Most of the drugs are either weakly acidic or weakly basic having poor aqueous solubility. The improvement of drug solubility and thereby its oral bio-availability remains one of the most challenging aspects of the drug development process especially for oral-drug delivery systems. There are numerous approaches available and reported in literature to enhance the solubility of poorly water-soluble drugs. The techniques are chosen on the basis of certain factors such as properties of drug under consideration, nature of excipients to be selected, and nature of intended dosage form.

1.1.2    Techniques for enhancing solubility

Solubility improvement techniques can be categorized into physical modification, chemical modification of the drug substance, and other techniques.

1.1.2.1    Physical modification

Particle size reduction: The solubility of a drug is often intrinsically related to drug particle size; as a particle becomes smaller, the surface area to volume ratio increases. The larger surface area allows greater interaction with the solvent which causes an increase in solubility (Sandip et al., 2013). Conventional methods of particle size reduction, such as comminution and spray drying, rely upon mechanical stress to disaggregate the active compound. Particle size reduction thus permits an efficient, reproducible and economic means of solubility enhancement. The mechanical forces inherent in comminution, such as milling and grinding, however, often impart significant amounts of physical stress upon the drug product which may induce degradation. The thermal stress which may occur during comminution and spray drying is also a concern when processing thermosensitive or unstable active compounds. Using traditional approaches for nearly insoluble drugs may not be able to enhance the solubility up to the desired level. Particle size reduction can be achieved by micronization and nanosuspension (Kumari et al., 2013. Micronization: Micronization is a conventional technique for particle size reduction. Micronization increases the dissolution rate of drugs through increased surface area, but does not increase equilibrium solubility (Satish et al., 2011). Decreasing the particle size of drugs, which causes increase in surface area, improves their rate of dissolution. Micronization of drugs is done by milling techniques using jet mill, rotor stator colloid mills and so on. Micronization is not suitable for drugs having a high dose because it does not change the saturation solubility of the drug (Blagden et al., 2007). These processes were applied to griseofulvin, progesterone, spironolactone, diosmin and fenofibrate. For each drug, micronization improved their digestive absorption, and consequently their bioavailability and clinical efficacy. Micronized fenofibrate exhibited more than 10-fold (1.3 % to 20 %) increase in dissolution at 30 minutes in biorelevant media (Chaumeil et al.,1998 ;Vogt et al., 2008)

Nanosuspension: Nanosuspension technology has been developed as a promising technique for efficient delivery of hydrophobic drugs. This technology is applied to poorly soluble drugs that are insoluble in both water and oil. A pharmaceutical nanosuspension is a biphasic system consisting of nanosized drug particles stabilized by surfactants for either oral and topical use or parenteral and pulmonary administration. The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 200 and 600 nm (Muller et al., 2000 and Nash, 2002). Various methods utilized for preparation of nanosuspensions include precipitation technique, media milling, high-pressure homogenization in water, high pressure homogenization in non-aqueous media, and combination of precipitation and high-pressure homogenization (Patravale et al., 2004) Inclusion Complex Formation-Based Techniques: Among all the solubility enhancement techniques, inclusion complex formation technique has been employed more precisely to improve the aqueous solubility, dissolution rate and bioavailability of poorly water soluble drugs. Inclusion complexes are formed by the insertion of the nonpolar molecule or the nonpolar region of one molecule (known as guest) into the cavity of another molecule or group of molecules (known as host). The most commonly used host molecules are cyclodextrins (CDs). Three naturally occurring CDs are α-Cyclodextrin, β-Cyclodextrin and γ-Cyclodextrin (Satish et al., 2011).

