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1 SOLID DISPERSION Presented by, Miss. Sujata L. Gavali Under the guidance of , Prof. D.D.Chougule (dept . Of pharmaceutics) PRINCIPAL,A.B.C.P , Sangli

Flow of presentation:

Introduction Advantages and limitations Types of solid dispersion Suitable properties of carriers Method of preparations Applications 2 Flow of presentation

Introduction:

Definition Why these systems come ahead ? Poor solubility of drug Instability Eg. Griseofulvin, Sulphathiazole, Phenytoin, chloramphenicol. To improve solubility : Decrease particle size Increase wetting characteristics Decreasing stagnant layer thickness 3 Introduction

Advantages:

Processing equipments available at large and small scale Thermo labile products Relatively high drug doses are possible Most carriers are act as solid Solvent Carriers (mainly surface active agent) can maintain super saturation in GIT 4 Advantages

Limitation:

Laborious and expensive method of preparation. Reproducibility of physicochemical characteristics. Difficulty incorporating into formulation of dosage forms . scale-up of manufacturing process. Selection of carriers. 5 Limitation

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6 l Solid Dispersion id Dispersion Disintegration Fast dissolution Disintegration Dr Drug in hydrophobic carrier philic carrier Slow release Drug in hydrophilic carrier e Sustain the dissolution dissolution Fast release Disintegration Fast dissolution Slow release Colloidal particles in fine oily globules Drug in hydrophilic carrier Disintegration

Types of Solid Dispersion:

A) Simple eutectic mixtures B) Solid solutions According to their miscibility Continuous Discontinuous solid solutions According to the way in which the solvate molecules are distributed in the solvendum Substitutional crystalline solid solutions Interstitial crystalline solid solutions Amorphous solid solutions C) Glass solutions 7 Types of Solid Dispersion

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8 In this system both compounds having complete solubility in liquid state but limited solubility in solid state It is usually prepared from the rapid solidification of the fused liquid of two components to obtain physical mixture of very fine crystals of two components. Simple eutectic mixture

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9 Solid B + liquid A T A 100% Solid A + liquid B B 100% Liquid solution Solid solution T Fig. 1-Phase diagram of Eutectic mixture Eutectic point E

Solid solutions:

According to their miscibility 1) Continuous solid solutions : In this drug and carrier are miscible in all proportions. The bonding strength between the two components is stronger than the bonding strength between the molecules of each of the individual components . 2) Discontinuous solid solutions: Solubility of each of the components in the other component is limited. Goldberg suggested that the term `solid solution' should only be applied when the mutual solubility of the two components exceeds 5%. 10 Solid solutions

According to the way in which the solvate molecules are distributed in the solvendum:

1. Substitutional crystalline solid solutions : The solute molecules can either substitute for solvent molecules in the crystal lattice Solute molecules differs by less than 15% or so from that of the solvent molecules Forms continuous and discontinuous solution 11 According to the way in which the solvate molecules are distributed in the solvendum Fig. 2 Substitutional crystalline solid solution

2. Interstitial crystalline solid solutions:

The dissolved molecules occupy the interstitial spaces between the solvent molecules in the crystal lattice Criteria for solute molecule: a molecular diameter that is no greater than 0.59 of the solvent molecule's molecular diameter The volume of the solute molecules should be less than 20% of the solvent . . 12 2. Interstitial crystalline solid solutions Fig. 3 Interstitial crystalline solid solution

3. Amorphous solid solutions::

The solute molecules are dispersed molecularly but irregularly within the amorphous solvent Carriers : urea, sugars such as sucrose, dextrose and galactose Organic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) and various cellulose derivative 13 3. Amorphous solid solutions: Fig. 4 Amorphous solid solution

4. Glass solutions and glass suspensions :

A glass solution is a homogenous, glassy system in which a solute dissolves in a glassy solvent It is characterized by transparency and brittleness below the glass transition temperature Tg Carriers that forms glassy structures : citric acid, urea PVP, PEG, sugars such as dextrose, sucrose, galactose Glassy state obtained by abrupt quenching of melt 14 4. Glass solutions and glass suspensions

:

freely water-soluble with intrinsic rapid dissolution properties. non-toxic and pharmacologically inert. heat stable with a low melting point for the melt method. soluble in a variety of solvents and pass through a vitreous state upon solvent evaporation for the solvent method. able to preferably increase the aqueous solubility of the drug and chemically compatible with the drug and not form a strongly bonded complex with the drug. 15 Suitable properties of carrier

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16 Fig. no: 5 The advantage of a surface-active carrier over a non-surface-active carrier

Carriers:

Carriers for solid dispersion- Sugars- dextrose, sorbitol, mannitol,sucrose,maltose. Acids - Citric acid, tartaric acid, succinic acid. Polymeric materials- PEG 4000, PEG 6000, polyvinyl pyrrolidone. Cellulose derivatives-HPMC. Surfactant-polymethylene sterate. 17 Carriers

Limitations of Surface active carrier :

Bioavailability problems with poorly water-soluble drug. The desired dose of a drug cannot be solubilized and filled into the hard gelatin capsules In excess heating causes crystallization of drug in solid dispersion The bioavailability of a drug may vary depending on the amount of carrier administered along with it. 18 Limitations of Surface active carrier

