AMORPHOUS SOLID DISPERSION

SUCHANDRA BAGCHIM.S.(PHARMACEUTICS)

NIPERA1517PE10

FLOW OF SEMINAR INTRODUCTION Glass transition temperature Polymers as carrier matrix Factors affecting formulation development Crystallization inhibition Advantages of polymers Antiplasticization Methods of preparation Mechanism Broad aspect preparation Characterization In vitro evaluation Conclusion

INTRODUCTION

To have a better understanding of the differences in the thermodynamic properties of crystalline and amorphous form, consider a crystalline drug which when heated, undergoes melting tempareture (Tm), on cooling orderly arrangement takes place and forms thermodynamically stable crystal lattice with sufficient timings to arrange them in proper long range order.However, if molten drugs undergo sudden cooling it may undergo supercooled liquid state without undergoing crystallization process below Tm which is in equilibrium with molten drugs.On further cooling the the system remains in equilibrium state unless the glass transition (Tg) is reached below which it undergoes non equilibrium state.(low viscosity rubbery state) and converts to frozen glassy state of the drug.

Glass transition temperatureA material in glassy state behaves like brittle solids but without crystalline structure but having only short range order. This transition is necessary because if super cooled liquid state exist below glass transition temperature then a point comes whereby the crystal would have a higher entropy compared to the supercooled liquid. The total entropy of the system would become negative before reaching to absolute zero temperature, violating the third law of thermodynamics.The glass transition is the second order thermodynamic transition characterized by step change in the heat capacity which is also associated with change in derivative of extensive thermodynamic properties such as volume, enthalpy, entropy.The amorphous form of the drug has higher enthalpy, entropy, free energy and volume as compared to crystalline form which is responsible for higher apparent solubility. In contrast the apparent solubilty of amorphous form remains less than theoretical estimation but more than crystalline form which further increases dissolution rate, but solubility again tends to decrease due to spring and parachute effect.

Polymers as carrier matrixPolymers are chemically composed of repetitive structural units called monomers which are linked with each other forming a extended structural framework.They can be classified on the basis of their origin such as Natural(starch, cellulose, proteins) Semi synthetic ( hydroxypropyl methylcellulose)HPMC Synthetic (polyvinyl pyrrolidone) PVPFrom the monomer perspective they can be classified as Homopolymers ( one type of monomer) methylcellulose Copolymers (more than two types of monomers) crosspovidonePolymers can be classified on the basis of complex three dimensional structures such as Amorphous (poly acrylic acid) Semi crystalline( poly lactic acid) Crystalline(poly ethylene glycol)

Factors affecting formulation developments Molecular mobility Thermodynamic properties Environmental stress Preparation methods and Condition Play major role in the physical/chemical stability of the amorphous form of the drug.

Crystallization inhibitionBefore developing amorphous solid dispersion (ASD) based formulation, it is important to estimate the suitability of the compound to form amorphous state. Glass Forming Ability(GFA) and fragility can provide a qualitative estimation of the tendency of the drug to undergo devitrification and clarify the physical stability of the drug.GFA and fragility is the indication for life expectancy of the ASD.The crystallisation of amorphous form is a two step process, although they occur simultaneously. Nucleation(lower temperature) Crystal growth(higher temperature)A supersaturation process also favours crystallization process.(initiation)And a certain initiation energy is also required to start crystallization process to overcome high interfacial tension between small particles.Hence this state of supersaturation where no crystallization process initiates is called metastable zone, which is a smart choice of polymeric excipients can expand this region by causing increase in the degree of supersaturation or decrease in interfacial energy.

Advantages of polymers

Increase in aqueous solubility(by inhibiting precipitation of the dissolved drug)

Retard nucleation(by decreasing the free concentration available for nuclei seed formation).

Increases viscosity of the system Alters the frequency of atomic/ molecular transport to the surface of

the nucleous. Have sufficiently high configurtional entropy due to their large

molecular size.This decreases the chances of recrystallization

Antiplasticization

Reduction in plasticity or hardening of materialMixing of low Tg drug with high Tg polymer leads to plasticization at molecular level.Hence intermediate of both the Tg are favourable for antiplasticization.

