module 2 ( L.10-15 )

liquid dosage form ( limitation )

• bulkiness

• leakage from container

• physical & chemical stability < solid dosage form

• shelf-life ( require special storage )

• difficult to administer

what is solution

chemically & physically homogenous mixture of more substance

solution = solute + solvent

exam pf solution

• two or more gases

• solid in liquid

• liquid in solid

factor to consider when formulation liquid dosage

• route of administration

• disease state

• intended patient pop ( age/type )

• physicochemical property of drug

what is solubility

• max conc.. or amount of substance ( solute ) that may be completely dissolve in given amount of solvent ( at given temp and pressure )

( solid in liquid )

solubility of liquid in liquid

miscibility = solubility of liquid in another liquid

why solubility important ( when formulation drug into liquid form )

formulation

• influence design , chose of excipient , dosage type , manufacturing process

stability

• influence its chemical stability

• poorly soluble drug = precipitate or degrade

why solubility important ( when administration into body )

bioavailability

• drug must dissolve for absorption & to exert therapeutic effects

• affects rate of dissolution & extent of absorption into blood stream

• poor solubility = slow or incomplete drug release . DE absorption , DE bioavailability

dosing

• affect dose require to achieve desired therapeutic effect

  • poor solubility = inaccurate dosing

type of solubility

intrinsic ( S_o )

• solubility of PURE , in-ionise drug in give temp

• not incl salt , ionisation and co-solvent

• serve as baseline

apparent ( S )

• solubility of drug consider all form in solution

  • reflect real-world solubility

factor that affect solubility

• temp.

• pressure

→ significant effect on solubility of gas

→ IN solubility of gas in liquid

• nature of solute

• nature of solvent

how do we express solubility

• solubility is quantitative ( associate w/n. and unit )

ex. percentage , molarity , parts

• BCS classification

USO definition = n. of mL of solvent in which 1g of solute will dissolve at specified temp

degree of saturation

amount ofd solute dissolves in solvent relative to max amount that can be dissolve ( specified temp and pressure )

solubility curve

graphical representation = how solubility change of substance against any relevant variable ( ex. w/ temp , pH , solvent )

• for solid , solubility IN w/IN temp. ( curve moves upward w/IN temp )

"study saturated or unsaturated, useful predicting dug behaviour”

dissolution & salvation & hydration ( definition )

dissolution = process by which substance goes into solution

salvation = attraction and association of molecule of solvent w/molecule or ions of solute

hydration = when water is used as solvent

solubility VS dissolution rate

solubility = max amount of solute that will dissolve in give solvent

• thermodynamic property → tell how much drug can dissolve , nut nit how fast it dissolve

dissolution rate = speed at which dissolution occur

• kinetic property → tell how fast drug goes into solution

type of dissolution process

1. break of solute-solute bonds

2. breaking of solvent-solvent bond

3. salvation ( interaction b/e solute & solvent )

factor affect dissolution rate

• temp

→ IN , IN dissolution rate of most solid ( solution absorbs E )

• agitation/stirring /mixing

→ move dissolve solute away from surface of solid , IN dissolute rate

• particle size reduction ( IN SA to volume )→ IN dissolution rate ( more solute is exposed to solvent )

predicting solubility during pre-formulation

goal → optimal formulation design

challenge → poor solubility is major cuz of drug development failure

pole of pre-formation studies

→ access drug solubility early

→ identify potential formulation challenges

→ Guide section of formulation strategies

outcome

→ DE development time & cost

→ improve & regulatory sucess

solubility of solute in given solvent

for solute to dissolve in solvent , bond b/w solute must be broken and new bond must formed b/w solute & solvent

• compound dissolves due to intermolecular force b.w solvent & solute

like dissolve like

used to predict solubility of solute in solvent

predicting solubility

solubility→ governed by strength of intermolecular interaction b/w solute & solvent

solute must interact with solvent

nature of solvent ( factor affect )

• polarity

• H-bond

• pH ( if solute is weak electrolytes

solvent polarity

• dielectric constant

→ measure of how mush substance become polar , when place in external electric field

