Dispersion What is a dispersion at molecular level? What makes them physically stable?

Interfacial Phenomena
Coarse dispersion 10 to 50 m Fine dispersion 0.5 to 10 m Colloidal 1 nm to 0.5 m

What happens at interface is critical!!

Disperse systems
Definition: - A substance, the disperse (discontinuous) phase, is dispersed as particles over the dispersion medium (continuous phase) - Phases can be solids, liquids or gasses Disperse phase (discontinuous phase) Dispersie medium (continuous phase)

Suspensions

Colloids: Particle size: 1 nm - 1 Qm No sedimentation by Brownian movement

Suspensions: Particle size: > 1Qm Sedimentation

Suspensions
Pharmaceutical suspensions are uniform dispersions of solid drug particles in a vehicle in which the drug has minimum solubility.
Colloidal suspension Coarse suspension 1 nm to 0.5 m 1 to 100 m

May be for oral, ophthalmic, parenteral, or topical use Oral suspensions may be aqueous preparations with flavored, sweetened vehicles or powder products for oral suspension Marketed preparations:
ready-to-use dry powders which must be reconstituted before administration

SUSPENSIONS

Examples of Pharmaceutical Suspensions: 1. Antacid oral suspensions 2. Antibacterial oral suspension 3. Dry powders for oral suspension (antibiotic) 4. Analgesic oral suspension 5. Anthelmentic oral suspension 6. Anticonvulsant oral suspension 7. Antifungal oral suspension

Interfacial Phenomena
flocculation or caking
determined by forces of attraction (van der Waals) versus forces of repulsion (electrostatic)

deflocculated
repulsion> attraction affected by [electrolytes]

flocculated
attraction > repulsion

B. Amsden

CHEE 440

Electrical Properties
particles may become charged by
adsorption of ionic species present in soln or preferential adsorption of OHionization of -COOH or -NH2 group
+ + + + + +

- hydroxyl ion

solid

B. Amsden

CHEE 440

Electric Double Layer

tightly bound + + + + + + diffuse

+ + + + + +
gegenion

+ -

+ - + + +

electroneutral bulk

zeta potential Nernst potential

B. Amsden CHEE 440

Electrical Double Layer

Electroneutral solution
+

Surface charge
Stern layer (fixed)

Nernst potential Zeta potential

Electrical Prop s cont d

Nernst potential
potential difference between the actual solid surface and the electroneutral bulk

Zeta potential
potential difference between the tightly bound layer and the bulk governs electrostatic force of repulsion between solid particles
B. Amsden CHEE 440

Colloidal Systems
What are colloids? Colloids are particles of a few Qm or smaller suspended in a liquid Colloids have high surface areas/mass When working with colloidal systems it is necessary to control: Stability controlled by: Surface charges on the particles pH and/or ionic strength of the dispersing media Selective adsorption of ions Particle size

Zeta Potential and Dispersion Stability

Positive zeta potential STABLE +30 mV 0 mV
If all the particles have a large negative or positive zeta potential, they will NOT STABLErepel each other because of electrostatic repulsion forces -- stable dispersion

-30 mV STABLE Negative zeta potential

Zeta Potential & Dispersion Stability



If all the particles have a large negative or positive zeta potential, they will repel each other because of electrostatic repulsion force ---stable dispersion In general, the higher the zeta potential, the more stable the particle dispersion. The dividing lines for aqueous dispersion is considered to be >+30mV or <-30mV So, if all the particles have a zeta potential which is more negative than -30mV or more positive than +30mV the dispersion should remain stable no guarantee though

Desirable Features
particles should settle slowly formulation should allow the easy redispersion of sedimented particles a flocculated suspension is desirable than a deflloculated suspension a suspension should not be too viscous to reduce the sedimentation rate

Well Formulated Suspension

Resuspend easily upon shaking Settle slowly after shaking Homogeneous mix of drugPhysically and chemically stable during its shelf life Sterile (parenteral, ocular) Gets into syringe (parenteral, ocular)

Untuk cairan obat luar :

Produk tersebut harus cukup cair sehingga dapat tersebar dengan mudah ke seluruh daerah yang sedang diobati tapi juga tidak boleh sedemikian mudah bergerak sehingga gampang hilang dari permukaan dimana obat tersebut digunakan Cairan tersebut harus dapat kering dengan cepat dan membentuk suatu lapisan pelindung yang elastis sehingga tidak akan mudah terhapus Mempunyai warna dan bau yang nyaman

Untuk tujuan farmasi :

Kestabilan fisik suspensi didefinisikan sebagai tidak menggumpal tetap terdistribusi merata di seluruh system. Karena kondisi ini jarang terjadi maka dapat dikatakan, jika partikel-partikel tersebut mengendap, maka partikel-partikel tersebut harus mudah disuspensi kembali dengan sedikit pengocokan.

