PREFORMULATION

By:- Saiesh P.Phaldesai 1st year M-Pharma Pharmaceutics Srinivas college of pharmacy Mangalore

CONTENTS

Solubilization. Surfactant and its importance. Temperature. pH. Cosolvency. Solid dispersion. β-Cyclodextrin drug dispersion technique. References.

SOLUBILIZATION

Solubilization an important property of

association colloids in solution is an ability of the micelles to increase the solubility of material that normally insoluble or only slightly soluble in the dispersion medium used this phenomenon known as Solubilization.

SOLUBILITY ANALYSIS

Ionization constant (pKa) Can be calculated by Henderson Hasselbach

equation- For acidic drugs….pH= pKa+ log [ionized drug]/ [unionized

drug] For basic drugs…pH=pKa+ log [unionized drug]/ [ionized drug] E.g. Aspirin (pKa-3.5)

PH SOLUBILITY PROFILE

The solubility of acidic or basic drug will show differences in solubility with changes in pH.

The solubility of an acidic or basic drug depends on the pKa of the ionizing functional group and the intrinsic solubilities for both the ionized and unionized forms.

The relationship between solubility of the acidic drug and pH is given by the equation

pH= pKa +log [Cs]/[Ca] Where pKa =negative logarithm of the ionization

constant of the acid [Cs]= molar concentration of the salt form in water [Ca ] = molar concentration of free acid in water

Knowing the pKa , [Ca ],and pH total amt. of the drug solubilized in the water can be calculated

Total solubility of the weak acid St is given by St =[Ca] +[Cs] equation for the weak bases is St =[Cb] +[Cs]

COMMON ION EFFECT

If salt of weak acid or weak base is added to the solution of acid or base resp. dissociation of acid or base is diminished further.

E.g. the addition of sod. Acetate to sol. of acetic acid suppresses the dissociation of acetic acid.

E.g. CH3COOH-----H+ +CH3COO

PARTITION COEFFICIENT

It is an ratio of Unionized drug distributed between organic & aqueous phase at equilibrium.

Po/w = (Coil/Cwater)equilibrium Partition Coefficient study is useful in the

A.D.M.E

DISSOLUTION

It is controlled by several physicochemical properties- chemical form, crystal habit, particle size, solubility, surface area and wetting properties.

Noyes-Whitney eqn. dC / dt= AD (Cs-C)/hV Where, dC = Dissolution rate dT A = surface area of dissolving solid D = diffusion coefficient H = diffusion layer thickness

C = solute concentration in the bulk medium V = volume of dissolution medium Cs = solute concentration in diffusion layer

GENERAL METHOD OF INCREASING THE SOLUBILITY

Addition of co-solvent E.g. Phenobarbitone (insoluble in water) add

glycerol, alcohol increased solubility

Addition of complexing agent Described as shown in the equation – n [D] +m [L] ↔[Dn: Lm ]s where:- [D]=conc. Of the drug in the solution [L] =Conc. Of ligand in the solution [Dn: Lm]=Conc. Of the drug ligand complexE .g= solubility of benzocaine in caffeine

Apparent Solubility of Hexaethylmelamine is increased much as 90 fold via complexation with the Gentisate ion

SURFACTANT• Surfactants are wetting agents that lower the surface • tension of a liquid, allowing easier spreading, and • lower the interfacial tension between two liquids Classification Some commonly encountered surfactants of each type include:

• Ionic – Anionic (based on sulfate, sulfonate or carboxylate anions)

• Sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, and other alkyl sulfate salts

• Sodium laureth sulfate, also known as sodium lauryl ether sulfate (SLES)

– Cationic (based on quaternary ammonium cations)

• Cetyl trimethylammonium bromide (CTAB) a.k.a. hexadecyl trimethyl ammonium bromide, and other alkyltrimethylammonium salts

• Cetylpyridinium chloride (CPC)

Zwitterionic (amphoteric) Dodecyl betaine Dodecyl dimethylamine oxide

Nonionic Alkyl poly(ethylene oxide) Copolymers of poly(ethylene oxide) and poly(propylene

oxide) (commercially called Poloxamers or Poloxamines)

HLB SCALE

Griffin an arbitrary scale of value to serve insure of hydrophilic lipophilic balance of surface active agent

The higher the HLB of the an agent, the more hydrophilic it is

The spans, sorbitan ester are lipophilic and have low HLB value (1.8-8.6)