• tell you how good solvent is @separating & stabilising charge

• help predict ow well solute will dissolve in it

predictor ( rough measure ) of polarity

• polar ( ex. water )

• seme-polar ( ex. glycerol )

• non-polar ( ex.octane )

polarity of water ( refresher )

• polar covalent bonds b/e O & H

• O is more electronegative→ pull electron closer → permanent dipole

polar solvent & solubility of ionic solute

• polar solvent = high dielectric constant & (+ ) /(-) dipole

• ionic solute = strong electrolyte

mechanism = ion-dipole interaction

→ solute attraction to =/- dipole on solvent , inter ionic attraction weaken , ionic lactic breaks , ions dissociate, solvation → ions stabilise in solution

ionic molecular and charge strength

ionic compound → generally water soluble , bit ionic bond side in strength

( water CANT break all ionic bond )

attraction b/w ions in solid < F. of attraction b/w ions and water = compound does not dissolve

charge strength → magnitude of charge on an ion ( solute )

→ how strongly it interact w/water → show solubility

w/small charge = higher solubility

w/large charge = lower solubility

solubility of ionic compound ( general rule )

cation & anion in ionic compound can be used to predict it’s AQ solubility

( as charge IN , solubility will change ( IN/DE ) )

polar solvent & solubility od neutral compound

mechanism = dissolve by formation H-bond

• polar group ( solute ) are attracted to polar solvent ( strong dipole ) → solute-solute bond break → solute stabilised in solution

non-polar solvent & solubility of non-polar solute

• not DE interionic attraction in ionic crystals or H-bond → not dissolved polar solute

mechanism = via van der Waals F

• solvent surround solute → temporary dipole → weak wan der Waals attraction → solute disperses throughout solvent → solubility

semi-polar solvent and solubility

• - & + dipole charge has polar and non-polar → intermediate polarity

polar = interact via dipole=dipole or H-bond

non-polar = via van der Waals

nature od solute

chemical nature

• charge strength

• ability to form H-bond w/solvent

• hydrophobic ( hydrophilic )nature of molecule , ration of polar to non-polar group )

• degree of ionisation of functional group

physical nature

• solid state ( crystalline ) form

ability to form H-bond w/solvent ( nature of solute )

• H-bond form when H-atom attach to electronegative atom (F , O , N )

• determined by examining structure feature of both solute and solvent

• look for polar functional group

→ like dissolve like rule , polar solute can interact strongly with/polar solvent via H-bond

hydrophobic nature of solute

ration od polar to non-polar

→ solubility of substance change w/its size and polarity

• IN H-bond , IN hydrophilicity

degree of ionisation & solubility

fraction of solute that dissociate into ion in solution

solute

• strong electrolyte( ionic compound )

• weak electrolytes

( IN ionisation , IN ions in solution → solubility)

degree of ionisation ( strong electrolytes)

complete ionised → HIGH solubility

• ionice compound

• strong acid & base

degree of ionisation ( weak electrolytes)

weak electrolytes = weak acid & base

• weak electrolytes are poorly water soluble

• highly influenced by pH

→ weak acid are more soluble in base

→ weak acid are more soluble in acid

solubility challenges of weak electrolytes

( most of drug are weak electrolytes)

• poor solubility

→ difficult of formulation as liquid dosage form

→ drug must solubilised adequately for efficient absorption

→ precipitate out of solution at certain pH oe ion conc. change

strategies to improve AQ solubility

1. modify solid state ( co-crystals , amorphous )

2. salt-formulation

3. co-solvency

4. pH adjustment

5. complexation

6. surfactants/micelles

7. colloidal delivery system or nanoformulation

solubility and solid state of solute

solid

→ Amorphous ( lack order )

→ Crystal ( highly ordered )

crystal

→ polymorphs = diff crystalline form of same molecule

→ Pseudo-polymorph ( solvate/hydrate ) = contain water or other solvent as guest molecule

crystalline

• crystalline form

→ lower E state = most stable

→ rigid structure & stronger = low solubility ( DE H-bond w/water )

