Pre Formulas i

Prof. Dr. Basavaraj K.

Prof. Dr. Basavaraj K. NanjwadeNanjwade M. Pharm., Ph.DM. Pharm., Ph.D

Department of Pharmaceutics

Department of Pharmaceutics

KLE University College of Pharmacy

KLE University College of Pharmacy

BELGUM!"#$$%$, Karnata&a, 'n(ia.

BELGUM!"#$$%$, Karnata&a, 'n(ia.

Cell )o.* $$#% #+-%$$$

Cell )o.* $$#% #+-%$$$

E!mail* n

CONTENTS

CONTENTS

33 'ntro(uction'ntro(uction

33 4rganoleptic properties4rganoleptic properties 33 PurityPurity

33 Particle si5e, shape an( surface areaParticle si5e, shape an( surface area

33 6olu1ilisation, 6urfactants an( its importance6olu1ilisation, 6urfactants an( its importance

33 7emperature, p8, co!solvency, soli( (ispersion, 9!7emperature, p8, co!solvency, soli( (ispersion, 9! cyclo(e:trin (rug!(ispersion system

cyclo(e:trin (rug!(ispersion system 33 Preformulation sta1ility stu(iesPreformulation sta1ility stu(ies

33  consi(eration of  consi(eration of physico!chemical characteristics ofphysico!chemical characteristics of ne0 (rug molecules 0ith respect to (ifferent (osage ne0 (rug molecules 0ith respect to (ifferent (osage

Preformulation

Preformulation

33 Preformulation is 1ranch of Pharmaceutical science thatPreformulation is 1ranch of Pharmaceutical science that utili5es 1iopharmaceutical principles in the (etermination utili5es 1iopharmaceutical principles in the (etermination of physicochemical properties of the (rug su1stance.

of physicochemical properties of the (rug su1stance.

33 Prior to the (evelopment of any (osage form ne0 (rug ,Prior to the (evelopment of any (osage form ne0 (rug , it is essential that certain fun(amental physical ; it is essential that certain fun(amental physical ; chemical properties of (rug po0(er are (etermine( .

chemical properties of (rug po0(er are (etermine( .

33 7his information may (ictate many of su1se<uent event7his information may (ictate many of su1se<uent event ; approaches in

; approaches in formulation (evelopment.formulation (evelopment.

INTRODUCTION

INTRODUCTION

DEFINITION

DEFINITION

:

:

!n"e#$iga$ion of phy#icochemical proper$ie#

!n"e#$iga$ion of phy#icochemical proper$ie#

of $he ne% &r'g compo'n& $ha$ co'l& affec$

of $he ne% &r'g compo'n& $ha$ co'l& affec$

&r'g performance an& &e"elopmen$ of an

&r'g performance an& &e"elopmen$ of an

efficacio'# &o#age form(.

efficacio'# &o#age form(.

Preform'la$ion commence# %hen a ne%ly

Preform'la$ion commence# %hen a ne%ly

#yn$he#i)e&

&r'g

#ho%#

a

#'fficien$

#yn$he#i)e&

&r'g

#ho%#

a

#'fficien$

pharmacologic promi#e in animal mo&el $o

pharmacologic promi#e in animal mo&el $o

%arran$ e"al'a$ion in man.

Introdution

3 7he preformulation is the first step in the rational (evelopment of a (osage form of a (rug su1stance alone an( 0hen com1ine( 0ith e:cipients.

3 41/ective *

7o generate useful information to the formulator to (esign an optimum (rug (elivery system.

3 Before em1ar&ing on a formal programme of  preformulation, scientist must consi(er the

follo0ing *

%. vaila1le physicochemical (ata =inclu(ing chemical structure, (ifferent salt availa1le>.

-. nticipate( (ose.

. 6upply situation an( (evelopment sche(ule. . vaila1ility of sta1ility ? in(icating assay.

!O"#S O$ PRE$OR%U#"TION

3 7o esta1lish the necessary physicochemical

 parameters of ne0 (rug su1stances.

3 7o (etermine &inetic rate profile.

3 7o esta1lish physical characteristics.

3 7o esta1lish compati1ility 0ith common

Preliminar& Evaluation

a> Compoun( i(entity.

 1> @ormula an( molecular 0eight. c> 6tructure.

(> 7herapeutic in(ications* ! Pro1a1le human (ose. ! Desire( (osage form=s> ! Bioavaila1ility mo(el ! Competitive pro(ucts

e> Potential ha5ar(s f> 'nitial 1ul& lots*

! Lot num1er 

! Crystalli5ation solvent=s> ! Particle si5e range

! Melting point ! A volatiles g> nalytical metho(s* ! 8PLC assay ! 7LC assay

Preliminar& Evaluation

OR!"NO#EPTIC PROPERTIES

CO#OR ODOUR T"STE

4@@!8'7E PU)GE)7 C'D'C

CEM!FELL4 6UL@U4U6 B'77E  

68')F @U'7F 6EE7

4M7'C 767ELE66

3 Color is generally a function of a (rugs inherent chemical structure relating to a certain level of unsaturation.

3 Color intensity relates to the e:tent of con/ugate( unsaturation as 0ell as the presence of chromophores. 3 6ome compoun( may appear to have color although

structurally saturate(.

3 7he su1stance may e:hi1it an inherent o(or characteristic of ma/or functional groups present.

3 4(or greatly affects the flavor of a preparation or foo( stuff.



_Taste'(

3 'f taste is consi(ere( as unpalata1le, consi(eration is to 1e given to the use of a less solu1le chemical form of the (rug.

3 7he o(our an( taste may 1e suppresse( 1y using appropriate flavors an( e:cipients or 1y coating the final pro(uct.

PURIT)

3 Designe( to estimate the levels of all &no0n ; significant impurities ; contaminates in the (rug su1stance un(er evaluation.

3 6tu(y performe( in an analytical research ; (evelopment group.

3 't is another parameter 0hich allo0s for comparison 0ith su1se<uent 1atches.

