Solid Dispersion System in Drug Delivery

hearty Dispersion System in Drug oral communicationThe oral route remains the preferred route of dose administration due to its convenience, good forbearing compliance and low medicine production monetary values. In order for a dose to be engrossed into the systemic circulation following oral administration, the drug must be dissolved in the gastric liquids. The dynamic pharmaceutical ingredient in a substantive dosage anatomy must undergo extravagance before it is available for absorption from the gastrointestinal tract.1Currently, approximately 40% of the marketed immediate inflammation (IR) oral drugs argon categorized as practically in alcohol-soluble (1.1 Biopharmaceutics classification systemThe Biopharmaceutical programification System (BCS) was introduced in the mid-1990s to kick downstairs the drug substances with respect to their aqueous solubility and membrane permeability. BCS is a useful tool for decision-making in reflection development from a biopharm aceutical point of view.Solubility improvement st driftgies are required for Class II and Class IV drugs.1.2 Approaches to improve the solubility or to development the available surface area for detachment corporeal modificationsParticle sizeMicronizationNanosuspensionsModifications of the crystal habitPolymorphsPseudopolymorphs (including solvates)Complexation/solubilizationUse of surfactantsUse of cyclodextrinsDrug statistical distribution in bearersEutectic mixtures inviolable dispersions (non-molecular)Solid effectsChemical modificationsSoluble prodrugsSalts1.3 Solid DispersionsThe term fast dispersion refers to a group of substantive products consisting of at least two different components, generally a hydrophilic ground substance and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be sprinkle molecularly, in amorphous particles (clusters) or in crystalline particles.7Much of the research that has been reported on upstanding disp ersion technologies involves drugs that are poorly wet-soluble and amplyly permeable to biological membranes as with these drugs licentiousness is the rate limiting step to absorption. Hence, the hypothesis has been that the rate of absorption in-vivo will be concurrently accelerated with an summation in the rate of drug dissolution. Therefore, solid dispersion technologies are peculiarly promising for improving the oral absorption and bioavailability of BCS Class II drugs.1.3.1 Types of solid dispersionsOn the basis of release tools and molecular arrangement in the matrix, solid dispersions are distinguished into following types9A. Simple eutectic mixture Eutectic mixture is prepared by fast solidification of fused melts of two components that show a complete liquid miscibility with negligible solid-solid solubility. It involves loose nuclear or molecular inter exercise and not on the composition of chemical substance bonds. When the eutectic mixture is exposed to gastroin testinal fluids, both the poorly soluble drug and the postman may at the same time crystallize out as a very low-down particles result in an increase the surface area and improved dissolution and absorption of the drug.B. Solid solution A solid solution represents a homogenous one form system, where the solid solution is dissolved in a solid termination and the two components crystallize together. The solid solution achieves scurrying dissolution than a eutectic mixture because the drug particles in a solid solution are reduced to molecular size and dissolution of the drug takes place in the solid farming prior to the exposure to the liquid medium.C. Glass solution It is a homogenous glassy system in which a solute dissolves on glassy solvent results in change magnitude dissolution and absorption of the drug. It is characterized by a transparency and brittleness below the glass forming temperature. Glass solution is a metastable and the strength of the chemical bonding is mu ch less as compared to solid solution. Therefore, the release of the drug was found to be faster than a solid solution.D. Amorphous precipitations in crystalline carrier An amorphous form of a drug produces faster dissolution rate. The drug may precipitate out in an amorphous form in a crystalline carrier from solid dispersions prepared by break up or solvent method. A strong interaction between the drug and carrier resulting in the formation of channels within the matrix seems to be a possible mechanism for improved dissolution of the drug.E. Compound or complex formation The formation of a complex between the drug and the carrier may either decrease of increase the dissolution and the absorption rate