Pengendapan dalam suspensi

Physical stability

Theory of Sedimentation The factors involved in the rate of velocity of settling of the particles in a suspension are best expressed in the equation of the Stoke s law Stokes equation applies to uniform, perfectly spherical particles settling in a very dilute suspension with no hindrance or turbulance FACTORS TO BE CONSIDERED
Particle size Density of the vehicle-polyethylene glycol -polyvinyl pyrolidone -glycerin -sorbitol -sugar.

Sedimentation rate (1)

Three forces acting on the falling particle: - gravity (constant, q) - upwards forces (constant, o) - friction (increases with increasing speed, o)

Equilibrium of forces p constant speed

Stokes Law

R = kecepatan akhir (cm/dt) d = diameter partikel Vs dan Vo = kerapatan fase terdisper dan medium pendispersi Lo = viskositas medium pendispersi (poise)

v Stability
Particles need to come into contact (collide) to coalesce Therefore, higher concentrations (via settling) promote coalescence or caking

External Forces Acting on Particles

Gravity Brownian Movement

V(V-Vo)g Sedimentation equilibrium: Gravity is neutralized by Brownian movement

2-5 Qm

Calculations
Determine the absolute viscosity of syrup using a ball of radius of 0.2 cm. The density of the ball is 2.33g/cc and the density of the syrup is 1.33 g/cc at 250 C. The rate of falling is 4.35 cm/sec. Determine the velocity of settling of sulfur in water. The average particle radius is 5.5 m. The density of sulfur and water at 250 C. is 1.96 and 0.997 g/c.c., respectively. The viscosity of water at 250 C. is 0.00895 poise.

Calculations
If the height of the bottle is 10 cm how long will it take to completely settle?

Particle size determination:

From the previous example, calculate the average particle size of sulfur. What is the necessary viscosity to reduce the sedimentation rate from 0.0071 cm/sec to 0.00071 cm/sec?

State Flocculated Deflocculated

Rate of settling Fast Slow

Sedimentation volume High Low

Nature Porous, easy to redisperse Compact, difficult to redisperse

Sedimentation behavior
Deflocculated suspension Flocculated suspension
- Low sedimentation rate - Liquid above sediment remains turbid (particles of < 1 Qm do not sediment due to Brownian movement) - Sedimentation is build up from the bottom - Compact sediment difficult to redisperse - High sedimentation rate - Liquid above sediment is clear (also particles < 1 Qm sediment) - Sedimentation is build up from the top - Loose sediment easy to redisperse

Deflocculated is also referred to as peptised

Structures sediment
Deflocculated suspension Flocculated suspension

Vu !F ! Degree of sedimentation: Original volume Vo

Volume sediment

Settling and Aggregation

The suspension shall form loose networks of flocks that settle rapidly, do not form cakes and are easy to resuspend. Settling and aggregation may result in formation of cakes (suspension) that is difficult to resuspend or phase separation (emulsion)

flock

cake

Sedimentation Volume
V = Vu /V0 ; ideally, V should be equal to 1.0

Sedimentation

Stokes law:

dVs - Vf)g v= L

Take care: - Wetting particles (contact angle) - Shape of the particles (compare: parachute) - High particle concentration - Non-Newtonian liquids (yield stress) - Convection by differences in temperature

Improvement of stability

Stokes law:

dVs - Vf)g v= L

- Decreasing particle size, d - Decreasing difference in density,Vs - Vf  - Increasing viscosity, L

Formulation of Suspensions
2 common approaches : 1.use of a structured vehicle
caking still a problem