• strategies to improve solubility

→ chess most suitable polymorph to balance b/w process ability and stability

amorphous

• amorphous form

→ high E state = unstable

→ solubility > crystalline form ( IN H-bond due ri semi-random state )

• strategy to IN solubility

→ convert drug from its crystalline from into its amorphous

improve solubility via salt formation

• 60% of drug are formulates as self ( converting drug into salt form by adding ionise group )

• dissociate on AQ environment to ON AQ solubility

• most preferred approach to IN AQ drug solubility of weak electrolytes

• presence of acidic or basic functional group is essential

selecting salt type

• dictate largely by physiochemical properties of API but also

→ formulation/route of administration

→ drug release profile & desire bioavailability

→ regulatory consideration

• salt of basic

• salt of acidic

improving solubility by co-solvency

• mixture of solvent used to enhance drug solubility

• work together to IN solubility beyond each individual solvent could achieve on its own

• important in formulation od injectable solution

• adjust solvent polarity

→ DE water -water H-bond

→ alter ionisation balance ( pH adjustment maybe require )

→ IN drug 0solvent interaction = IN solubility of unionised drug

limitation and selection consideration ( co-solvency )

limitation

• risk of precipitation on dilution ( after administration)

selection consideration

• biocompatibility ( route-administration)

• dose limits

• toxicity at high conc.

effect of dilution on drug solubility by co-solvent

• dilution DE solubility

→ DE linear w/dilution

→ solubilising capacity of co-solvent formulation DE exponentially

• consequence of precipitation

→ pain

• approaches to minimise precipitation

→ DE drug load formulation

→ adjust rate of administration

pH to achieve solubility requirement

2 parameter when formulating weak electrolytes drug

• solubility of drug at desired pH

• pH that must be maintain to prevent precipitation of drug from solution of known or desired conc.

→ predict by pHP equation - calc solubility of weak electrolyte ( drug ( at given pH of solution

• buffer are used to adjust / maintain pH

definition of complexation

complexation = interaction between/w one or more molecule of 2 compound ( ex. ligands and substance )

mechanism of interaction in complexation

1. covalent ( coordinate )

2. non-covalent

cause of complexation

• drug or solute can interact with/other component in formulation

( ex. other drug , excipient )

• bor biological compound

deliberate or unintentional complexation as a result of

• change in pH , solvent

• chelation

• adsorption

• interaction w/storage container

• in-vivo

• drug incompatibility

consequence of complexation

( physical and chemical properties of complexing SPP are alter )

• change in solubility, efficacy , stability . taste , absorption or elimination

type of complexes

1. coordination complexes-

→ metal complexes

2. molecular

→ small-small molecule

→ small -large molecule

→ large -large molecule

coordination complexes-

• complexes form via coordinates bond

• electron rich ( ligand ) bonds w/electropositive atom ( substate ) by donating its pair of electron

coordination covalent bond VS covalent bond

coordination covalent bond = covalent bond in which BOTH electron come from same atom

covalent bond = form by 2 atom charge pair of electron

molecular

complexes form by multiple attractive non-covalent interaction ( H-bond , electrostatic attraction, van der Waal F or hydrophobic )

coordination complexes ( metal complexes )

most commode type of coordination complex

• central metal atom or ion ( cation ) surround by (-) charge or neutral molecule possessing lone pair electron

• ligand senate pair of electron

• metal ion accept pair of electron ( ex. substrate )

metal complexes ex. anti-cancer drug

• platinum , Palladium , gold

• metal ion bond to essental biomolecule

→ DNA , protein , enzyme

→ inhibits their function , cuz cell death

metal complexes ex. clinical implication

x. tetracycline ( antibiotic )

small - small molecule complexes

molecule bearing functional group w/opposite polarity can interact w/each other in solution

small - small molecule complexes ( ex. drug-caffeine )

ex. drug-caffeine complexes ( IN drug solubility)

→ solid state = brevet crystallisation or create amorphous forms

→ co-solevnt = interact w/both drug molecule and water )

small-small molecule ( ex. Procaine Pencilline G )

• combination of penicillin (antibiotic ) and procaine ( anaesthetic )