3 4ccasionally, an impurity can affect sta1ility. e.g.

! Metal contamination ! ppearance

3 7he techni<ues use( for characteri5ing the purity of a (rug are the same as those use( for other purpose in a  preformulation stu(y.

3 7hin layer chromatography is a 0i(e ranging applica1ility ; is an e:cellent tool for characteri5ing the purity.

3 8PLC, paper chromatography ; gas chromatography are also useful.

3 More <uantitative information can 1e o1taine( 1y using <uantitative (ifferential scanning colorimetry.

P"RTIC#E SI*E

3

_{Particle si5e is characteri5e( using these}

terms *

i. ery coarse =HI>

ii. Coarse =H-$>

iii. Mo(erately coarse =H$>

iv. @ine =HJ$>

3 Particle si5e can influence variety of

important factors *

! Dissolution rate

! 6uspen(a1ility

! Uniform (istri1ution

! Penetra1ility

! Lac& of grittiness

P"RTIC#E SI*E

%et+ods to Determine Partile Si,e

3 6ieving

3 Microscopy

3 6e(imentation rate metho(

3 Light energy (iffraction

-. Sievin met+od '

3

_{ange * "$ ? %"$ m}

3

_{6imple, ine:pensive}

3

_{'f po0(er is not (ry, the apertures get clogge(.}

/. %iroso0& '

3

_{ange * $.- ? %$$ m}

3

_{Particle si5e can 1e (etermine( 1y the use of}

cali1rate( gri( 1ac&groun(.

3

_{Most (irect metho(.}

3

_{6lo0 ; te(ious metho(.}

1. Sedimentation met+od '

3 _{ange * % ! -$$ m}

3 _{n(reasen pipette is use(.}

3 Particle si5e is calculate( 1y sto&es la0 *

&



here,

h  (istance of fall in time, t n_o  viscosity of the me(ium

1- ₀ h (ρ_s-ρ₀) gt

2. #i+t ener& diffration '

3 ange * $." ? "$$ m

3 Particle si5e is (etermine( 1y the re(uction in light reaching the sensor as the particle, (isperse( in a li<ui( or gas, passes through the sensing 5one.

3 _{Nuic& ; fast.}

3. #aser +olora0+& '

3 _{ange * %. ? %$$ m}

3  pulse( laser is fire( through an aerosoli5e( particle spray ; photographe( in three (imensional 0ith holographic camera, allo0ing the particles to 1e in(ivi(ually image( ; si5e(.

6. Cascade impaction :

3

_{7he principle that a particle (riven 1y an}

airstream 0ill hit a surface in its path,

 provi(e that its inertia is sufficient to

overcome the (rug force that ten(s to &eep in

it in airstream

PO4DER $#O4 PROPERTIES

 _{Po0(er flo0 properties can 1e affecte( 1y change in particle}

si5e, shape ; (ensity.

 7he flo0 properties (epen(s upon follo0ing! %. @orce of friction.

-. Cohesion 1et0een one particle to another.

 @ine particle posses poor flo0 1y filling voi( spaces

 1et0een larger particles causing pac&ing ; (ensification of  particles..

Determination Of Powder $low Pro0erties

 By (etermining "nle Of Re0ose.

  greater angle of repose in(icate poor flo0.

 't shoul( 1e less than $O. ; can 1e (etermine( 1y follo0ing e<uation.

tan   hr.

0here,   angle of repose. hheight of pile.

Angle O !epose ( In deg"ee)

T#pe O Flo$

25 Ecellen$

2530 oo&

 Measurement of free flo0ing po0(er 1y compressibility.

 lso &no0n as Carr's index.

CARR’S INDEX(% !("A##ED DENSI"$  #&RED DENSI"$  _X  )) "A##ED DENSI"$

 _{'t is simple, fast ; popular metho( of pre(icting po0(er}

flo0 characteristics.

Carr5s Inde6

T&0e of flow

"!%" E:cellent

%-!%J Goo(

%I!-% @air 7o Passa1le

-!" Poor  

!I ery Poor  

3 Particle shape 0ill influence the surface area, flo0 of  particles, pac&ing ; compaction properties of the  particles.

3  sphere has minimum surface area per unit volume. 3 7herefore, these properties can 1e compare( for

spheres ; asymmetric particles, in or(er to (eci(e the shape.

3 7he follo0ing e:pression can 1e o1taine(*

Property 6phere particle surface area R(_s- _S

s : ( p

3 7herefore, surface area  R(_s- _{ S} s : ( p -olume  =%J>R(_s _{ S} v : ( p 

3 6olving for S_s ; S_v 1y e<uating the appropriate properties  provi(es*

8s L R(s

- _{; S}

v L R(s 

3 hen particle shape is spherical, the (_s  ( _p 3 7hus, S_s   R  .%- ; S_v  RJ  $."- 3 7herefore, 6hape factor _L S_{s L} .%-  J Con$

&p

SUR$"CE "RE"

3 Particle si5e ; surface area are inversely

relate( to each other.

3 6maller the (rug particle, greater the surface

area.



S0eifi surfae

is (efine( as the surface area

 per unit 0eight =60> or unit volume =6v> of

 Estimation of Sv'

6v L 6urface area of the particles

olume of particles L n Ss ( -n S_v ( L Ss S_v (

3  ccor(ing to shape factor,  S_{s L}

 S_v

*

 Estimation of 6₀*

6_{0 L} 6urface area _L 6urface area

eight (ensity : volume

L 6v

M

L

J

%et+ods for determinin

 surfae area

-. "dsor0tion met+od '

8 Par$icle# %i$h a large #pecific #'rface are goo& a&#oren$# for $he a&#orp$ion of ga#e# 9 of #ol'$e# from #ol'$ion.

8 he "ol'me of ni$rogen ga#, 7_m, in cm3 _{$ha$ 1 g of $he}

po%&er can a&#or %hen $he monolayer i# comple$e i# more acc'ra$ely gi"en y '#ing $he ;E e<'a$ion, ho%e"er, %hich can e %ri$$en a#:

P _ 1 ₌ >1? . P 7>P @ P? 7  7  P

3 here,

  olume of gas in cm _{a(sor1e( per gram of po0(er} 

at pressure P.