2.flocculation
no cake formation

less common approach is to combine above

B. Amsden

CHEE 440

Controlled Flocculation
electrolytes
most widely used reduce zeta potential decrease force of repulsion change pH bridge formation

alcohol
reduction in zeta potential

surfactants
form adsorbed monolayers on particle surface efficacy is dependent on charge, concentration
B. Amsden CHEE 440

Controlled Flocculation polymers

adsorb to particle surface bridging viscosity, thixotropy protective colloid action most effective

B. Amsden

CHEE 440

Structured Vehicles pseudoplastic or plastic dispersion medium examples

methylcellulose, bentonite

negatively charged increase viscosity

B. Amsden

CHEE 440

Combined Approach possibility of incompatibilities of suspending agent and flocculating agent

structured vehicles have negative charge incompatible if particle carries a negative charge

B. Amsden

CHEE 440

Preparation of Suspensions
reduce drug powder to desired size add drug and wetting agent to solution prepare solution of suspending agent add other ingredients electrolytes, color, flavor homogenize medium package

B. Amsden

CHEE 440

Pertimbangan Rheologi
Prinsip rheologi bisa diterapkan untuk penyelidikan dari factor-faktor berikut : viskositas dari suatu suspensi apabila mempengaruhi pengendapan dari partikelpartikel zat terdispersi perubahan dalam sifat-sifat aliran dalam suspensi bila wadahnya dikocok dan dituang dari botol kualitas penyebaran dari cairan (lotio) bila digunakan untuk suatu bagian permukaan yang akan diobati pembuatan suspensi

Thixotropic suspension
A thixotropic suspension is the one which is viscous during storage but loses consistency and become fluid upon shaking. A well-formulated thixotropic suspension would remain fluid long enough for the easy dispense of a dose but would slowly regain its original viscosity within a short time. particles should settle slowly formulation should allow the easy redispersion of sedimented particles a flocculated suspension is desirable than a deflloculated suspension a suspension should not be too viscous to reduce the sedimentation rate

Emulsions Dispersed system - two immiscible liquid phases, one of which is dispersed as globules in the other
o/w - oleaginous internal phase and an aqueous external phase w/o - aqueous internal and an oleaginous external phase

Microemulsion: Droplets size range 0.01 to 0.1 m Macroemulsion: Droplets size range approximately 5 m.

Definition An emulsion is a dispersion in which the dispersed phase is composed of small globules of a liquid distributed throughout a vehicle in which it is immiscible.

dispersion

B phase

A phase

Emulsion

solution

Types of emulsions
Basic types multiple

O/W

W/O

W/O/W

O/W/O

Internal External Internal External phase phase phase phase oil-in-water water-in-oil

Water inoil-in-water Oil-in-waterin-oil

Types of Emulsion
Qm Water Oil

Oil-in-water emulsion

Water-in-oil emulsion

Multiple Emulsions
Qm Water Oil

Water-in-oil-in-water emulsion

Oil-in-water-in-oil emulsion

Instability emulsions

Sedimentation

Floating

Sedimentation

Creaming

Possibly combined with flocculation (secondary minimum)

Combined with coalescence cracking of breaking

Settling & Creaming

Stokes Law

v Stability
Particles need to come into contact (collide) to coalesce Therefore, higher concentrations (via settling) promote coalescence or caking

Schematic of the emulsion breakdown processes.

Contoh Soal
Suatu emulsi o/w mangandung minyak mineral dengan BJ 0,9 terdispers dalam suatu fase air yang mempunyai BJ 1,05. Jika partikel minyak mempunyai diameter ratarata 5 m, fase luar mempunyai viskositas 0,5 poise berapakah kecepatan creaming dalam cm per hari ?

Physical Stability -> Phase Separation

Phases separation starts with growth in particle size Physical contact -> first step in coalescence Flocculation and aggregation
Come together but do not fuse No disruption of interface Surfactants slow process Fusion of particles -> next step

Coalescence
Come together & fuse Disruption of interface Surfactants slow process

Phase separation (final endpoint)

Result of continued coalescence

Improvement stability emulsions

Surfactants adsorb at interfaces Interfacial energy decreases (interfacial energy: energy required to create new interface)

oil

hydrophobic hydrophilic

water

Emulsification

Emulsifier

Theories of Emulsification:
1) Surface Tension Theory: - lowering of interfacial tension. 2) Oriented-Wedge Theory: - mono molecular layers of emulsifying agents are curved around a droplet of the internal phase of the emulsion. 3) Interfacial film theory: - A film of emulsifying agent prevents the contact and coslescing of the dispersed

phase.

