6) Stability Of Suspensions

6.1 Introduction

Pharmaceutical suspensions are thermodynamicallyunstable system, so they always tend towards the ultimate loss of stability. What one examines at a time is only the apparent stability of the product.

Sediaan farmasi berupa suspensi secara termodinamika adalah sistem yang tidak stabil, jadi cenderung kehilangan kestabilan. Uji pada suatu waktu hanya mengukur kestabilan suatu produk.

Stability of suspension can be considered in two ways:

1. Physical 2. Chemical

Stabilitas suspensi dapat digolongkan menjadi dua:

1. secara fisik2. secara kimia

6.2 Physical Stability

1, 3, 5

The definition of physical stability in context ofsuspensions is that the particles do not sediment for a specific time period and if they sediment, do not form a hard cake. To achieve this desired target, one must consider the three main factors affecting the physical stability.

Definisi dari kestabilan fisika khususnya suspensi yaitu partikel yang tidak membentuk sedimen(endapan) untuk periode waktu tertentu dan jika mengendap, tidak membentuk cake keras. Untuk melihat target ini,kita harus melihat tiga faktor yang mempengaruhi kestabilan fisika.

6.2.1 Particle-Particle Interaction And Its Behaviour 1, 5

Derjaguin, Landau, Verwey & Overbeek explained atheory of attractive & repulsive forces in context of lyophobic colloidsviz., DLVO theory. This theory allows us to develop insight into the factorsresponsible for controlling the rate at which the particles in the suspensionwill come together to produce aggregate to form duplets or triplets. Theprocess of aggregation will accelerate the sedimentation and affect theredispersibility.

For this, the potential energy curves may be used toexplain the sedimentation behaviour which generally is indicative of theinteraction of the two charged surfaces which gives rise to two types pfsuspension systems i.e. deflocculated and flocculated.

Untuk ini, kurva energi potensial mungkin digunakan untuk menjelaskan pengendapan yang diindikasi dari interaksi dua permukaan yang diberikan untuk dua tipe sistem suspensi secara umum contoh deflokuasi dan flokuasi.

In deflocculated suspension systems, the particledispersed carry a finite charge on their surface. When the particles approachone another, they experience repulsive forces. These forces create a highpotential barrier, which prevent the aggregation of the particles. But when thesedimentation is complete, the particles form a closed pack arrangement withthe smaller particles filling the voids between the larger ones. And furtherthe lower portion of the sediment gets pressed by the weight of the sedimentabove. And this force is sufficient to overcome the high energy barrier. Oncethis energy barrier is crossed, the particles come in close contact with each otherand establish strong attractive forces. This leads to the formation of hardcake in a deflocculated system. The re-dispersion of this type of system is difficult as enough work is to be done in order to separate the particle and create a high energy barrier between them.

The another type viz., the flocculated system inwhich the particles remain in the secondary minimum, which means that theparticles are not able to overcome the high potential barrier, so they remainloosely attached with each other. So, the particles here still experience ahigh energy barrier, but are easily re-dispersible.

Fig 6.1.Potential energy curves forparticle interaction in suspension systems.

To conclude, the deflocculated system provides theapparent stability, while the flocculated system is necessary to achieve thelong-term stability. And so far for the flocculation to occur, repulsive forcesmust be diminished until the same attractive forces prevail.

Electrolytes serve to reduce the effective range ofthe repulsion forces operating on the suspended particles, as evidenced by thedecrease in Zeta Potential and the formation of the bridge between the adjacentparticles so as to link them together in a loosely arranged structure.

6.2.2 Interfacial Properties Of Solids

1

A good pharmaceutical suspension should not exhibitthe settling of suspended particles. This can be achieved by reducing theparticle size to a level of 5mto exhibit the Brownian motion.

Asfor the size reduction, work (W) is to be done which is represented as

W = ∆G = γ

SL

. ∆A.

Where, ∆G = increase in surface free energy

γ

SL

= interfacialtension between liquid medium & solid particles.

∆A. = increase in surface area of interface due tosize-reduction.

`The Size reduction tends to increase thesurface-free energy of the particles, a state in which the system isthermodynamically unstable.

In order to approach the stable state, the systemtends to reduce the surface free energy and equilibrium is reached when ∆G = 0, which is not desirable.

Thus,the following two approaches are used to retain the stability.

1)By reducing the ∆A.

Provided that they are loosely attached(flocculated system) and are easily re-dispersible.

2)By reducing the interfacial tension, the system can be stabilized, but cannotbe made equal to zero, as dispersion particles have certain positiveinterfacial tension. Thus, the manufacture must add certain surface-activeagents to reduce γ SL to a minimum value, so that the system canbe stabilized.

6.2.3 Poly-Dispersity: (Variation inparticle size)

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Rangeof particle size might have an influence on the tendency towards caking.

When the drug material is in the dispersed state, thedispersed material will have an equilibrium solubility that varies relative toits particle size. Small particles will have higher equilibrium solubility thanthe larger particles. So, these small particles will have a finite tendency tosolubilize subsequently precipitate on the surface of the larger particles(considering the fluctuations in temperature)

Thus, the larger particle grows at the expense of thesmaller particles. This phenomenon is known as “

Ostwald Ripening”.

This phenomenon could result in the pharmaceuticallyunstable suspensions (caking) & alter the bio-availability of the product,through an alteration in the dissolution rate.

Thisproblem can be surmounted by the addition of polymer (Hydrophilic Colloid) suchas cellulose derivatives, which provides the complete surface coverage of theparticles, so that their solubilization is minimized to some extent.

Another way is to have uniformity in particle size ofthe dispersed material, which is to be considered prior to the manufacturing ofsuspensions.

6.3 Chemical StabilityOf The Suspensions

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Most of the drug materials although insoluble, whensuspended in a liquid medium has some intrinsic solubility, which triggers thechemical reactions such as hydrolysis, to occur leading to degradation.

So, the particles that are completely insoluble in aliquid vehicle are unlikely to undergo chemical degradation.

The Chemical stability of thesuspensions is governed by the following facts:

It is assumed that the decomposition of thesuspension is solely due to the amount of the drug dissolved in aqueous phase.

This solution will be responsible for drugdecomposition and more drug will be released from insoluble suspended particleswithin the range of solubility. It behaves like a reservoir depot. So, theamount of the drug in the solution remains constant inspite of the decomposition with time,

Thus, primarily suspensions behave as a zero order.But once all the suspended particles have been converted into the drug in thesolution, the entire system changes from zero order to first order, as now thedegradation depends upon the concentration in the solution. Thus, it can besaid that suspension follows apparent zero-order kinetics.

Conclusion:

The suspension is stable till thesystem follows zero order, but once it enters the first order kinetics, thedegradation is rapid. But, if the suspension is concentrated, the system willrequire more time to convert from zero order to first order. And this is thereason that a concentrated suspension is often stable enough to market, but adilute is not.

But a concentrated suspension affects the physicalstability of the suspension. So, the manufacturing pharmacist should optimizeboth physical & chemical parameters of the dispersed particles to achievethe desired stability of the suspensions.

{mospagebreak title=Packaging Of Suspensions }