P  Pressure of the a(sor1ate, in mm8g. P_o 6aturation vapor pressure =monolayer>

_m mount of vapor a(sor1e( per unit mass a(sor1ent, 0hen the surface is covere( 0ith monomolecular 

  layer 

 1  Constant that e:press the (ifference 1et0een the

Con$.

%et+ods for determinin

 surfae area

P

7> P₀ @ P?

7O4E=ER SI*E REDUCTION

IS NOT RE9UIRED IN $O##O4IN! C"SES

3 8E) DUG '6 U)67BLE.

3 DEGDE ') 64LU7'4) @4M.

3 P4DUCE U)DE6'BLE E@@EC76.

T

Solu:ili,ation is defined as t+e s0ontaneous

0assae of 0oorl& water solu:le solute

moleules into an a>ueous solution of a soa0

or deterent in w+i+ a t+ermod&namiall&

sta:le solution is formed ?.

 It is t+e 0roess :& w+i+ a00arent solu:ilit& of an ot+erwise s0arinl& solu:le su:stane is inreased :& t+e 0resene of surfatant mielles .

  MICELLES:

- T+e me+anism involves t+e 0ro0ert& of surfae ative aents to form olloidal areates @nown as mielles .

 4+en surfatants are added to t+e li>uid at low onentration t+e& tend to orient at t+e air(li>uid interfae .

 On furt+er addition of surfatant t+e interfae :eomes om0letel& ou0ied and e6ess moleules are fored into t+e :ul@ of li>uid.

 "t ver& +i+ onentration surfatant moleules in t+e :ul@ of li>uid :ein to form mielles and t+is

 Solu:ili,ation is t+ou+t to our :& virtue of t+e solute dissolvin in or :ein adsor:ed onto t+e mielle.

 T+us t+e a:ilit& of surfatant solution to dissolved or solu:ili,e water insolu:le materials starts at t+e C%C and inrease wit+ inrease in t+e onentration of mielles.

 Solu:ili,ation of an& material in an& solvent de0ends on 0ro0er seletion of solu:ilisin aents.

 T+e 0roess of solu:ili,ation involves t+e :rea@in of inter(ioni or intermoleular :onds in t+e soluteA t+e se0aration of t+e moleules of t+e solvent to 0rovide s0ae in t+e solvent for t+e soluteA interation :etween t+e solvent and t+e solute moleule or ion.

Ste0/' %oleules of t+e solid :rea@s awa& from t+e :ul@ 

Ste0 1' T+e free solid moleule is interraded into t+e +ole in t+e solvent



_{T+e amount of su:stane t+at 0asses}

into

solution

in

order

to

esta:lis+

e>uili:rium at onstant tem0erature and

0ressure to 0rodue a saturated solution.

 If solu:ilit& is -mml indiates need for salt formation to im0rove solu:ilit&.

  If solu:ilit& is -mml in 07 - to A 0reformulation stud& s+ould :e initiated.

  Solu:ilit& s+ould ideall& :e measured at two tem0eratures' 2FC and 1FC.

 2FC to ensure P+&sial sta:ilit&.

D

De

es

sc

c""iip

pttiio

on

n

&

&a

a""tts

s o

o

 s

so

oll'

'e

en

nt

t ""e

e



ii""e

ed

d

o" one pa"t o solte

o" one pa"t o solte

7ery

7ery #ol'le

#ol'le



 1

1

Areely

Areely #ol'le

#ol'le

1

1 

 10

10

Bol'le

Bol'le

10 

10

 30

30

Bparingly

Bparingly #ol'le

#ol'le

30

30 

 100

100

Bligh$ly

Bligh$ly #ol'le

#ol'le

100

100 

 1000

1000

7ery #ligh$ly

7ery #ligh$ly

1000  10,000

1000  10,000



 Preformulation solu:ilit& studies fous on druPreformulation solu:ilit& studies fous on dru solvent s&stem t+at ould our durin t+e deliver& of solvent s&stem t+at ould our durin t+e deliver& of dru andidate.

dru andidate.



 $or $or e.. e.. " " dru dru for for oral oral administration administration s+ould s+ould :e:e e6amined for solu:ilit& in media +avin isotoni e6amined for solu:ilit& in media +avin isotoni +loride ion onentration and aidi 07.



 "nal&ti met+od t+at are 0artiularl& useful"nal&ti met+od t+at are 0artiularl& useful for solu:ilit& measurement inlude 7P#CA U= for solu:ilit& measurement inlude 7P#CA U= s0etroso0&A $luoresene s0etroso0& and s0etroso0&A $luoresene s0etroso0& and !as +romatora0+&.

!as +romatora0+&.



 Reverse Reverse 0+ase 0+ase 7P#C 7P#C offer offer aurate aurate andand effiient mean of olletin solu:ilit& data of effiient mean of olletin solu:ilit& data of dru.





 _{Ionization constant (pKa)}

 _{Ionization constant (pKa)}

Can :e alulated :& 7enderson 7assel:a+ Can :e alulated :& 7enderson 7assel:a+ e>uation(

e>uation( $or

$or aidi aidi drusG.07 drusG.07 0KaH 0KaH lo lo ioni,ed ioni,ed druJdruJ unioni,ed

unioni,ed druJdruJ

$or :asi drusG.07 0KaH lounioni,ed druJ $or :asi drusG.07 0KaH lounioni,ed druJ

ioni,ed



 pH Soluilit! "#o$il%

 T+e solu:ilit& of aidi or :asi dru will s+ow differene in solu:ilit& wit+ +anes in 07.

 07 solu:ilit& 0rofile of a dru an :e esta:lis+ed :& runnin t+e e>uili:rium solu:ilit& e60eriment wit+in 07 rane of 1(2.



 "a#tition Co%$$ici%nt 

 It is t+e ratio of unioni,ed dru distri:uted :etween orani and a>ueous 0+ase at e>uili:rium.