Tweens, polyoxyethylene derivative of the spans are hydrophilic and have high HLB value (9.6-16.7)

HLB SCALE

Most antifoaming agents

W/O Emulsifying agents Wetting and Spreading

agents O/W Emulsifying agents Detergents and

Solubilizing agents

0

3

6

9

12

15

18

The HLB of non ionic surfactant whose only hydrophilic portion is polyoxyethylene is calculated using the formula

HLB = E/5 Where, E = Percentage weight of ethylene oxide

A number polyhydric alcohol fatty acid ester, such as glyceryl monostearate may be estimated by using the formula

HLB = 20( 1- S/A)Where, S = saponification number of ester

A = acid number of fatty acid

The HLB of polyoxyethylene sorbitan monolaurate (tween 20) for S = 45.5 and A = 276

HLB = 20( 1- 45.5/276) = 16.7

IMPORTANCE OF SURFACTANT

Surfactants play an important role in many practical applications and products, including:

Detergents Fabric softener Emulsifiers Paints Adhesives Inks Soil remediation Wetting

Ski Wax Snowboard Wax Foaming Defoaming Laxatives Agrochemical formulations

Herbicides Insecticides

Quantum dot coating Biocides (Sanitizers) Hair Conditioners (after shampoo) Spermicide (Nonoxynol 9)

PH

pH may be defined as negative logarithum of hydrogen ion concentration

PH SCALE

0 Acidic

7 Neutral

14 basic

APPLICATION OF PH

Enhancing the solubility Sodium salicylate ppt as salicylic acid

when acidified Increasing stability

Vitamins are stable only with in a narrow pH range

Improving purity Insulin ppt from aqueous solution

between pH 5.0 and 6.0

PH VALUES OF SOME PHARMACEUTICAL PREPARATIONS

Drug name Formulation pH

Actified syrup 5-7.2

Benadryl Elixir 7.0

Orange syrup syrup 2.5-3.0

Vitamin B-complex

Elixir 4.0-5.0

Optimizing biological activity Pepsin as maximum activity at pH 1.5

Comforting the body Storage of product

TEMPERATURE EFFECT

The heat of solution Hs represent the heat released or absorbed when a mole of solute is dissolved in larger quality of solvent. Most commonly solution process is endothermic i.e. Hs is +ve & thus increasing the temperature solution, thereby solubility.

for such solute such as lithium chloride & other hydrochloride salt that are ionised when dissolved, the process is exothermic or Hs is –ve.

Ln S = -Hs[1/t]+c/R where S= Molkar solubility at temp. T R= gas constant.

COSOLVENCY Introduction to Cosolvency Definition Techniques of Solubilization Solubilization by Cosolvents Some Practical Considerations Conclusion

Introduction to Solid Dispersion Definition Carriers for Solid Dispersion Methods of Preparation Chracterization of Solid Dispersion system Recent Development β-Cyclodextrin Drug Dispersion system Characteristics of β-Cyclodextrins Physicochemical properties Current Status Conclusion

INTRODUCTION TO COSOLVENCY

Solubilization of poorly Soluble drug can be by addition of some water miscible solvents in which the drug has appreciable solubility.

This Solubility may be due to….. Independent solubility of substance in

each solvent, Disruption of Hydrophobic interactions of

Water molecules at the Nonpolar solute-water interface.

DEFINITION

The Phenomenon of Increasing the solubility of

poorly soluble drug in combination with other solvent/solvents is known as ‘Cosolvency’.

Techniques of Solubilization

Formation of Soluble salts, Molecular complexes, Cyclodextrin inclusion complexes, Solubilization by Surfactants, Solubilization by Cosolvents.

POLARITIES OF SOME COMMON SOLVENT

Solubilization by Co-solvents :- Polarity scales are used for this purpose,

because there is no absolute measure for the Polarity.

Measures of Polarity… Dielectric constant(ε),Solubility

parameter(δ), & Surface tension(γ) HLB scale is used to measure γ. Macroscopic properties of solute & solvent

are used to measure ε,δ & γ.

POLARITIES OF SOME COMMON SOLVENT

-: Solubilization by Cosolvents :-

Polarity scales are used for this purpose, because there is no absolute measure for the Polarity.

Measures of Polarity… Dielectric

constant(ε),Solubility parameter(δ), & Surface tension(γ)

HLB scale is used to measure γ.