Cryogenic Technique: Cryogenic techniques have been developed to enhance the dissolution rate of drugs by creating nanostructured amorphous drug particles with high degree of porosity at very low-temperature conditions. Cryogenic inventions can be defined by the type of injection device (capillary, rotary, pneumatic and ultrasonic nozzle) location of nozzle (above or under the liquid level) and the composition of cryogenic liquid (hydrofluoroalkanes, N2, Ar, O2 and organic solvents). After cryogenic processing, dry powder can be obtained by various drying processes like spray freeze (Kaur et al., 2012)

1.1.2.2   Chemical modification

Salt Formation: Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. Acidic or basic drug converted into salt has higher solubility than the parent drug. Alkali metal salts of acidic drugs like penicillin and strong acid salts of basic drugs like atropine are more water soluble than the parent drug (Deepshikha et al., 2012).

Co-crystallisation: Co-crystals may be defined as crystalline materials that consist of two or more molecular and electrically neutral species held together by non-covalent forces. They can be prepared by evaporation of a heteromeric solution or by grinding the components together or by sublimation, growth from the melt and slurry preparation. It is increasingly important as an alternative to salt formation, particularly for neutral compounds (Satish et al., 2011).

Co-solvent: It is well-known that the addition of an organic co-solvent to water can dramatically change the solubility of drugs. Weak electrolytes and nonpolar molecules have poor water solubility which can be improved by altering the polarity of the solvent. Solvents used to increase solubility are known as cosolvents the process is also commonly referred to as solvent blending.

Hydrotropy: This is designed to increase solubility in water due to presence of large amount of additives. It improves solubility by complexation involving weak interaction between hydrophobic agents (sodium benzoate, sodium alginate urea) and solute. Example is sublimation of theophylline with sodium acetate and sodium alginate (Satish et al., 2011) Solubilising Agents: The solubility of poorly soluble drugs can also be improved by various solubilizing materials. The aqueous solubility of the antimalarial agent halofantrine is increased by the addition of caffeine and nicotinamide (Satish et al., 2011).

1.2   Solid dispersions

According to Chiou and Riegelman (1971), a solid dispersion is, ―the dispersion of one or more active ingredient in an inert carrier at solid state prepared by melting (fusion), solvent or the melting-solvent method‖. Solid dispersion is a common strategy by which to improve the dissolution rate and absorption of poorly water soluble drugs using hydrophilic polymer carriers as dispersing agent. Solid dispersions using insoluble carriers loaded with hydrophilic drugs lead to a delivery system aimed at optimizing pharmacokinetics and reducing side effects such as gastric irritation due to non-steriodal anti-inflammatory drugs ( Pignatello et al .,2001).

1.2.1    Advantages of solid dispersions

1.2.1.1    Reduced drug particle size

When solid dispersions consisting of poorly soluble drug and highly soluble carrier are exposed to water or gastro -intestinal fluid, the soluble carrier dissolves, leaving the drug in very fine crystalline state that will rapidly go into solution. Due to increased surface area of insoluble compound, an enhanced dissolution rate and hence increased oral absorption is obtained (Sandip et al., 2013).

Solid dispersions are more efficient than all other particle size reduction techniques, since the latter have a particle size reduction limit around 2 – 5 mm which frequently is not enough to improve considerably the drug solubility or drug release in the small intestine and consequently, to improve the bioavailability (Gaurav et al., 2009). Molecular dispersions, as solid dispersions, represent the last state of particle size reduction, and after carrier dissolution the drug is molecularly dispersed in the dissolution medium (Sharma et al., 2011). Solid dispersions apply this principle to drug release by creating a mixture of a poorly water soluble drug and highly soluble carriers in which, a high surface area is formed, resulting in an increased dissolution rate and, consequently, improved bioavailability (Leuner and Dressman, 2000).

1.2.1.2      Particles with improved wettability

A strong contribution to the enhancement of drug solubility is related to the drug wettability improvement verified in solid dispersions (Karavas et al., 2006). It has been reported that the presentation of particles to the dissolution medium as separate entities may reduce aggregation. In addition, many of the carriers used for solid dispersions such as cholic acid and bile salts may have some wetting properties, however even carriers without any surface activity such as urea, improved drug solubility (Daisy et al., 2009).