 E$$%ct O$ T%&p%#atu#%

 T+e +eat of solution 7sA re0resents t+e +eat released or a:sor:ed w+en a mole of solute is dissolved in lare >uantit& of solvent.

 Endot+ermi reation

 Determination of solubility

 _{The following points should be considered}  _{The solvent & solute must be pure.}

 _{A saturated solution must be obtained before any}

solution is removed for analysis.

 _{The method of separating a sample of saturated}

solution from undissolved solute must be satisfactory.

 _{The method of analyzing solution must be reliable}  _{Temperature must be adequately controlled .}

Solubility Determination Method

 _{Solubility is normally depends on temperature}

so temperature is recorded in each solubility measurement.

 _{!lot of solubility against temperature is}

commonly used for solubility determination.

 Two methods are available for determination are as follow.

".Analytical method "".Synthetic method

Analytical method

 _{Temperature of equilibrium is fi#ed and}

concentration of the solute in the saturated solution is determined at equilibrium by a suitable analytical procedure.

 _{"n other words a saturated solution in the}

presence of an e#cess of the undissolved solute is prepared at an accurately $nown temperature. This situation can be achieved by suitable contact b%w solute and solvent.

 _{"n this method a weighed amount of solute is}

placed in the vessel.

 hile agitating the system at constant temperature $nown amount of solvent is added gradually until the solubility limit is reached.

 _{At equilibrium temperature and content of the}

system is recorded.

 _{This method is carried out at micro scale level by}

e#amining the small amount of the system under

 _{Addition of co'solvent}  p( change method

 _{)eduction of particle size}

 Temperature change method

 _(ydotrophy

 Addition of Surfactant

 _{Dielectrical *onstant}  *omple#ation

+eneral Method of "ncreasing

the Solubility





 _{These are poorly soluble in given solvent.}

  /or such poorly soluble materials to enhance their solubility the water miscible solvents are used in which the drug has good solubility.

 _{This process of improving solubility is $nown as}

co'solvency and the solvent used is $nown as co'

e.g. !henobarbitone is insoluble in water. A clear solution is obtained by dissolving in mi#ture of Alcohol +lycerin !ropylene glycol.

e.g. Of

Cosolvents:-!+ glycerin sorbitol !,+ +lyceryl formal glycofurol ethyl carbamate ethyl lactate and dimethyl acetamide.

p( change Method

 ea$ base-' Al$aloids 1ocal Anaesthesia

 _{ea$ acid-' Sulphonamides 2arbiturates}

  _{"n aqueous medium they dissociate poorly and}

undissociated portion is insoluble. e.g. 2enzoic acid !henobarbitone

  _{So solubility of the undissociated portion is}

improved by p( control.

/or wea$ acidic drug-' increase p( solubility is increase.

  _{)eduction in !article size improve solubility of}

drug.

 2asically reduction in particle size increase contact surface area of the particle there by ultimately it increase rate of solubility of drug.

 _{"n endothermic reaction by increasing}

temperature solubility is increase.

 _{"n e#othermic reaction by increasing temperature}

solubility is decrease.

e.g. Methyl *ellulose when mi#ed with water and temperature is raised it becomes insoluble. To

The term (ydotrophy has been used to designate the increase in solubility in water of various substances

due to the presences of large amount of additives. e.g.  Solubilization of 2enzoic acid with Sodium benzoate.

  _{Surfactants are molecules with well defined polar}

and non'polar region that allow them to aggregate in solution to form micelles. on polar drugs can partition into micelles and be solubilized.

e.g.  Surfactant based solution of Ta#ol that is solubilized in 345 solution of *remophor.

_{Dielectrical *onstant is the effect that substances}

has when it acts as a solvent on the case with which it separates oppositely charged atoms.

e.g. D,* of ater' 64 7erosene' 8 +lycerine' 96 2enzene' 8.8

*omple#ation

*omple#ation



 _{/or the *omple#ation occur both drug and ligand /or the *omple#ation occur both drug and ligand}

molecule should be able to donate or accept molecule should be able to donate or accept electrons.

electrons.



 _{The solubility of compound is the sum of solubility The solubility of compound is the sum of solubility}

of the compound and its comple#. of the compound and its comple#. e.g.

e.g. (g"(g"88 :Mercuric "odide; is sparingly soluble in:Mercuric "odide; is sparingly soluble in

water. "ts solubility in water is increased by forming water. "ts solubility in water is increased by forming comple# with 7".

Applications of solubilization

Applications of solubilization



 _{Drugs with limited aqueous solubility can beDrugs with limited aqueous solubility can be}

solubilized. These include oil'soluble vitamins solubilized. These include oil'soluble vitamins steroid hormones and antimicrobial agents etc.

steroid hormones and antimicrobial agents etc.



 _{Solubilization of orally administered drugs resultsSolubilization of orally administered drugs results}

in an improved appearance and improves in an improved appearance and improves unpleasant taste.

unpleasant taste.



 2oth oil'soluble and water'soluble compounds can2oth oil'soluble and water'soluble compounds can be combined in a single phase system as in case of be combined in a single phase system as in case of multivitamin preparations.



 Solubilization may lead to enhanced absorptionSolubilization may lead to enhanced absorption and increased biological activity.

and increased biological activity.



 _{"mproves "mproves the the intestinal intestinal absorption absorption of vitamin of vitamin A.A.} 

 _{Drug Drug absorption absorption from from ointment ointment bases bases andand}

suppositories also increased. suppositories also increased.



 1iquid 1iquid preparations preparations with with small small quantity quantity ofof

Applications of solubilization



 Aqueous concentrates of volatile oils can beAqueous concentrates of volatile oils can be prepared by solubilization.

prepared by solubilization.

 _{,#ample- ,#ample- soaps soaps used used for for solubilising solubilising phenolicphenolic}

compounds for use as disinfectants' 1ysol compounds for use as disinfectants' 1ysol )o#enol etc

)o#enol etc

..