Macroscopic properties of solute & solvent are used to measure ε,δ & γ.

Sr. no. Name Surface Tension

(γ)

Solubility

Parameter

(δ)

Dielectric

Constant (ε)

1 Water 72.0 23.4 81.0

2 Glycerin 64.9 16.5 42.5

3 Ethylene glycol

48.8 14.6 37.7

4 Furfural 43.5 12.5 41.9

5 Propylene glycol

37.1 12.6 32.0

NON-POLAR SOLUTES

Log PCO/C < Log PCO/w

If both are in Proportion then Partition coefficient in one partitioning system is linearly related to the Partition coefficient in a similar system.

i.e. σ = S Log PCO/w + T

where, σ = solubilising power of the solvent, S & T are the constants for each solvent. PCO/w & PCO/C = Partition coefficient in Octanol-water &

Octanol- -cosolvent system

Yalkowsky et.al. shown that σ is proportional to Log PC for a variety of solute.

Hence σ is dependent upon the solute polarity as measured by Log PCO/w & on the cosolvent polarity as measured by S & T.

SEMI-POLAR SOLUTES Semi-polar drugs has poor aqueous solubility due to

strong crystalline interactions & due to high activity coefficients in water.

Paruta treated the solubility of semipolar drugs in mixed aqueous system based on dielectric constant & martin used regular solution theory.

In above approaches, the mixed solvent is treated as a linear combination of water & cosolvent & max. in solubility curve attained when the polarity of the drug…

PD=FCPC+FWPW

where, PD = polarity of Drug f = fraction P = polarity.

POLAR SOLUTES

These are more difficult to characterize than non-polar & semi-polar solutes, b’coz the most polar solutes can dissociate to some extent in aq. Solution.

But polar solutes are nearly always crystalline & high melting, they tend to be solubilise in water, b’coz of their high affinity for water more than self interactions of the crystalline lattice.

Addition of a less polar solvent to the water the affinity of the solvent to solutes & thus solubility.

SOME PRACTICAL CONSIDERATIONS

Cosolvents have become the use of solubilising the drugs for both IV & IM administration b’coz of irritating effects of most surfactants & low toxicity of cosolvents.

Frequently used cosolvents are… Propylene glycol, ethanol, glycerine, PEG.

CONCLUSION

The increase in degree of solubilization of drug is dependent upon Non-polarity of the drug & the Non-polarity of cosolvent.

SOLID DISPERSION

INTRODUCTION TO SOLID DISPERSION

Various techniques for solubilization of Drugs which has poor solubility in water…

Micronisation Dispersion Solvent Deposition Complexation. Solid Dispersion provides… Particle size reduction & Increased rates of Dissolution

DEFINITION

It is the Dispersion of one or more Active ingredients in an inert carrier or matrix at Solid state prepared by the Fusion or Melting solvent method.

CARRIERS FOR SOLID DISPERSION

Characteristics : a) Readily soluble in water, b) Stable at processing temp. c) Chemically & P’cologically inert.

Examples :

SUGARS :- Dextrose, Sorbitol etc. ACIDS :- Citric Acid, Tartaric

Acid etc. POLYMERIC MATERIALS :- PEG 4000, PEG 6000,

Sodium Alginate etc.

METHODS OF PREPARATION

Melting method

Solvent method

Melting & Solvent method.

MELTING METHOD:- (FUSION METHOD)

Physical mix. Of a Drug + Water soluble carrier, ∆ & cooled, solidify in ice bath, Melt was poured on the ferrite or stainless steel plate, cooled by flowing air or water on opposite side, solid mass is crushed – pulverized – sieved.

Adv. :- a) Simplicity & economy b) Supersaturation.

Disadv. :- Decomposition or Evaporation.

Remedial Measures :- a) Use of sealed container, b) Melting under vacuum or a blanket of inert gas like

Nitrogen

SOLVENT METHOD:-

Dissolve physical mixture of two solid components in a common solvent, Evaporation of solvent.

E.g.:- β-Carotenes – PVP, Griseofulvin – PVP etc.

Adv. :- Prevention of thermal decomposition

Disadv. :- a) Incomplete removal of solvent b) Adverse effect of solvent on

chemical stability of drug, c) Selection of common volatile

solvents & Possible polymorphic changes.

