Solid Dispersion System in Drug Delivery

Solid Dispersion System in Drug DeliveryThe oral route remains the preferred route of do medicates administration due to its convenience, good patient compliance and low medicine production costs. In order for a drug to be absorbed into the systemic circulation following oral administration, the drug must be dissolved in the gastric tranquils. The active pharmaceutical ingredient in a unwavering state superman form must undergo dis event before it is visible(prenominal) for compactness from the gastrointestinal tract.1Currently, approximately 40% of the marketed immediate unfreeze (IR) oral drugs be reason as practically in dissolvable (1.1 Biopharmaceutics classification systemThe Biopharmaceutical Classification System (BCS) was introduced in the mid-1990s to classify the drug substances with respect to their aqueous solubility and membrane permeability. BCS is a useful tool for decision-making in formulation development from a biopharmaceutical point of view.Solubility i mprovement strategies ar required for Class II and Class IV drugs.1.2 Approaches to improve the solubility or to subjoin the available surface argona for dissolutionPhysical modificationsParticle sizeMicronizationNanosuspensionsModifications of the crystal habitPolymorphsPseudopolymorphs (including solvates)Complexation/solubilization usage of surfactantsUse of cyclodextrinsDrug diffusion in common mail newsboysEutectic categorisationsSolid scatters (non-molecular)Solid solutionsChemical modificationsSoluble prodrugsSalts1.3 Solid DispersionsThe term warm dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles.7Much of the research that has been reported on solid dispersion technologies involves drugs that be poorly weewee-solub le and highly permeable to biological membranes as with these drugs dissolution is the rate limiting step to immersion. Hence, the hypothesis has been that the rate of absorption in-vivo testament be concurrently accelerated with an increase in the rate of drug dissolution. Therefore, solid dispersion technologies are particularly promising for improving the oral absorption and bioavailability of BCS Class II drugs.1.3.1 Types of solid dispersionsOn the basis of release mechanisms and molecular arrangement in the matrix, solid dispersions are distinguished into following types9A. Simple eutectic mixture Eutectic mixture is wide-awake by rapid solidification of fused melts of two components that show a complete liquid miscibility with negligible solid-solid solubility. It involves loose atomic or molecular interaction and non on the formation of chemical bonds. When the eutectic mixture is exposed to gastrointestinal fluids, both the poorly soluble drug and the flattop whitethor n simultaneously crystallize out as a very pocketable particles result in an change magnitude the surface area and ameliorate dissolution and absorption of the drug.B. Solid solution A solid solution represents a homogenous one phase system, where the solid solution is dissolved in a solid effect and the two components crystallize together. The solid solution achieves sudden dissolution than a eutectic mixture because the drug particles in a solid solution are decreased to molecular size and dissolution of the drug takes place in the solid state prior to the exposure to the liquid medium.C. Glass solution It is a homogenous glassy system in which a solute dissolves on glassy resolving results in increased dissolution and absorption of the drug. It is characterized by a transparentness and brittleness below the glass forming temperature. Glass solution is a metastable and the strength of the chemical bonding is much less as compared to solid solution. Therefore, the release o f 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 melting or solvent order. 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 small particle size (Kelvins law)9,10An increased surface area available for dr ug dissolution because of the small size of the drug particles11,12An improvement in leak 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 such as carrier molecular burthen and root, 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 water soluble drug and highly solublecarriers. A high surface area is formed, resulting in an increased dissolution rate and consequently, improved bioa vailability.b. Particles with improved wettability Strong portion to the enhancement of drug solubility is related 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 significantly increase the wettability properties of drugs. Moreover, carriers can influence the drug dissolution profile by direct dissolution or co-solvent effects.c. Particles with higher porosity Particles in solid dispersions take been found to ready 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. The increased porosity of solid dispersion particles also hastens the drug release profi le.d. Drugs in amorphous state brusquely 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-synthetic and synthetic types are being used which include natural carbohydrates, semi-synthetic and synthetic hydrophilic polymers.S.No1Nature of carrierSugars make believe of the carrierDextrose, sorbitol, sucrose, fructose,maltose,galactose, xylitol, mannitolS.No2Nature of carrierAcids lean of the carrierCitric acid, tartaric acid and succinic acidS.No3Nature of carrierPolymorphic materials light upon of the carrierPolyvinyl pyrrolidone (PVP), polyethylene glycols, hydroxyl group propylmethylcellulose (HPMC), guargum, xanthan gum, sodium alginate, methyl cellulose, pectin, hydroxyl ethyl ce llulose (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. Preparation proficiencys of solid dispersionsThe following are the study processes for the preparation of solid dispersions.A. Solvent evaporation 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 preparation of dispersion and thermal decomposition of drugs and carriers can be preve nted. 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 sieved. 