 _{2arbiturates anticoagulant al$loidal drugs are2arbiturates anticoagulant al$loidal drugs are}

dissolved with polysorbate by

dissolved with polysorbate by solubilization.solubilization.

Applications of solubilization

S=)/A*TAT



 Surfactants:-are wetting agents that lower the surface tension of a liquid allowing easier spreading and lower the interfacial tension between two liquids.



_{*lassification}

Some commonly encountered surfactants of each type

include->. "onic 8. on ionic

*ationic

 IONIC 



 _Cationic

Surfactants:- @uaternary ammonium salts are more preferred because they are less affected by p(.

e.g. *etyl Trimethyl Ammonium 2romide :*TA2; (e#adecyl Trimethyl Ammonium 2romide and other Al$yltrimethyl Ammonium Salts *etylpyridinium *hloride :cpc;



 _Anionic

Surfactants:- They are the most commonly used surfactants containing *arbo#ylate Sulfonate Sulfate ions.

e.g. Sodium Dodecyl Sulphate

(SDS),



 Zwitterionic:- _{hen a single surfactant molecule e#hibit both}

anionic and cationic dissociations it is called amphoteric or ?witterionic.

The anion include carbo#ylates and phosphate group and the cation include quaternary ammonium group.

e.g. Dodecly 2etamine

Dodecly Dimethylamine 0#ide

 NONIONIC 

  _{These are most widely used because they are}

free from non compatability stability and potential to#icity and classified as water soluble and water insoluble non ionic surfactants.

e.g. 1ong chain fatty acids fatty alcohols

  _{ater solubility of these agents is further}

increased by addition of polyo#yethylene groups through ether lin$age with one of the alcohol group.

 HLB SCALE 

 Griffin in 1947 developed the system of the hydrophilic-lipophilic balance [ HLB ] of srfactant.

 _{!he hi"her the HLB of the an a"ent# the more}

hydrophilic it is.

 _{!$een# polyo%yethylene derivative of the spans are}

hydrophilic and have hi"h HLB vale &9.'-1'.7(

 _{!he lo$er the HLB of the a"ent# the more lipophilic it}

is.

 _{!he sorbitan ester are lipophilic and have lo$ HLB}

 HLB SCALE 

Most antifoaming agents

W/O Emulsifying agents

Wetting and Spreading agents

O/W Emulsifying agents

0  ! " #$ #%

* !he HLB of non ionic srfactant $hose only hydrophilic portion is polyo%yethylene is calclated sin" the formla

* HLB + ,

/here# , + 0ercenta"e $ei"ht of ethylene o%ide

 Imortance Of Surfactant 

 Surfactants play an important role in many

practical applications and products including-* Detergents * /abric Softener * ,mulsifier * !aints * Adhesive * "n$s





















Temperature, pH, Cosolvancy, Solid

dispersion

,ffect of Temperature

* !he solbility of a solte in a solvent is dependent on temperatre# natre of solte and natre of solvent.

* Heat of soltion represents the heat released or absorbed $hen a mole of solte is dissolved in a lar"e antity of solvent.

* 2ost of the sbstances are endothermic# absorbin" heat in the process of dissoltion.

* 3or this sbstances# an increase in temperatre reslts in an increase in solbility.

* ,%othermic sbstances "ive off heat in the process of dissoltion. !he solbility of sch sbstances $old decrease $ith increase in temperatre.

* are shold be ta5en as heat may destroy a dr" or case other chan"es in the soltion.

* ependin" on the type of reactions $eather it is e%othermic or endothermic heat is either released or absorbed.

e.". 2i%tre of chloroform and acetone. !he heat  prodced by the solte-solvent interaction is so mch "reater than the heat necessary to separate the molecles of acetone and chloroform# $hich can be detected as a rise in temperatre of the liid.

* 8pplications

* 0harmacetical soltions mst be administered

at or near room

temperatre. :o# it is more

important factor for prodct stora"e than the

formlation.

* !o increase the solbility of

sparin"ly

solble solte.

* !o increase the stability by redcin" the

,ffect of p(

* /ea5 electrolytes nder"o ioni;ation and are more solble $hen in ioni;ed form. !he de"ree of ioni;ation depends on dissociation constant &p<a( and the pH of the medim.

* :olbility is a fnction of pH# that is related to its p<a $hich "ives ratio of ioni;ed and nioni;ed forms of the sbstance.

!his can be sho$n as

pH = pKa + log [ A- ]

* =f the sbstance is bro"ht otside its p<a# i.e. the pH vale $here half the sbstance is ioni;ed and half is not# than solbility $ill be chan"ed becase $e are introdcin" ne$ intermoleclar forces# mainly ionic attraction.

* e.". >66H has p<a vale at pH arond 4. =f pH is increased then >66H is converted into >66

-. !his may interact $ith the H?

 of $ater.

* !he effect of pH on solbility for $ea5 electrolytes can be described by

pHp = pKa + log S –S0

S0

*   /here#

pHp + pH belo$ $hich the dr" precipitates from soltion as the ndissociated acid.

: + total solbility.

:@ + molar solbility of the ndissociated acid.

* =t is to be ensred that pH chan"e for one

sin"le compond shold not affect the other

reirements of prodct.

* e.". the chemical stability of dr" may depend

on pH# and this pH of optimm stability

shold not coincide $ith the pH of other

in"redients specially colors# preservatives and

flavors.

*osolvancy

* !o enhance the solbility of poorly solble

materials# the $ater miscible solvents are sed in

$hich the dr" has "ood solbility. !his process

of improvin" solbility is 5no$n as co-solvency.

* :olvents sed to increase the solbility are

* !he mechanism for solbility enhancement by

co-solvency is not clearly nderstood. Bt it is

 proposed that# solbility is increased may be

 by redcin" the interfacial tension bet$een the

solvent

and

hydrophobic

soltes

and

decreasin" dielectric constant of solvent.

* !he commonly sed and acceptable co-solvents in formlation of aeos liids for oral soltions are ,thanol# :orbitol# Glycerin# :everal members of 0,G series.