1.2.1.3    Particles with higher porosity

Particles in solid dispersions have been found to have a higher degree of porosity. The increase in porosity also depends on the carrier properties; for instance, solid dispersions containing linear polymers produce larger and more porous particles than those containing reticular polymers and, therefore, result in a higher dissolution rate (Sharma et al., 2011). The increased porosity of solid dispersion particles has been found to hasten the drug release profile (Leuner and Dressman, 2000).

1.2.1.4      Drugs in amorphous state

The enhancement of drug release can usually be achieved using the drug in its amorphous state, because no energy is required to break up the crystal lattice during the dissolution process. Poorly water soluble crystalline drugs, when in the amorphous state, tend to have higher solubility (Daisy et al., 2009). In solid dispersions, drugs are presented as supersaturated solutions after system dissolution, and it is speculated that, if a drug precipitates, it is as a metastable polymorphic form with higher solubility than the most stable crystal form (Leuner and Dressman, 2000; Karavas et al., 2006). For drugs with low crystal energy (low melting temperature or heat of fusion), the amorphous composition is primarily dictated by the difference in melting temperature between drug and carrier. For drugs with high crystal energy, higher amorphous compositions can be obtained by choosing carriers, which exhibit specific interactions with them.

1.2.1.5     Drugs with improved dissolution rate

Solid dispersions produce rapid dissolution rates that result in an increase in the rate and extent of absorption of the drug, and a reduction in presystemic metabolism. This latter advantage may occur due to saturation of the enzyme responsible for biotransformation of the drug, as in the case of 17-β-estradiol or inhibition of the enzyme by the carrier, as in the case of morphine-tristearin dispersion (Daisy et al., 2009).

1.2.2   Disadvantages /limitations of solid dispersion

Solid dispersion technique has been extensively confirmed to enhance the dissolution characteristics of sparingly soluble drugs although, the practical applicability of the system has remained limited mainly due to difficulties in manufacturing processes. Only a few products have been marketed so far. Amongst these are griseofulvin in polyethylene glycol (Gris-PEG® by Novartis), nabilone in polyvinylpyrrolidone solid dispersions (Cesamet® by Lily) and itraconazole in hydroxypropyl methylcellulose and polyethylene glycol 20,000 sprayed on sugar spheres (Sporanox® by Janseen ).

The main problems limiting the commercial application of solid dispersions involve the following.

1.2.2.1 Instability of solid dispersions

Physical instability of solid dispersions occurs mainly because there is the possibility that during processing (mechanical stress) or storage (temperature and humidity stress), the amorphous state may undergo crystallization and dissolution rate decreases with ageing. Similarly, certain carriers may exist in thermodynamically unstable states in a solid dispersion and undergo changes with time. Ritonavir capsules (Norvir®, Abbott) was withdrawn from the market because of crystallization (Serajuddin et al., 1999).

The effect of moisture on the storage stability of amorphous pharmaceuticals is also of significant concern, because it may increase drug mobility and promote drug crystallization. Most of the polymers used in solid dispersions can absorb moisture, which may result in phase separation, crystal growth or conversion from the amorphous to the crystalline state or from a metastable crystalline form to a more stable structure during storage. This may result in decreased solubility and dissolution rate (Gaurav et al., 2009)

1.2.2.2      Processing variability

Manufacturing conditions may greatly influence the physicochemical properties of solid dispersions. The heating rate, maximum temperature used, holding time at a high temperature, cooling method and rate and method of pulverization might affect the properties of solid dispersions prepared by the melting method including particle size distribution (Serajuddin et al., 1999). In addition the nature of solvent used, ratio of drug/solvent or carrier/solvent as well as rate and method used to evaporate the solvent may significantly influence the physicochemical properties of solid dispersions formed (Ruchi et al., 2009).