of the drug. The formation of soluble complex with low association constant resulted in increased rate of dissolution and absorption.The enhancement in dissolution rate of the drug can be ascribed toAn increasing solubility of the drug because of its amorphous state or fiddling part icle size (Kelvins law)9,10An increased surface area available for drug dissolution because of the small size of the drug particles11,12An improvement in wetting of the drug caused by the hydrophilic carrier13,141.3.2 Advantageous properties of solid dispersionsManagement of the drug release pen using solid dispersions is achieved by manipulation of the carrier and solid dispersion particle properties. Parameters much(prenominal) as carrier molecular weight and composition, drug crystallinity and particle porosity and wettability, when successfully controlled, can produce improvements in bioavailability.16a. Particles with reduced particle size Molecular dispersions, as solid dispersions, represent the last state on particle size reduction, and after carrier dissolution the drug is molecularly dispersed in the dissolution medium. Solid dispersions apply this principle to drug release by creating a mixture of a poorly piss soluble drug and super solublecarriers. A amply surface area is formed, resulting in an increased dissolution rate and consequently, improved bioavailability.b. Particles with improved wettability Strong contribution to the enhancement of drug solubility is related to to the drug wettability improvement in solid dispersions. It was observed that even carriers without any surface activity, such as urea improved drug wettability. Carriers with surface activity, such as cholic acid and bile salts, when used, can importantly increase the wettability properties of drugs. Moreover, carriers can influence the drug dissolution profile by direct dissolution or co-solvent effects.c. Particles with high porosity Particles in solid dispersions arrive at been found to have a higher head of porosity. The increase in porosity alike 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 dissolu tion rate. The increased porosity of solid dispersion particles also hastens the drug release profile.d. Drugs in amorphous state Poorly body of water soluble crystalline drugs, when in the amorphous state tends to have higher solubility. 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.1.3.3. Carriers used in solid dispersionsMany carriers of natural, semi- man-made and synthetic types are world used which include natural carbohydrates, semi-synthetic and synthetic hydrophilic polymers.S.No1Nature of carrierSugars agnomen of the carrierDextrose, sorbitol, sucrose, fructose,maltose,galactose, xylitol, mannitolS.No2Nature of carrierAcidsName of the carrierCitric acid, tartaric acid and succinic acidS.No3Nature of carrierPolymorphic materialsName of the carrierPolyvinyl pyrrolidone (PVP), polyethylene glycols, hydroxyl propylmethylcellulose (HPM C), guargum, xanthan gum, sodium alginate, methyl cellulose, pectin, hydroxyl ethyl cellulose (HEC), hydroxyl propyl cellulose (HPC) and dextrins.S.No4Insoluble or entericNature of carrierpolymerName of the carrierHydroxy propyl methyl cellulosepthalate, eudragit RL, eudragit L 100, eudragit S100, eudragit RS.S.No5Nature of carrierSurfactantsName of the carrierPolyethylene stearate, poloxamer 188, tweens and spans.S.No6Nature of carrierMiscellaneousName of the carrierNicotinic acid, succinamide, dextrans, gelatin, poly vinyl alcohol, urea, cyclodextrins, skimmed milk etc.,Table 1.2 Various carriers used in solid dispersions1.3.4. set proficiencys of solid dispersionsThe following are the major processes for the preparation of solid dispersions.A. Solvent vaporisation method In this method, the physical mixture of two components is dissolved in a common solvent and followed by the evaporation of solvent. The advantages of this method are low temperature requirements for the prepara tion of dispersion and thermal decomposition of drugs and carriers can be prevented. The higher cost of production, incomplete removal of solvent, adverse effects of solvent on the chemical stability of the drug and selection of common solvent are the drawbacks of this method.B. Melting method (Fusion method) The physical mixture of drug and water- soluble carrier was heated to melt and the molten mixture was then cooled and solidified mass was crushed, pulverized and tensed. The melting point of a binary system depends on its composition and proper manipulation of drug carrier ratios. Decomposition should be avoided due to fusion time and the rate of cooling.C. Kneading method The physical