* 3or parenteral prodcts# imethylacetamide is $idely sed. Bt in case of oral liids its application is limited# becase of its obAectionable odor and taste.

* :ome characteristics of co-solvent# $hich are sed in  preparation

1. =t mst be non-to%ic. on-irritatin".

  C. =t shold be able to solbili;e the dr" in "iven solvent.

 D. =t shold be able to cross the membrane.

* 8part from increasin" solbility# they are also sed to improve the solbility of volatile constitents sed to

Solid B Dispersion System

• Definition 

:olid dispersion is defined as dispersion of one or more active in"redients in an inert carrier or matri% at solid state prepared by the meltin"# solvent or meltin" solvent method.

*lassification

:2ased on /ast )elease Mechanism;

* :imple ,tectic 2i%tres * _{:olid :oltions}

* _{Glass :oltions and Glass :spensions}

* _{8morphos precipitation of dr" in crystalline} carrier 

* _{omponds or omple% formation bet$een dr"} and carrier 

A. ,utectic Mi#tures

* /hen t$o or more sbstances are mi%ed

to"ether they liefy de to the lo$erin" of

meltin" point than their individal meltin"

 point. :ch sbstances are called as etectic

sbstances.

* :imple binary phase dia"ram sho$in" etectic  point ,.

* !he etectic composition at  point , of sbstance 8 and B represents the meltin"  point.

* !8 and !B are meltin" point

of pre 8 and pre B.

* !he follo$in" factors may contribte to faster dissoltion rate of dr" dispersed in the etectic

mi%tres-1. =ncrease in dr" solbility.

C. :olbili;ation effect by the carrier $hich completely dissolves in a short time in diffsion layer srrondin" dr" particles.

D. 8bsence of a""re"ation and a""lomeration  bet$een fine crystallites of pre hydrophobic

dr".

 4.

,%cellent $ettability and

dispersibility

of a dr" as the

encirclin" solble carrier

readily dissolves and cases $ater to

contact as $et dr" particles.

. rystalli;ation of dr" in a metastable

form after solidification from fsed soltion#

$hich has hi"h

solbility.

* ,tectics are easy to prepare and economical

$ith no solvents involved. !he method

ho$ever cannot be applied to

- r"s $hich fail to crystalli;e from

mi%ed melt.

- !hermolabile dr"s.

- arriers sch as sccinic acid that

decompose at meltin" point.

2. Solid Solutions

* =t is made p of a solid solte dissolved in a solid solvent. =t is often called a Emi%ed crystalF becase the t$o components crystalli;e to"ether in a homo"enos phase system.

* =t is prepared by fsion method.

* 8 solid soltion of poorly solble dr" in a rapidly solble carrier achieves a faster dissoltion becase

*

_{8ccordin" to e%tent of miscibility }

1. ontinos

&iso-morphos#

nlimited#

complete( solid soltion.

C. iscontinos

&limited#

restricted#

incomplete( solid soltion.

*

_{8ccordin" to crystalline strctre of solid}

soltions 

1. :bstittional solid soltions.

C. =nterstitial solid soltions.

a( ontinos :olid :oltions

- _{!he t$o components are miscible or solble at}

solid state in all proportions.

  _{o established soltions of this 5ind has been}

sho$n to e%hibit fast release dissoltion properties.

 _{!he faster dissoltion rate $old be obtained if the}

dr" is present as a minor compartment.

 b( iscontinos :olid :oltions

*. +lass Solutions and +lass

Suspensions

* 8 "lass soltion is a homo"enos# "lassy system in $hich a solte is sally obtained by abrpt enchin" of the melt.

* 2any componds have been sho$n to be able to form "lasses readily pon coolin" from liid state. * !hese componds inclde scrose# "lcose# ethanol

• It is presumably due to their strong hydrogen bonding which may prevent their crystallization.

• Polymers possessing linear, flexible chains can freeze into a glass state to transparency and brittleness.

• The strength of chemical binding in a glass solution is much less compared to that in a solid solution.

• Hence, dissolution rate of drugs in the glass solution is faster than in solid solution.

• e.g. lass solution of citric acid

C. Glass Solutions and Glass

Suspensions

D. Amorphous Precipitation

of Drug in Crystalline Carrier

• Instead of forming a simple eutectic mixture in which  both drug and the carrier crystallize simultaneously from a solvent method of preparation, the drug may also precipitate out in an amorphous form in crystalline carrier.

• It has faster dissolution and absorption rates than crystalline form.

• e.g. !morphous novobicin has "# fold higher solubility than its crystalline form.

• $issolution and absorption of a drug can occur from a complex or a compound formed between the drug and an inert soluble carrier.

• %omplexation also implies that dissolution could be retarded as observed with P& '### ( phenobarbital. • However, the formation of a soluble complex with a

low association constant results in increased rates of

E. Compound or Complex

Formations

). %ombinations and

*iscellaneous *echanisms

• ! solid dispersion entirely belongs to any five groups discussed so far, but it can also be made up of combinations of different groups.

• These combinations increase the dissolution and absorption rate.

• The griseofulvin dispersed at high concentrations in P& may exist as individual molecules and as micro( crystalline particles.

Methods of Preparations

• *elting *ethod

• +olvent *ethod

• *elting ( +olvent *ethod

1. Melting Method or

Fusion Method

• The physical mixture of a drug and water soluble carrier is heated until it melts.

• The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring .

• The final solid mass is crushed, pulverized and sieved.

• To facilitate faster solidification, the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate.

• !dvantages

-• +implicity of method.

• +upersaturation of a solute or a drug in a system can often be obtained by uenching the melt rapidly from high temperature.

• $isadvantage

-• +ome drugs or carriers may decompose or evaporate during fusion process at high temperatures .

e.g. succinic acid used as a carrier for griseofulvin is

1. Melting Method or Fusion Method

. Sol!ent Method

• They are prepared by dissolving a physical

mixture of two solid components in a common

solvent, followed by evaporation of the

solvent.