MELTING & SOLVENT METHOD:-

The drug is first Dissolve in solvent then the solution incorporated directly into the melt of the carrier.

Adv. :- It has both melting as well as solvent method.

Disadv.:- It is limited to drugs with low therapeutic dose.

VARIOUS SYSTEMS OF SOLID DISPERSION

Simple Eutectic mixtures Solid Solutions a) Continuous Solid solution b) Discontinuous Solid solution - Substitutional Solid solution - Interstitial Solid solution Glass solution & Glass Suspension Amorphous precipitation in a crystalline carrier Compound or complex formation betn drug &

carriers.

CHARACTERIZATION OF SOLID DISPERSION SYSTEM

Thin layer Chromatography

Spectroscopic Method

Solubility determination

Dissolution rate method

Microscopic Method

Thermal analysis Cooling curve Method Thaw melt Method Thermo-Microscopic Method Differential Thermal Analysis Zone Melting Method

X-ray diffraction Method

RECENT DEVELOPMENT

Because of Difficulty to scale up for the manufacture of solid dispersion by Pulverization, Sieving, Mixing with relatively large amt. of Excipients & encapsulation in to hard gelatin capsules or compressing in to Tablet,in recent yrs. Surface active, self emulsifying carriers & devp. of technologies which are used to encapsulate solid dispersion directly in to Hard gelatin capsule as melts are Developed.

E.g. a) Poloxamer 188 as a carrier for Ibuprofen,

b) Poloxamer 407 as a carrier for Nifedipine,

c) PEG, Myri 2, Eudragit E100 as a carrier for Indomethacin.

Β-CYCLODEXTRIN DRUG DISPERSION SYSTEM

Cyclodextrins are cyclic, non-reducing, water soluble oligosaccharides.

Cyclodextrin has beneficial effects on solubility, dissolution rate, chemical stability & absorption rate of a drug.

They are available in three forms… - α,β & γ Cyclodextrins consisting of six,

seven & eight D-glucopyranose units.

CHARACTERISTICS OF Β-CYCLODEXTRIN

Sr. no. Characteristics β-Cyclodextrin

01. No. of Glucose units 7

02. Molecular wt. 1135

03. Solubility in water (g/100ml) at RT

1.85

04. Optical rotation 162 + 0.5

05. Cavity diameter 6.0 + 6.5

07. Diameter of outer periphery (A0)

15.4 + 0.4

08. Approx. volume of cavity (A0)

262

PHYSICOCHEMICAL PROPERTIES

It has cylindrical shape with a central axial cavity. All secondary hydroxyl groups are located on one

side of the molecule, while all primary hydroxyl groups are on the other hand.

The lining of the internal cavity is formed by the oxygen-bridge atoms, which makes the cavity slightly aploar.

Marketed Solid formulations:- Piroxicam- β-CD tablets & suppositories. Benexate- β-CD Capsules. Omeprazole- β-CD Capsule.

CURRENT STATUS

It is not yet considered as standard inactive ingredients in p’ceuticals due to the uncertain regulatory acceptance of a formulation containing non-standard inactive ingredient.

25 CD based products are available currently in the Market.

CONCLUSION

Use of CD’s is a practical way to improve the physicochemical & p’ceutical properties of Drug molecules.

Play an Imp. Role in the development of formulations due to their effects on Solubility & absorption of Drug.

They are safe & non-toxic both orally & parenterally.

They enhances the solubility,Dissolution rate & bioavailability to improve chemical & physical stability

Reduces unpleasant side effects & bitter taste & to achieve sustained action.

REFERENCES The Theory and Practice of Industrial Pharmacy by

Leon Lachman and H.A.Lieberman, 3rd and 4th edition.

Text book of Physical Pharmacy by Alfred Martin, Varghese publication.

Text book of Pharmaceutical Dosage Forms by H.A.Lieberman and Leon Lachman.

Text book of Modern Pharmaceutics by Gilbert &Banker.

Text book of pharmaceutical practice by M .Aulton. Pharmaceutical dosage forms –parenteral

medications ,volume 1by Kenneth E. Avis ,Leon Lachmann,Herbert A Liebermann,Marcel Dekker inc, 270 Madison Avenue ,New York

Pharmaceutical dosage forms –parenteral medications ,volume 1by Kenneth E. Avis ,Leon Lachmann,Herbert A Liebermann,Marcel Dekker inc, 270 Madison Avenue ,New York

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