Surfactants and Micelles Surface active agents have a certain affinity for both polar & nonpolar solvents Amphiphilic nature adsorb at interfaces At a concentration that is characteristic of each amphiphile, these molecules will aggregate to produce micelles

Viscositas dari fase luar dapat ditingkatkan tanpa melewati batas-batas konsistensi yang dapat diterima dengan menambah suatu zat pengental (viscosity improver atau thickening agent) Ukuran partikel dari bola-bola bisa dikurangi dengan menghomogenkannya.
Ini merupakan dasar untuk kestabilan terhadap creaming dari corpus yang homogen.

Stability
Phase Inversion O/W W/O
Change water washable, etc. E.g. divalent salts Ca++, Mg++ in hard water

Inversi juga bisa dihasilkan dengan mengubah perbandingan dengan penambahan volume fase internal.

Sifat Rheologi Emulsi

Kebanyakan emulsi, kecuali emulsi encer, menunjukkan aliran Non Newton Faktor-faktor prinsip yang mempengaruhi sifat-sifat aliran dari emulsi adalah sifat viskositas yang berhubungan dengan fase terdispers, fase kontinu dan zat pengemulsi

Faktor-faktor yang berhubungan dengan fase terdispers :

perbandingan volume fase distribusi ukuran globul viskositas dari fase dalam itu sendiri

Jika konsentrasi volume fase terdispers rendah (< 0,05), system tersebut adalah Newton. Dengan naiknya konsentrasi volume, system tersebut menjadi lebih tahan terhadap aliran dan menunjukkan karakteristik aliran pseuodoplastik. Pada konsentrasi yang cukup tinggi, terjadi aliran plastis. Jika konsentrasi volume mendekati 0,74 mungkin terjadi inversi dengan berubahnya viskositas secara nyata.

Pengurangan ukuran partikel rata-rata akan menaikkan viskositas.

Makin luas distribusi ukuran partikel, makin rendah viskositasnya jika dibandingkan dengan system yang memiliki ukuran partikel rata-rata serupa tetapi dengan distribusi ukuran partikel yang lebih sempit.

Makin tinggi konsentrasi zat pengemulsi, akan makin tinggi pula viskositas produk tersebut.

Example:
Determine the absolute viscosity of syrup using a ball of radius of 0.2 cm. The density of the ball is 2.33g/cc and the density of the syrup is 1.33 g/cc at 250 C. The rate of falling is 4.35 cm/sec. v = 2r2 (D - d) g/9n n= 2r2 (D - d) g/9v = 2 (0.2)(0.2) [2.33 - 1.33] 980/9(4.35) = 2.0 poise

Determine the velocity of settling of sulfur in water. The average particle radius is 5.5 m. The density of sulfur and water at 250 C. is 1.96 and 0.997 g/c.c., respectively. The viscosity of water at 250 C. is 0.00895 poise. v = 2r2 (D - d) g/9n = 2 (5.5*10-4)(5.5*10-4)(1.96 - 0.977) *980/9(0.00895) = 7.1*10-3 cm/sec.

If the height of the bottle is 10 cm how long will it take to completely settle? -3/10 1/x = 7.1*10 x = 1408 sec = 23.5 appprox. 24 minutes It sediment too fast. Increase viscosity to reduce the sedimentation.

Particle size determination:

From the previous example, calculate the average particle size of sulfur. v = 2r2 (D - d) g/9n r2= v9n /2 (D - d) g = (0.0071)(9)(0.00895)/2(1.96 0.997)980 r = 5.5*10-4 cm -4 cm diameter = 11*10

What is the necessary viscosity to reduce the sedimentation rate from 0.0071 cm/sec to 0.00071 cm/sec? v = 2r2 (D - d) g/9n = 2r2 (D - d)g/9v = 2 (5.5*10-4)2 (1.96 - 0.997)(980) /9(0.00071) = 0.0894 poise