• The method is used to prepare solid

dispersions

of

griseofulvin(

• !dvantage

-( Thermal decomposition of drugs or carriers can be  prevented because of low temperature reuired for

the evaporation of organic solvents. • $isadvantages

-( High cost of preparation.

( $ifficulty in completely removing the solvent.

". Melting Sol!ent Method

• _{It is prepared by first dissolving the drug in a} suitable solvent and then incorporating this solution in a melt of P& without removing the solvent.

• _!dvantages

-+ame as above two methods • _$isadvantage

-)rom practical stand point, it is only limited to drugs with a low therapeutic dose, e.g. below #mg.

#. $ot Melt Extrusion Method

• In this method, a blend of active ingredients,  polymeric carrier and other processing aids li/e  plasticizers and antioxidants is heated and softened. • This softened material is called as extrudate.

• 0hen the extrudate is cooled at room temperature, the polymeric thermal binder solidifies and bonds the

• !dvantages

-( There are no concerns with solvent handling or  recovery after processing

( It is simple and continuous process for  preparation of tablets and granulations.

( The process is faster and there were fewer steps than the wet granulation method.

( %an be used for formulating sustained release granules.

e.g. $iltiazem granules.

Methods of Determination

of Solid Dispersion Systems

• Thermal analysis

a1 %ooling curve method

 b1 Thaw(melt method

c1 Thermoscopic method

d1 $ifferential thermal analysis 2$T!1

e1 3one *elting *ethod

• 4(5ay diffraction *ethod

• *icroscopic method

• +pectroscopic method

• Thin layer chromatography

• +olubility determinations

Methods of Determination

of Solid Dispersion Systems

A. %hermal Analysis

• It is used to study the physico(chemical

interactions of two or more components.

• Principle - %hange in thermal energy as a

function of temperature.

a& Cooling cur!e method

 -  ( The physical mixtures of various

compositions are heated until a

homogenous melt is obtained.

b)

%ha'(melt method )

( Here a sample of solidified mixture in a

capillary melting point tube is heated

gradually till the thaw point.

( The thaw point is referred to as crossing

solidus line.

( It is useful in differentiating between a

simple eutectic system and a limited

solution.

c

& %hermoscopic method )

( Polarized microscopy is used with hot

stage to study phase diagrams of

binary

systems.

( The physical mixture is gradually

heated on a slide until it completely liuefies.

( !fter cooling, the mixture is heated at rate

of ' degree per minute.

( The thaw and melting points are

d)

*D%A& -(

!n effective thermal method for

studying

 phase euilibria of either

pure compound or

mixture.

( $ifferent effects, associated with

physical

or chemical changes are

automatically

recorded as function of

time or temperature as

the substance is heated in uniform rate.

( In addition6 evaporation, sublimation,

 polymorphic transition, desolvation

can be

detected.

e& +one Melting Method

 -( It is primarily used for ultra

 purification of metal and inorganic and

organic metal.

,. -(ay Diffraction Method

• In this method the intensity of x(ray diffraction or

reflection from a sample is measured as a function of diffraction angles.

• %ounter and film methods detect diffraction intensity. • %ounter method provides better resolution of

diffraction and relative intensity which can be easily compared.

• This method is used to characterize physico(chemical  properties of riseofulvin dispersed in P& '### and

C. Microscopic Method

• It has been used to study polymorphism and

morphology of solid dispersion.

• The fine particles of crystallization in glass

P8P can be easily detected by polarizing

microscope.

• The resolution of electron microscope was

used to study dispersed particle size of iopanic

acid in P8P.

D. Spectroscopic Method

• In the 98 study, the spectra of pure drug and

the dispersed drug are scanned.

• e.g. The spectrum of the dispersed beta : 

carotene resembles that beta:carotene is

dissolved in organic solvents but do not

indicate the molecular dispersion of drug in

 polymer.

E. %hin /ayer Chromatography

• T;% characteristics of pure and dispersed

drugs are studied to test whether the drugs are

decomposed by process.

• ! single spot with same <5 

 =value is expected

for both the pure and processed samples in thin

layer plate.

F. Solu0ility determinations

• 5esults from aueous solubility studies of drug

in various concentrations of carrier would

indicate interactions between drug and carrier.

• +uch studies indicated wea/ or insignificant

interactions between griseofulvin and P&

7###.

• Increased rate of dissolution due to solubility

of the drug by carrier can be predicted by this

method.

Pharmaceutical Applications

• To obtain a homogenous distribution of small

amount of drugs at solid state.

• To stabilize unstable drugs.

• To dispense liuid or gaseous compounds.

• To formulate a faster release priming dose in a

sustained release dosage form.

• To formulate sustained release dosage or

 prolonged release regimens of soluble drugs

(cyclodextrin drug dispersion system2

techni3ues for studies of crystals2

(cyclodextrin drug dispersion system

• The poorly dissolution of relatively insoluble drug

has for long been a problem in the formulation of

oral dosage form.

• This limits the aspect such as



_{!bsorption >}

  _{?ioavailability}

• +everal approach have been followed in improving the solubility of drug, one of them being complexation using cyclodextrin.

• %yclodextrin is cyclic structure oligomers of glucose which are obtained from the starch digests of the  bacteria ?acillus macerans.

• The most abundant cyclodextrins available are a(cyclodextrin ( 7 glucose units

b(cyclodextrin ( @ glucose units g(cyclodextrin ( A glucose units

Chemistry of 0(cyclodextrin

• %yclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone.

• The interior cavity is hydrophobic and the outside of the molecule is hydrophilic.

Characteristics of (cyclodextrin

• *olecular wt. : ""B

• +olubility : ".AgC"##ml • %avity diameter : 7.' !o

• $iameter of outer periphery : ".' !o

#e$ho% of prepara$ion of

β

&cyclo%e'$rin

comple'

• Physical mixture method

• Eneading method

• %o(evaporation method

• +olid dispersion method

• +pray drying method

Physical mixture method

• Here the drug and b(cyclodextrin 2"-D1 are mixed  physically with spatula > then the pulverized powder

is passed through "##G. • &g. $iclofinac sodium

4neading method

• Here the

water(methanol solution27-'1.