mixture of drug and carrier were triturated using small quantity of positive solvent and water mixture, usually alcohol and water (11v/v). The slurry is kneaded for 45 minutes and dried at 45C. The dried mass is pulverized and sieved through sieve no. 60 and the fraction was collected. The adva ntages of this method are low temperature requirements for solid dispersion preparation and system of organic solvent is less. This method of preparation avoids thermal degradation of drug and employs less quantity of organic solvents.D. Melting solvent method This method involves profligacy the drug in a suitable solvent and the incorporation of the solution directly into the molten carrier. This method possesses the advantages of both solvent and melting methods.E. Supercritical fluid methods Supercritical fluid methods are mostly applied with carbon dioxide (CO2), which is used as either a solvent for drug and matrix or as an antisolvent. This technique consists of dissolving the drug and the carrier in a common solvent that is introduced into a particle formation vessel through a nozzle, simultaneously with CO2. When the solution is sprayed, the solvent is rapidly extracted by the SCF, resulting in the precipitation of solid dispersion particles on the walls and penetrate o f the vessel. This technique does not require the use of organic solvent and since CO2 is considered environmentally friendly, this technique is referred to as solvent free. This technique is known as Rapid Expansion of Supercritical Solution (RESS).F. Lyophilization/ obstruct Drying This technique is an alternative to the solvent evaporation method. Here the drug and carrier are dissolved in common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion.G. Melt agglomeration process This technique is used to prepare solid dispersion where a binder acts as a carrier. The solid dispersion is prepared by heating binder, drug and excipient to a temperature above the melting point or spraying the dispersion of drug in the molten binder on the heated excipients using a high shear mixer. The effect of binder type, method preparation and particle size are the critical factors influencing the solid dispersion preparation by this method. These parameters results in variou s dissolution rates, mechanism of cumulation formation and growth, agglomerate size and distribution.1.3.5. Limitations of solid dispersion systemsProblems limiting the commercial application of solid dispersions areLaborious and dearly-won method of preparation.Reproducibility of physico-chemical characteristics.Difficulty in incorporating into the aspect of dosage forms.Crystallization of the amorphous drug in the dispersion.Poor scale up of manufacturing process and physical and chemical stability of drug and the vehicle.1.4 FDTsFast-disintegrating and fast-dissolving tab keys are becoming popular as novel delivery systems for drug administration. They are more convenient for children, elderly patients, patients with swallowing difficulties, and in the absence of potable liquids. The most desirable locution for use by the elderly is one that is light(a) to swallow aristocratic to handle. Taking these requirements into consideration, attempts have been made to develop a fas t-disintegrating tablet. Since such a tablet can molder in only a small amount of water in the oral cavity, it is easy to take for any age patient, regardless of time or place. For example, it can be interpreted anywhere at anytime by anyone who do not have easy access to water. It is also easy to dose the aged, bedridden patients, or infants who have problems swallowing tablets and capsules. Recently, many companies have researched and developed various types of fast-disintegrating dosage forms.18These tablets debunk a fast and spontaneous de-aggregation in the mouth, soon after the contact with saliva, though they can be handled or extracted from the package without alteration. The active agent can thus rapidly dissolve in the saliva and be absorbed through whatever membrane it encounters, during deglutition, unless it is protected from pre-gastric absorption. To fulfill these requirements, tablets must be passing porous, incorporating hydrophilic excipients, able to rapidly a bsorb water for a rapid deaggregation of the matrix. Different technological techniques, such as freeze drying or molding or direct compression are currently industrious to prepare the formulations of this type present on the pharmaceutical market.1.4.1 Advantages of Fast Disintegrating Drug Delivery System (FDDS) 19,20 consolation of administration to patients who refuse to swallow a tablet, such as pediatric