1.2.2.3    Method of preparation

Total removal of toxic organic solvents used in the preparation of the dispersions is the main problem associated with the solvent method. When fusion method is used, high melting temperature may chemically decompose drugs and / or carriers (Reena and Vandana, 2012).

1.2.2.4     Dosage form development

It is usually very difficult to develop solid dispersions into a suitable dosage form because pulverizing, sieving, mixing and compressing of solid dispersions, which are usually soft and tacky are difficult. Solid powders with low particle size have poor flowability and may stick to the tabletting machines, making it difficult to handle (Sharma et al., 2011). The physicochemical properties and stability of solid dispersions may be affected by scale-up processes because heating and cooling rates of solid dispersions prepared in a large scale may differ from that of a small scale. It is also expensive and not practical to evaporate hundreds and even thousands of liters of organic solvents to prepare solid dispersions for kilogram quantities of drug (Serajuddin et al,. 1999).

1.2.3    Pharmaceutical applications of solid dispersions

Solid dispersions could be utilized for the following;

  1. To obtain a homogenous distribution of small amount of drug in the solid state.
  2. To transform liquid forms of a drug into solid formulations such as powders, capsules or tablets. Examples, prostaglandin, unsaturated fatty acids, nitroglycerin, clofibrate and benzaldehyde can be incorporated into PEG-6000 to give a solid.
  3. To stabilize unstable drugs and protect against decomposition by processes such as hydrolysis, oxidation, racemization and photo-oxidation as in the case of nabilone and PVP dispersions.
  4. To formulate a fast release priming dose in sustained release dosage forms.
  5. To reduce presystemic inactivation of drugs like morphine and progesterone.
  6. To avoid undesirable incompatibilities.
  7. To mask unpleasant taste and smell of drugs as in the case of famoxetine. The bitter taste of famoxetine was greatly suppressed when the solid complex was formulated as aqueous suspension.
  8. To reduce the side effects of certain drugs. The damage to the stomach mucous membrane by certain non-steriodal anti-inflammatory drugs (NSAIDs) can be reduced by administration as an inclusion complex.
  1. To improve drug release from ointments, gels and creams.
  2. To formulate a sustained release preparation of soluble drugs by dispersing drug in poorly soluble and insoluble carrier.
  3. To enhance bioavailability, dissolution rate and absorption of drugs by increasing the solubility of poorly water soluble drugs ( Sharma et al., 2011).

1.3    Ibuprofen

Scheme1: structure of ibuprofen

Ibuprofen a weakly acidic, non-steroidal anti-inflammatory drug (NSAID) that has been widely used in the treatment of mild to moderate pain. Ibuprofen is used in the management of mild to moderate pain and inflammation in conditions such as dysmenorrhoea, headache (including migraine) postoperative pain, dental pain, musculoskeletal and joint disorders such as ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis including juvenile idiopathic arthritis, peri-articular disorders such as bursitis and tenosynovitis, and soft-tissue disorders such as sprains and strains. It is also used to reduce fever (Kumar et al., 2012 Ibuprofen is a white crystalline powder or colourless crystals with a slight characteristic odour. British Pharmacopoea (BP) solubilities are; practically insoluble in water, very soluble in alcohol, acetone, chloroform, and in methyl alcohol, slightly soluble in ethyl acetate. The drug has been classified as class II drug as par the Biopharmaceutical Classification System (BCS) having low solubility and high permeability through the stomach as it remains 99.9% unionized in the stomach, because of its solubility limitation and fast emptying time from stomach to intestine (30 min to 2 h) the required quantity cannot enter into systemic circulation. After this time, it goes to the small intestine where it is solubilized but cannot permeate through its membrane because of its pH dependent solubility and permeability.