• To the above solution reuired drug is added in small amount.

• The slurry is then /neaded for ' min. > dried at 'oc.

• The dried mass is pulverized and sieved through "##G.

Co(e!aporation method

• In this method, a. solution of b(cyclodextrin is added to an alcoholic solution of drug.

• The resulting mix. is stirred for " hr. > evaporated at 'oc until it is dried.

• The dried mass is pulverized and sieved through "##G.

Solid dispersion method

• Here the drug > molar ty. of b(cyclodextrin is dissolved in methanol.

• The solution is then evaporated in vacuum at '#oc with rotatory evaporator.

• The powder is stored under vacuum in dessicator for B days > analysed.

+pray drying method

• In this, the drug > double molar of (cyclodextrin are dissolved in methanol.

• The solution was then spray dried under foll. conditions :

)eed rate : "# mlCmin Inlet temp. ( Joc

utlet temp. ( 7oc Press. :  bar 

• The powder is then collected > stored under vacuum in dessicator for B days > analysed.

• &g. Faproxene

5eutrali6ation method

• Here the drug > b(cyclodextrin are dissolved in #."F H%l > then #."F FaH is added to precipitate the complex at pH(@..

• The ppt. is washed with distilled water.

• Then it is pulverized > sieved through J#G and stored in dessicator over fused %a%lD.

Applications

• To increase a. solubility

• To increase dissolution rate of drug • To improve bioavailability of drug

• To increase chemicalCphysical stability • To decrease drug irritation

Crystallinity

• %rystal habit > internal structure of drug can affect  bul/ > physicochemical property of molecule.

• %rystal habit is description of outer appearance of crystal.

• Internal structure is molecular arrangement within the solid.

• %hange with internal structure usually alters crystal habit.

&g. %onversion of sodium salt to its free acid form  produce both change in internal structure > crystal

habit.

Different shapes of crystals

• Cu0ic or isometric ( not always cube shaped. !lso find as octahedrons 2eight faces1 and dodecahedrons 2"# faces1.

• %etragonal( similar to cubic crystals, but longer along one axis than the other, forming double  pyramids and prisms. • 7rthorhom0ic ( li/e

tetragonal crystals except not suare in cross section 2when viewing the crystal on end1, forming rhombic

• $exagonal ( six(sided  prisms. 0hen you loo/ at

the crystal on(end, the cross section is a hexagon.

• %rigonal ( possess a single B(fold axis of rotation

instead of the 7(fold axis of the hexagonal division.

• _{%riclinic ( usually not}

symmetrical from one side to the other, which can lead to some fairly strange

shapes.

• $epending on internal structure compounds is classified as

". %rystalline D. !morphous

• %rystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three dimensional array.

• In amorphous form atom or molecule are randomly  placed.

• +olubility > dissolution rate are greater for amorphous form then crystalline, as amorphous form has higher thermodynamic energy.

&g. !morphous form of Fovobiocin is well absorbed whereas crystalline form results in poor absorption.

Polymorphism

• It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice.

• $ifferent crystalline forms are called polymorphs. • Polymorphs are of D types

". &natiotropic D. *onotropic

• The polymorph which can be changed from one form into another by varying temp. or pressure is called as &nantiotropic polymorph.

&g. +ulfur.

• ne polymorph which is unstable at all temp. >  pressure is called as *onotropic polymorph.

&g. lyceryl stearate.

• Polymorph differ from each other with respect to their physical property such as

  +olubility *elting point   $ensity   Hardness %ompression characteristic

Polymorphism

•• $uring preformulation it is important to identify the$uring preformulation it is important to identify the  polymorph that is stable a

 polymorph that is stable at room temp.t room temp. &g.

&g. "1%hloromphenicol "1%hloromphenicol exist exist in in !,? !,? > > % % forms,forms, of these ? form is more stable > most

of these ? form is more stable > most   preferable.

  preferable. D15iboflavin

D15iboflavin has has I,II I,II > > III III forms, forms, the the III III formform shows

shows D# D# times times more more water water solubility solubility thanthan form

form I.I.

Polymorphism

%echni3ue

%echni3ue

s

s

for

for

studies

studies

of

of

crystals

crystals

•• *icroscopy

*icroscopy

•• Hot stage microscopy

Hot stage microscopy

•• Thermal analysis

Thermal analysis

Microscopy

Microscopy

•• Material with more than one refractive index areMaterial with more than one refractive index are anisotropic & appear bright with brilliant colors anisotropic & appear bright with brilliant colors against black polarized background.

against black polarized background.

•• The color intensity depends upon crystal thickness.The color intensity depends upon crystal thickness.

•• Isotropic material have single refractive index andIsotropic material have single refractive index and this substance do not transmit light with crossed this substance do not transmit light with crossed  polarizing filter and ap

Microscopy

Microscopy

•• dvantage !dvantage ! "y

"y this this method# method# we we can can study study crystal crystal morphology morphology && difference between polymorphic form.

difference between polymorphic form. •• $isadvantage !$isadvantage !

This

This re%uire re%uire a a well well trained trained optical optical crystallographer# crystallographer# asas there are many possible crystal habit & their there are many possible crystal habit & their appearance at different orientation.

Hot stage microscopy

Hot stage microscopy

•• The polarizing microscope fitted with hot stage isThe polarizing microscope fitted with hot stage is useful for investigating polymorphism# melting point useful for investigating polymorphism# melting point & transition temp.

& transition temp. •• $isadvantage !$isadvantage !

In

In this this techni%ue# techni%ue# the the molecules molecules can can degrade degrade duringduring the melting process.

Hot stage microscopy

Hot stage microscopy

•• e!"l#! of ho# !#age

e!"l#! of ho# !#age

micro!copy

micro!copy

•• $

$iia

ag

grra

am

mm

ma

a##iic

c

repre!en#a#ion

repre!en#a#ion