METHODS FOR PREPARATION AMORPHOUS SOLID DISPERSIONS NANOSUSPENSION TECHNIQUE CRYOGENIC TECHNIQUE CYCLODEXTRIN BASED INCLUSION COMPLEXES ELECTROSTATIC SPINNING ELECTROSTATIC BLOWING ELECTROSPRAYING FILM CASTING HYDROTROPHY MECHANICAL ACTIVATION METHOD

MECHANISMS

SOLUBILIZING MECHANISM-MICELLAR SOLUBILIZATION,COMPLEXATION, INCREASED POROSITY, DECREASED PARTICLE SIZE IT SHOULD BE DIFFERENTIATED FROM POLYMER BASED ASD.

Binary systems are most commonly used for the preparation of ASDs due to simple formulation strategies, ease of scale up and lower cost of production.Sometimes more complex ternary, quaternary systems also have been produced depending on requirement and stability issues.Sufectants could be used to increase stability but tolerance by the body is an issue as it causes toxicity.phase separation and demixing can be prevented by arresting the molecular mobility during preparation.

Broad aspect of preparation Fusion methodIt is also known as melt method.A physical mixture of drug and polymer is heated to form molten mixture which is then cooled and solidified with rigorous stirring.The resultant solid mass is then crushed, pulverized and sieved to obtain desired particle size.Hot Melt Extrusion MethodIn which intense mixing is carried out by the extruder.It provides shape to the particles.Advantages over fusion method:-1. Solvent free process2. Fewer processing steps no compression processes, no drying of products

etc3. Thorough mixing leading to particle deaggregate.Polymers used are HPMC, HMPCAS,PVP,PVPVA,PEO

SOLVENT METHODPreparation of the solution of both the drug and polymer in a single solvent followed by removal of solvent to obtain solid dispersion. This increases solubility and stability of the dispersion.The main advantage is thermal decomposition of drug and polymer can be prevented by this technique.Disadvantage is finding a suitable solvent for both the drug and polymer due to their differences in solubility as well as polarity.Phase separation which may occur due to removal of solvent.Hence vaccum dryer, rotary dryer are suitable and for thermolabile substances and better entappment efficiency spraydrying techniques are also involved.

SUPER CRITICAL FLUID METHODSCF posses both the properties of liquid and gas, under super critical fluid point the material have liquid like sovent properties and gas like viscosity, diffusivity and thermal conductivity.Althoug these properties are beneficial to increase solubility.Here super crictical carbondioxide as either solvent for the drug and polymer or as antisolvent.The polymer and drug dissolved in CO2 and spryed through the nozzle into low pressure regioncausing adiabetic expansion of the CO2 and rapid cooling.Thus this technique allows the production of drug particles in greatly reduced particle size.

Characterization techniques

First hand toolBasic thermal, spectroscopic and diffraction techniques(finger print analysis) Phase composition studiesUse of DVS,XRPD,SSNMR,RAMAN and Thermal Analysis Molecular arrangementRaman, IR,SSNMR,XRD,MICROSCOPY Advanced levelXRPD,SAXS,WAXS,XRD,NMR relaxometry and other techniques.

In vitro

Dissolution behaviourHere comes the spring parachute effectThe drug first dissolves along with soluble polymer matrix to produce a supersaturated solution(spring)followed by decline in drug concentration in the media due to either absorption or precipitation(parachute) effect.Desirable is to maintain supersaturation without precipitation to avoid crystallisation and to enhance solubility and dissolution by diffustion controlled mechanisms depending on concentration gradient and hypothetical sink condition maintenance.Hence drug polymer interaction plays major role in inhibiting crystallisation process either by interfearing with nucleation process or crystal growth.

Conclusion

The emerging pharmaceutical scenario of drug discovery has shifted the major portion of newer drugs from hydrophilicity to lipophilicity.Large number of drug molecules in this pipeline are poorly water soluble presenting significant challenges in formulation scientists. Amorphous solid dispersion have provided an atrractive alternative for overcoming such limitations by altering “molecular architechture”.Hence this technique is generally preferred technique for such lead drugs

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