and geriatric patients, mentally ill, handicapped and uncooperative.Convenience of administration and accurate dosing as compared to liquids.No need of water to swallow the dosage form, which is highly convenient feature for patients who are traveling and do not have immediate access to water. proper mouth feel property of FDDS helps to change the basic view of medication as bitter pill, particularly for pediatric patients.Ability to provide the advantages of liquid medication in the form of solid preparation.Rapid dissolution of drug and absorption, which may produce rapid on set of action.Some drugs are absorbed from the mouth, pharynx and gorge as the saliva passes down into the stomach in such cases bioavailability of drugs is increased.Pregastric absorption can result in improved bioavailability and as a result of reduced dosage, improved clinical performance through a reduction of unwanted effects.1.4.2 Approaches for fast disintegrating tabletsA. Patented technologiesCurrently, four fast-dissolving/disintegrating technologies have reached the U.S. marketZydis (R.P. Scherer, Inc.)WOWTAB (Yamanouchi Pharma Technologies, Inc.)OraSolv (Cima Labs, Inc.)DuraSolv (Cima Labs, Inc.)B. Three others are available outside the U.S.Flash loony toons (Fuisz Technologies, Ltd.),Flash tab (Prographarm Group),OraQuick (KV Pharmaceutical Co., Inc.)Nanocrystal TechnologyC. Conventional technologies immobilise -drying or lyophilizationTablet Molding beam compressionSpray dryingSublimationMass extrusionDirect compressionIt is the easiest way to manufacture tablets. Co nventional equipment, commonly available excipients and a limited number of touch on steps are problematical in direct compression. Also high doses can be accommodated and utmost weight of the tablet can easily exceed that of other production methods. Directly compressed tablets decomposition reaction and solubilization depends on the single or combined action of disintegrates, water soluble excipients and effervescent agent. Disintegrate cleverness is strongly affected by tablet size and hardness. Large and hard tablets have a licentiousness time more than that usually required. As consequences, products with optimal radioactive decay properties often have medium to small size and /or high friability and low hardness. Breakage of tablet edges during handling and tablet good luck during the opening of blister, all results from insufficient physical resistance.Disintegrants have a major role in the disintegration and dissolution process of mouth dissolving Tablets made by dir ect compression. To ensure a high disintegration rate, choice of suitable type and an optimal amount of disintegrant is important. Other formulation components such as water soluble excipients or effervescent agents can further enhance dissolution or disintegration properties. But the main drawback of using effervescent excipients is their highly hygroscopic nature.The understanding of disintegrant properties and their effect on formulation has advanced during the last few years, particularly regarding so called superdisintegrants. Disintegration efficiency is standpointd on a pinch equivalent concept, which is the combined measurement of squireing force development and amount of water absorption. jampack equivalent expresses the capability of disintegrant to transform absorbed water into swelling force. The optimization of tablet disintegration was delineate by means of disintegrant critical concentration. Below this concentration, the tablet disintegration time is inversely p roportional to disintegrate concentration and above that disintegration time remains approximately constant or even increases.The simultaneous presence of disintegrate with a high swelling force called disintegrating agent and substances with low swelling force ( starch, cellulose and direct compression sugar) defined as, swelling agent was claimed to be a key factor for the rapid disintegration of the tablet, which also offers physical resistance.1.4.3 Mechanism of tablet disintegration and water absorptionWhen mouth dissolving tablets placed in the mouth, upon contact with saliva the tablet disintegrates or dissolve instantaneously. The mechanisms involved in the tablet disintegration mechanisms are protrusionWicking (capillary)DeformationParticle horrid forcesChemical reaction (acid base reaction)a. SwellingNot all disintegrates swell in contact with water swelling is believed to be a mechanism in which certain disintegrating agents (like starch) impart their disintegrating effe ct. By swelling in contact with water, the adhesiveness of other ingredients in a tablet is overcome causing