→ salt complex , DE penicillin, cuz slo absorption, longer half-life , prolonged therapeutic effect , DE frequency of administration

small-small molecule ( ex. aminophylline )

aminophylline > water-soluble than theophylline = more suitable for IV administration

small-small molecule ( ex. cation/antion )

precipitate ( insoluble complex )

• electrostatic attraction b/w oppositely charge ions

small-large molecule

• enzyme-substance ( drug ) interaction

• drug binding to plasma protein ( can’t interact w/its receptor )

→ DE drug solubility

→ DE volume of distribution

→ DE elimination

• association complexes ( ex. micelles )

• inclusion/occlusion complexes

ex.cyclodextrin-dug complexes

large-large molecule

complexes b/w nucleotides base in DNA molecule via H-bond

inclusion complexes

• complex in which molecule ( host ) w/ cavity can accommodate substance ( guest )

ex.cyclodextrin( CD ) complexes

pharmaceutical application of cyclodextrin( CD ) complexes

• IN solubility

• IN stability

• IN bioavailability

• DE tease masking

→ poorly soluble drug not automatically able to for, inclusion complex w/ CD BE size , shape & polarity and potency at low dose

effect of cyclodextrin( CD ) complexes on drug solubility

• appropriate choice of host and guest = high selectivity → IN solubility

release of guest from cyclodextrin( CD ) complexes

• non-covalent , so guest molecule continually associated from host

• large guest = slower formation & dissolution

major mechanism of release

→ dilution

→ competitive displacement

→ change in ionic strength & temp

partitioning ( definition )

process of drug’s movement over time across membrane

= distribution of molecule ( solutes ) b/w immiscible solvent

S_water ⇌ S_oil

• solute distributes or partition in defines conc. ration = partition constant or partition ratio

affinity for polar & non-polar

affinity for water ( polar ) = never enter bloodstream

affinity for lipid ( non-polar ). = never dissolve in water

partition coefficient ( P )

to predict likelihood that drug will dissolve in water and cross cell membrane ( quantify relative affinity for each other )

how is partition coefficient ( P ) determined

logP

• partition coefficient ( P ) value vary ( small - large )

• relative lipophilic / hydrophilic or lipophilicity of compound ( unionised or neutral SPP )

• help estimate both drug solubility & permeability

log P value

logP ( - ) → hydrophilic

logP = 0 → balance

logP ( + ) → lipophilic

lipophilicity change as function of pH for ionisable compound

lipophilicity of ionisable compound

• logP = measure lipophilicity Drug_unionied

• many drug are ionisable → exist as mixture of ionised & unionised

• proportion of each form depend on pH ( vary across body )

• ionise form is more water-soluble and less membrane-permeable = inaccurate prediction of drug behaviour

---

• lipophilicity isn’t fixed for ionises → change w/pH

• logD = measure lipophilicity of ionisable compound ( where partitioning is pH dependent )

→ non-ionise = log P = logD at all pH

→ ionise = logD change w/pH

P vs D ( lipophilicity )

P = true partition coefficient , when all drug is in unionised form

D = apparent partition coefficient , when AQ phase is ionise due to pH

pharmaceutical impotence of partitioning

• logP help in formulation dosage from

→ balance of lipophilicity & hydrophilicity for drug candidate

→ predict of AQ solubility

→ adsorption to packing

• logP help to predict ADME

→ lipphilicity = predictive of frug permeability across biological membrane ( → bioavailability)

logP help in formulation dosage from

• partitioning affect preservative efficacy

→ microorganism grow in AQ phase

→ optimum in formulation , essential to resist microbial growth

( unionise form = bacterial penetration )

partitioning & preserving efficacy

• conc. in AQ phase ( region of bacterial growth )

• DE , if preservative partitions into immiscible oily phase

( unionise form = cross bacterial wall )

logP help to predict ADME

• lipophilicity & drug behaviour in body ( major determinate of ADME )

• bioactivity vs logP → parabolic relationship

• fluid/tissue diff in pH , size , nature content

( lipophilicity can change over pH range )