Solid Dispersions: An Overview To Modify …

1 International Journal of PharmTech ResearchCODEN (USA): IJPRIF ISSN : 0974-4304 , , pp 1338-1349, Oct-Dec 2009 Solid Dispersions: An Overview To ModifyBioavailability Of Poorly Water Soluble DrugsRuchi Tiwari1*, Gaurav Tiwari1, Birendra Srivastava2 and Awani K. Rai11 Pranveer Singh Institute of Technology, Dept. of Pharmaceutics, Kalpi Road, Bhauti,Kanpur-208020, Uttar Pradesh, India2 Jaipur National University, Jagatpura, Jaipur, Rajasthan, IndiaINTRODUCTIONAn ideal drug delivery system should be able to deliveran adequate amount of drug , preferably for an extendedperiod of time for its optimum therapeutic activity. Mostdrugs are inherently not long lasting in the body andrequire multiple daily dosing to achieve the desired bloodconcentration to produce therapeutic activity.

2 Toovercome such problem, controlled release and sustainedrelease delivery systems are receiving considerableattention from pharmaceutical industries worldwide. Acontrolled release drug delivery system not only prolongsthe duration of action, but also results in predictable andreproducible drug -release kinetics. One advantage ofcontrolled release dosage forms is enhanced patientcompliance. drug delivery systems based on theprinciples of Solid dispersion (1). The enhancement oforal bioavailability of poorly water soluble drugs remainsone of the most challenging aspects of drug 1 indicates that salt formation, solubilization,and particle size reduction have commonly been used toincrease dissolution rate and thereby oral absorption andbioavailability of such drugs, there are practicallimitations of these techniques.

3 The salt formation is notfeasible for neutral compounds and the synthesis ofappropriate salt forms of drugs that are weakly acidic orweakly basic may often not be practical. Even when saltscan be prepared, an increased dissolution rate in thegastrointestinal tract may not be achieved in many casesbecause of the reconversion of salts into aggregates oftheir respective acid or base forms. The solubilization ofdrugs in organic solvents or in aqueous media by the useof surfactants and cosolvents leads to liquid formulationsthat are usually undesirable from the viewpoints ofpatient acceptability and commercialization. Althoughparticle size reduction is commonly used to increasedissolution rate, there is a practical limit to how muchsize reduction can be achieved by such commonly usedmethods as controlled crystallization, grinding, etc.

4 Theuse of very fine powders in a dosage form may also beproblematic because of handling difficulties and of the research that has beenreported on Solid dispersion technologies involves drugsthat are poorly water-soluble and highly permeable tobiological membranes as with these drugs dissolution isthe rate limiting step to absorption. Hence, the hypothesishas been that the rate of absorption in vivo will beconcurrently accelerated with an increase in the rate ofdrug dissolution. In the Biopharmaceutical ClassificationSystem (BCS) (Figure 2) drugs with low aqueoussolubility and high membrane permeability arecategorized as Class II drugs (2). Therefore, soliddispersion technologies are particularly promising forimproving the oral absorption and bioavailability of BCSC lass II drug delivery is the simplest and easiestway of administering drugs (3).

5 Because of the greaterstability, smaller bulk, accurate dosage and easyproduction, Solid oral dosages forms have manyadvantages over other types of oral dosage , most of the new chemical entities (NCE)under development these days are intended to be used asa Solid dosage form that originate an effective andreproducible in vivo plasma concentration after oraladministration (4, 5). In fact, most NCEs are poorly watersoluble drugs, not well-absorbed after oraladministration, which can detract from the drug sinherent efficacy (6, 7). Moreover, most promisingNCEs, despite their high permeability, are generally onlyabsorbed in the upper small intestine, absorption beingreduced significantly after the ileum, showing, therefore,that there is a small absorption window (8, 9).

6 Consequently, if these drugs are not completely releasedin this gastrointestinal area, they will have a lowbioavailability. Therefore, one of the major currentchallenges of the pharmaceutical industry is related tostrategies that improve the water solubility of drugs (10). drug release is a crucial and limiting step for oral drugbioavailability, particularly for drugs with lowGaurav Tiwari et PharmTech ,1(4) 1339gastrointestinal solubility and high permeability. Byimproving the drug release profile of these drugs, it ispossible to enhance their bioavailability and reduce sideeffects. Solid dispersions are one of the most successfulstrategies to improve drug release of poorly solubledrugs. These can be defined as molecular mixtures ofpoorly water soluble drugs in hydrophilic carriers, whichpresent a drug release profile that is driven by thepolymer addition to the improvement ofbioavailability, most of recent researches on soliddispersion systems have been being directed toward theirapplication to the development of extended-releasedosage forms.

7 However several factors such ascomplicated preparation method, low reproducibility ofphysicochemical properties, difficulty of formulationdevelopment and scale-up and physical instability forsolid dispersion make it difficult to apply the systems tosolid dispersion dosage forms. Especially in order tomaintain a supersaturation level of drug for an extendedtime, re-crystallization of drug must be prevented duringits release from dosage form (11). Dissolution retardationthrough the Solid dispersion technique has become a fieldof interest in recent year. Shaikh et al prepared prolongedrelease Solid dispersions of acetaminophen andtheophylline by a simple evaporation method using ethylcellulose as water insoluble carrier. (12). Oral devicesmade to be retained in the stomach for a long time and toensure slow delivery of drug above it s absorption site,could provide increased and more reproducible drugbioavailability (13).

8 During the last decade, the sustained releasetechnique has been largely utilized to obtain thecontrolled release of pharmaceutical forms of both watersoluble and sparingly soluble drugs using hydrophobicand hydrophillic polymers, respectively. Limitations inthe development of Solid dispersions were mainly due tophysical instability of these systems. During this timephase separation of components can occur. Furthermore,polymeric materials are not in thermodynamicequilibrium below their glass transition temperatures(Tg), so the Solid polymer approaches its more stablestate (lower energy). If these macromolecularrearrangements occur during the experiments, a variationof the mechanical and permeation properties of thematerials can be observed. This process is known as Physical ageing (14).

9 Figure 1. Approaches to Increase solubility/ Tiwari et PharmTech ,1(4) 1340 Figure 2. Biopharmaceutical Classification System break down of the pharma new chemical entity OF Solid DISPERSIONS OVEROTHER STRATEGIES TO IMPROVEBIOAVAILABILITY OF POORLY WATERSOLUBLE DRUGSI mproving drug bioavailability by changing their watersolubility has been possible by chemical or formulationapproaches (15). Chemical approaches to improvingbioavailability without changing the active target can beachieved by salt formation or by incorporating polar orionizable groups in the main drug structure, resulting inthe formation of a pro- drug . Solid dispersions appear tobe a better approach to improve drug solubility than thesetechniques, because they are easier to produce and moreapplicable.

10 For instance, salt formation can only be usedfor weakly acidic or basic drugs and not for , it is common that salt formation does notachieve better bioavailability because of its in vivoconversion into acidic or basic forms (16). Moreover,these type of approaches have the major disadvantagethat the sponsoring company is obliged to performclinical trials on these forms, since the product representsa NCE. Formulation approaches include solubilizationand particle size reduction techniques, and soliddispersions, among others. Solid dispersions are moreacceptable to patients than solubilization products, sincethey give rise to Solid oral dosage forms instead of liquidas solubilization products usually do. Milling ormicronizations for particle size reduction are commonlyperformed as approaches to improve solubility, on thebasis of the increase in surface area.