the tablet to disintegrate.b. Wicking (porosity and capillary action)Effective disintegrants that do not swell are believed to impart their disintegrating action through porosity and capillary action. Tablets porosity provides a way for the discernment of fluid into tablets. The disintegrants particles (with cohesiveness and compressibility) themselves act to enhance porosity and provide these capillaries into the tablets. Liquid is drawn up or wicked into these ways by capillary action and rupture the inter-particulate bonds causing the tablet to break into small parts.c. DeformationStarch grains are generally thought to be elastic in nature that is the grains that are deformed under pressure will return to their original shape when that pressure is removed. But, with the compression forces involved in tabletting, these grains are permanently deformed and are said to be ene rgy rich with these energies being released upon exposure to water, that is the ability for starch to swell is higher in energy rich starch grains than in starch grains that have not been deformed under pressure. It is believed that no single mechanism is responsible for the action of most disintegrants. But rather, it is more likely the results of interrelationships between these major mechanisms.d. Due to disintegrating particle/particle repulsive forcesAnother mechanism of disintegration attempts to explain the swelling of tablets made with non-swellable disintegrants. Guyot-Hermann has proposed a particle repulsion speculation based on the observation that nonswelling particle also causes disintegration of tablets. The electric repulsive forces between particles are the mechanism of disintegration and water is required for it. Researchers found that repulsion is secondary to wicking.e. Chemical reaction (acid base reaction)Disintegration of tablet included with citric acid and tartaric acid along with the sodium bicarbonate, sodium carbonate, potassium carbonate these react in contact with water to liberate carbon dioxide that disrupts the tablet.Name of the productImodium Lingualactive voice IngredientsLoperamide hydrochlorideDose2 mgName of the fruitPepcidin Rapitab brisk IngredientsFamotidineDose20mg and 40 mgName of the harvest-homeMosid MTActive IngredientsMosapride citrate.Dose2.5mg and 5mgName of the point of intersectionCalritin ReditabsActive IngredientsLoratadineDose10 mgName of the ProductNimulid MDActive IngredientsNimesulideDose50mg and 100mgName of the ProductZyrof MeltabActive IngredientsRofecoxibDose50 mgName of the ProductFeldene MeltActive IngredientsPiroxicamDose10mg and 20 mgName of the ProductMaxalt-MLTActive IngredientsRizatriptanDose5mg and 10 mgName of the ProductPepcid RPDActive IngredientsFamotidineDose20mg and 40 mgName of the ProductZyprexa ZydisActive IngredientsOlanzapineDose5mg, 10mg, 15mg and 20 mgName of the ProductZ ofran ODTActive IngredientsOndansetronDose4 mg and 8 mgName of the ProductRemeron SoltabActive IngredientsMirtazepineDose15mg, 30mg and 45 mgName of the ProductNuLevActive IngredientsHyoscyamine sulfateDose0.125 mgTable 1.3 Marketed fast disintegrating tabletsPiroxicam, a non-steroidal anti inflammatory agent, belong to BCS class II is widely used as a first line drug in the symptomatic relief of rheumatoid arthritis and osteoarthritis. Its low aqueous solubility has to be overcome through formulation strategies.Skimmed milk can be used as a drug carrier as it is inexpensive, easily available, biodegradable, and does not exhibit toxicity problems as experienced with PEG and PVP.24-26Polymersascarriersalsohavelimitationsinenhancingthesolubilityof poorlysoluble drugsdue totheirhigh viscosity. So the use of skimmed milk in the formulation of the SD of the drugs with limited aqueous solubility may be a potential and cost effective way to overcome the problem.27Skimmed milk is a colloid al suspension of casein micelles, spheric proteins and lipoprotein particles. The principal casein fractions are a-s1, a-s2, b-casein and k-casein. b-casein is amphiphilic and acts as a detergent molecule with surfactant property. The milk also contains whey proteins with principle fractions of the b-lacto globulin, a-lactalbumin, bovine serum albumin and immunoglobulins. These molecules were found to be surface active with a superior solubility than caseins.28Aminoacids have been suggested either as additives in peroral application or in the form of aminoacid salts to reduce gastrointestinal disorders arising due to piroxicam like NSAIDs. The surface active agents and amino acid confine are expected to be the reason for increased permeation of the drug from the solid dispersion.29,30