Thus solubility and dissolution become the rate limiting steps for absorption. Drugs with low dissolution rates generally show erratic and incomplete absorption leading to low bioavailability when administered orally. To enhance solubility and improve dissolution rate of ibuprofen is challenging and rational because its serum concentration and therapeutic effects are correlated; rapid ibuprofen absorption is a prerequisite for quick onset of action.

Pharmacokinetics: Ibuprofen is absorbed from the gastrointestinal tract and peak plasma concentration is attained about 1 to 2 h after ingestion. Ibuprofen is absorbed following rectal administration. There is some absorption following topical application to the skin. Ibuprofen is 90 to 99 % bound to plasma proteins and has a plasma half life of about 2 h. It is rapidly excreted in the urine mainly as metabolite and their conjugates; about 1% is excreted in urine as unchanged ibuprofen and about 4% as conjugated ibuprofen. There appears to be little, if any, excreted in breast milk. However, the bioavailability of ibuprofen is relatively low after oral administration, since it is practically insoluble in water (Patel et al., 2010).

1.4   Piroxicam

Scheme 2: structure of piroxicam

Piroxicam is an oxime derivated non steroidal anti-inflammatory drug with low solubility and high permeability classified as class II in the Biopharmaceutical Classification System. It is used as an analgesic in acute and long time treatment of rheumatoid arthritis, osteoarthritis and in a variety of other chronic musculoskeletal disorders such as dysmenorrhea. Piroxicam is practically insoluble in water, sparingly soluble in alcohol but soluble in methylene chloride. After oral administration piroxicam is completely but slowly and gradually absorbed through the GIT and reaches the maximum blood concentration after 2-4 h. Since the drug is slightly soluble in biological fluid, piroxicam dissolution rate turns is the absorption rate limiting step and consequently, it critically affects its analgesic effect onset (Kulkarni et al., 2012).

1.5      Eudragit RS 100

Eudragit RS 100 is a neutral copolymer of polyethylacrylate, methylmethacrylate and trimethylammonium ethylmethacrylate chloride. The ammonium groups are present as salts and make the polymers permeable. It is a solid substance in form of colourless, clear to cloudy granules with a faint amine-like odour. Eudragit RS 100 is inert to the digestive tract content, pH independent and at the same time capable of swelling. Eudragit is used mainly to form controlled release formulations, but also shows stabilizing effects. Eudragit can be used to mask taste and color (Pignatello et al., 2001). Eudragit RS 100 has been employed in previous studies to improve the dissolution rate of a wide range of drugs via solid dispersions. Ofokansi et al. (2012) reported that the dissolution rate of trandolapril was increased in solid dispersions based on Eudragit RS 100 and PEG 8000.

1.6   Hydroxypropyl methylcellulose (HPMC)

HPMC is a semi synthetic inert viscoelastic polymer used as an ophthalmic lubricant, as well as an excipient and controlled-delivery component in oral medicaments, found in a variety of commercial products. HPMC is a solid, and is a slightly off-white to beige powder in appearance and may be formed into granules. The compound forms colloids when dissolved in water. This non-toxic ingredient is combustible and can react vigorously with oxidizing agents. The high interest in HPMC as an excipient is mainly due to the fact that it is non-toxic, easy to handle, relatively cheap, easy to compact and compatible with numerous drugs. HPMC consists of a backbone of cellulose with methyl and hydroxypropyl moieties substituted onto the glucose units HPMC is commercially available in many different viscosity grades. When used at high concentration, HPMC forms a gelatinous layer around the drug particles upon contact with aqueous media which can act as a barrier to drug release; the drug is released slowly from such matrix by diffusion processes. Usually higher molecular weight HPMC are used for sustained relesase in tablet formulation while lower molecular weight HPMC is employed in solid dispersions to enhance drug release (Rahman et al., 2011).