Methods of Preparation Solid Dispersions :

Melting method Solvent method Melting solvent method (melt evaporation) Melt extrusion method Lyophilisation Technique Melt Agglomeration Process 7 . Super Critical Fluid 8. Self emulsifying agent 9. Electrospinning 19 Methods of Preparation Solid Dispersions

1. Melting method :

Physical mixture of heat directly melt solidify in ice drug and carrier bath with stirring 20 1. Melting method Pulverize, crush & seive the mass Pour homogeneous melt in thin format on ferrite plate or stainless steel plate Cool by flowing air or water on opposite side of plate Advantages: Simple, Economic ,Supersaturation of drug during cooling Disadvantages: Decomposion of thermolable drug and phase separation

2. Solvent Method :

21 2. Solvent Method Physical mixture of the drug and carrier Dissolve in common solvent Evaporate Formation of clear solvent free film Dry the film to constant weight Advantage : Prevent Thermal decomposition of drug and carrier Disadvantages : 1) The higher cost of preparation. 2) The difficulty in completely removing liquid solvent Challenges : 1) Mixing of drug 2) Phase separation

3. Melting solvent method (melt evaporation):

22 3. Melting solvent method (melt evaporation) Dissolve drug in suitable liquid solvent Incorporate in melt of PEG Evaporate Formation of clear solvent free film Dry the film to constant weight Advantage : It is unique method involves both fusion and solvent evaporation

4. Melt extrusion method :

23 4. Melt extrusion method Mixture of Drug and carrier Process in twin screw & Extruder Melt simultaneously Homogenize extrude and shape it as tablets, granules, pellets, sheets, sticks or powder Intermediate Process for conventional tablet Advantage: In Hot melt extrusion method the drug/carrier mix is only subjected to an elevated temperature for about 1 min, which enables drugs that are somewhat thermo labile to be processed

5. Lyophilisation Technique:

Freeze-drying involves transfer of heat and mass to and from the product under preparation It is a molecular mixing technique where the drug and carrier are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion. 24 5. Lyophilisation Technique

6. Melt Agglomeration Process :

This technique has been used to prepare Solid Dispersion wherein the binder acts as a carrier Heat binder, drug and excipient to a temperature above the melting point of the binder A rotary processor has been shown to be alternative equipment for melt agglomeration Important parameter for Melt Agglomeration: binder type, method of manufacturing and particle size 25 6. Melt Agglomeration Process

7. Supercritical fluid method :

26 7. Supercritical fluid method Drug + Matrix dissolved in CO2 Sprayed through nozzle Into expansion vessel with low pressure Particles are formed Adiabatic expansion of mix. takes place results in rapid cooling Solvent free method Advantage : Organic solvents are not used Disadvantage : Solubility and Problem in scaling up.

8. Self-emulsifying agent:

The self-emulsifying agent will act as dispersing or self emulsifying agent preventing the formation of any water insoluble surface layer, although the liberated drug remain undissolved in the dissolution medium. The concentration of drug exceed than saturation solubility drug will disperse in finely divided state Faciliated dissolution of drug in GIT 27 8. Self-emulsifying agent

9. Electrospinning:

Drug + through Orifice Matrix Solution Subjected to electrical field forms fibers with diameter of nano or microscale- fibre further process 28 9. Electrospinning Advantages : Simple, Fibre diameter adjusted Disadvantages : high molecular weight and fibre forming polymer only used

Applications :

To obtain a homogeneous distribution of a small amount of drug in solid state. To stabilize the unstable drug. To dispense liquid (up to 10%) or gaseous compounds in a solid dosage. To formulate a fast release primary dose in a sustained released dosage form. To formulate sustained release regimen of soluble drugs by using poorly soluble or insoluble carriers. To reduce pre systemic inactivation of drugs like morphine and progesterone. Polymorphs in a given system can be converted into isomorphous, solid solution, eutectic or molecular addition compounds. 29 Applications

Marketed Preparations:

Gris-PEG® (griseofulvin) - Novartis Sporanox® (itraconazole) -Janssen pharmaceuticals,Inc. Prograf® (tacrolimus) -Astellas pharma,Inc. Cesamet® (nabilone) - Lily. Crestor® (rosuvastatin) - Astra Zeneca Solufen® (ibuprofen) - Jordan pharma. Intelence® (etravirine) 30 Marketed Preparations

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31 Solubility is a most important parameter for the oral bioavailability of poorly soluble drugs The selection of the carrier has the influence on the dissolution characteristics of the dispersed drug SCF and Electrospining are superior techniques over the other methods Solid dispersion technology is one of the possible modes that increases the solubility Conclusion

References: :

Review Article on solid dispersion : A promising technique to enhance solubility of poorly water soluble drug from International journal of Drug delivery vol.3 Solid dispersion :A overview from Pharmaceutical information Articles & Blogs. Solid dispersion: An overview to modify Bioavailability of poorly water soluble drugs from International journal of pharma. tech Research vol.1 Wadke DA,Serajuddin A, Jacobson H, “ Preformulation testing". In Liberman HA ,Schwartz JB,eds.pharmaceutical dosage forms Tablet New York .NY: Marcle Dekker;1989:1-73. 32 References:

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33 THANK YOU

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