This document provides an overview of amorphous solid dispersions. It discusses glass transition temperature and how polymers can inhibit drug crystallization as a carrier matrix. Preparation methods like hot melt extrusion and solvent evaporation are described. Characterization techniques involve thermal analysis, spectroscopy and diffraction to analyze phase composition and molecular arrangement. In vitro tests examine the "spring and parachute" effect where drug dissolution increases initially before precipitation occurs without proper inhibition. Amorphous solid dispersions provide a formulation strategy for improving solubility of poorly water soluble drug candidates.

1. AMORPHOUS SOLID
DISPERSION
SUCHANDRA BAGCHI
M.S.(PHARMACEUTICS)
NIPERA1517PE10

2. 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

3. 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.

4. Glass transition temperature
A 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.

5. Polymers as carrier matrix
Polymers 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) PVP
From the monomer perspective they can be classified as
 Homopolymers ( one type of monomer) methylcellulose
 Copolymers (more than two types of monomers) crosspovidone
Polymers 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)

6. 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.

7. Crystallization inhibition
Before 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.

8. 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

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

10. 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

11. 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.

12. Broad aspect of preparation
Fusion method
It 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 Method
In which intense mixing is carried out by the extruder.
It provides shape to the particles.
Advantages over fusion method:-
1. Solvent free process
2. Fewer processing steps no compression processes, no drying of products etc
3. Thorough mixing leading to particle deaggregate.
Polymers used are HPMC, HMPCAS,PVP,PVPVA,PEO

13. SOLVENT METHOD
Preparation 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.

14. SUPER CRITICAL FLUID METHOD
SCF 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.

15. Characterization techniques
 First hand tool
Basic thermal, spectroscopic and diffraction techniques(finger print analysis)
 Phase composition studies
Use of DVS,XRPD,SSNMR,RAMAN and Thermal Analysis
 Molecular arrangement
Raman, IR,SSNMR,XRD,MICROSCOPY
 Advanced level
XRPD,SAXS,WAXS,XRD,NMR relaxometry and other techniques.

16. In vitro
Dissolution behaviour
Here comes the spring parachute effect
The 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.

17. 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