1.7     Trona

Trona is a compound of sodium chemically called sodium sesquicarbonate or sodium monohydrogen dicarbonate (Na2Co3. NaHCO3) 2H2O). Trona is a Swedish term, deriving ultimately from the Arabic “natrum”, native salt. Trona is a commonly used salt in several countries in east, west and central Africa. In Nigeria trona is commonly called ―Kaun‖ in Yoruba, ―Kanwa‖ in Hausa and ―Akanwu‖ in Igbo language. The main use of trona in homes is as a tenderizer in preparing tough food like beans, maize and meat, utilizing its ability to facilitate or speed up the softening of food during cooking. It is used as a source of sodium compounds. In Nigeria, trona is escavated or minced in northern part of the country particularly in Kano and Maiduguri areas extending to border countries like Chad and Niger. Attama et al. (2007) have shown that trona could enhance the permeation of ointments.

1.8      Statement of research problem

Poorly water soluble drugs present a problem in pharmaceutical formulation. More than 90 % of drugs approved since 1995 have poor solubility (Satish et al., 2011). With recent advances in molecular screening methods for identifying potential drug candidates, an increasing number of poorly water soluble drugs are being identified as potential therapeutic agents. According to recent estimates, nearly 40-50 % of new chemical entities are rejected because of poor solubility (Satish et al., 2011). Poor solubility would lead to poor oral bioavailability, high intra and inter subject variability and lack of dose proportionality. This frequently results in potentially important products not reaching the market or not achieving their full potential. Poorly water-soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration (Reena and Vandana, 2012). The enhancement of dissolution rate and oral bioavailability is one of the greatest challenges in the development of poorly water soluble drugs. For orally administered drugs, solubility is the most important rate limiting parameter to achieve their desired concentration in systemic circulation for pharmacological response. Problem of solubility is a major challenge for formulation scientists (Sharma et al., 2009). Any process, technology or excipient that improves solubility could therefore be useful in:

  1. Bringing more new products to the market.
  2. Reducing development timelines
  3. Reducing production cost.
  4. Bringing new life to old products and with improved therapeutic outcomes

1.9        Justification

Ibuprofen and piroxicam are poorly water soluble drugs. The efficacy of these drugs can be severely limited by poor aqueous solubility, leading to low dissolution rate and thus low absorption in the gastrointestinal tract following oral administration hence compromising oral biovailability (Tapan et al., 2010). Improvement in the extent and rate of dissolution is highly desirable for such compounds, as this can lead to an increased and more reproducible oral bioavailability and subsequently to clinically relevant dose reduction and more reliable therapy (Reena and Vandana, 2012). Any compatible additive that could therefore, enhance the solubility of these drugs would enhance their bioavailability and reduce their side effects.

1.10         Hypothesis

Null hypothesis

Solid dispersions cannot be used to improve the aqueous solubility and dissolution of ibuprofen and piroxicam.

Alternate hypothesis

Solid dispersions technique can improve the aqueous solubility and dissolution of ibuprofen and piroxicam.

1.11                Aim

The aim of the study is to enhance the solubility, dissolution and ultimately bioavailability of ibuprofen and piroxicam using solid dispersion technique.

1.12          Objectives

  1. To formulate solid dispersions of ibuprofen and piroxicam using Eudragit RS100, hydroxypropyl methylcellulose (HPMC) as carriers by the solvent evaporation method.
  2. To formulate solid dispersions of ibuprofen and piroxicam incorporating trona in addition to the two inert carriers above.
  3. To characterize the prepared solid dispersions of ibuprofen and piroxicam using DSC and FT-IR.
  4. To determine the compatibility of ibuprofen and piroxicam with trona, Eudragit RS 100 and hydroxypropyl methylcellulose using FT-IR.
  5. To evaluate the potential of solid dispersions to enhance the solubility and dissolution of ibuprofen and piroxicam.
  6. To evaluate the effect of trona on solubility and dissolution of ibuprofen and piroxicam in the solid dispersions.
  7. To evaluate the anti-inflammatory properties of the formulated solid dispersions in an animal model.
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