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 native solvent and water mixture, usually alcohol and water (11v/v). The slurry is kneaded for 45 minutes and dehydrated at 45C. The dried mass is pulverized and sieved through sieve no. 60 and the fraction was collected. The advantages of this method are low temperature requirements for solid dispersion preparation and usage 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 dissolving 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 bottom of the vessel. This technique does not require the use of organic solvent and since C O2 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/ Freeze 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 lyophilize 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 various dissolution rates, mechanism of agglomerate formation and growth, agglomerate size and distribution.1.3.5. Limitations of solid dispersion systemsProblems limiting the commercial exertion of solid dispersions areLaborious and expensive method of preparation.Reproducibility of physico-chemical characteristics.Difficulty in incorporating into the formulation 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 FDTs dissipated-disintegrating and fast-dissolving tablets are becoming popular as novel delivery systems for drug administration. They are more convenient for children, elderly patients, patients with sinking difficulties, and in the absence of potable liquids. The most desirable formulation for use by the elderly is one that is easy to swallow easy to handle. Taking these requirements into consideration, attempts have been made to develop a fast-disintegrating tablet. Since such a tablet can disintegrate in only a small substance 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 taken anyplace 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 display 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 saved from pre-gastric absorption. To fulfill these requirements, tablets must be highly porous, incorporating hydrophilic excipients, able to rapidly absorb water for a rapid deaggregation of the matrix. Different technological techniques, such as free ze drying or molding or direct compression are currently employed to prepare the formulations of this type present on the pharmaceutical market.1.4.1 Advantages of Fast Disintegrating Drug Delivery System (FDDS) 19,20Ease of administration to patients who refuse to swallow a tablet, such as pediatric and geriatric patients, mentally ill, disabled and uncooperative. doojigger 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.Good 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 onset of action. around drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the sto mach 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 sexually transmitted disease (Fuisz Technologies, Ltd.),Flash tab (Prographarm Group),OraQuick (KV Pharmaceutical Co., Inc.)Nanocrystal TechnologyC. Conventional technologiesFreeze -drying or lyophilizationTablet MoldingDirect compressionSpray dryingSublimationMass extrusionDirect compressionIt is the easiest way to manufacture tablets. Conventional equipment, commonly available excipients and a limited number of processing steps are i nvolved in direct compression. Also high doses can be accommodated and final weight of the tablet can easily exceed that of other production methods. Directly compressed tablets riot and solubilization depends on the single or combined action of disintegrates, water soluble excipients and effervescent agent. Disintegrate efficacy is strongly affected by tablet size and hardness. Large and hard tablets have a disintegration time more than that usually required. As consequences, products with optimal disintegration properties often have medium to small size and /or high friability and low hardness. respite of tablet edges during handling and tablet fault 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 direct compression. To ensure a high disintegration rate, choice of suitable type and an optimal amount of disintegrant is important. Othe r formulation components such as water soluble excipients or effervescent agents can further enhance dissolution or disintegration properties. except 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. dissolving efficiency is ground on a force equivalent weight concept, which is the combined measurement of swelling force development and amount of water absorption. Force equivalent expresses the capability of disintegrant to transform absorbed water into swelling force. The optimization of tablet disintegration was defined by means of disintegrant critical concentration. Below this concentration, the tablet disintegration time is inversely proportional to disintegrate concentration and above that disintegration time remains approximately constant or even increases.The simultaneou s front end 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 pose in the mouth, upon contact with saliva the tablet disintegrates or dissolve instantaneously. The mechanisms involved in the tablet disintegration mechanisms areSwellingWicking (capillary vessel)DeformationParticle obscene 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 effect. 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 penetration 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 tell to be energy rich with these energies being released upon exposure to water, that is the ability for starch to swell is higher in energy rich s tarch 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 horror theory 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, honey oil carbonate these react in contact with water to liberate carbon d ioxide that disrupts the tablet.Name of the overlapImodium Lingual nimble IngredientsLoperamide hydrochlorideDose2 mgName of the ProductPepcidin RapitabActive IngredientsFamotidineDose20mg and 40 mgName of the ProductMosid MTActive IngredientsMosapride citrate.Dose2.5mg and 5mgName of the ProductCalritin 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 ProductZofran ODTActive IngredientsOndansetronDose4 mg and 8 mgName of the ProductRemeron SoltabActive IngredientsMirtazepineDose15mg, 30mg and 45 mgName of the ProductNuLevA ctive IngredientsHyoscyamine sulfateDose0.125 mgTable 1.3 Marketed fast disintegrating tabletsPiroxicam, a non-steroidal anti inflammatory agent, belonging 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 go through 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 colloidal suspension of casein micelles, globular proteins and lipoprotein particles. The principal casein fractions are a-s1, a-s2, b-casein and k-casein. b-casein is am phiphilic and acts as a detergent molecule with surfactant property. The milk also contains milk 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 content are expected to be the reason for increased permeation of the drug from the solid dispersion.29,30