Dr. Jigar Shah Institute of Pharmacy...Preformulation study is the first step in the rational development of dosage forms of a drug substance. It can be defined as an investigation

Preformulation StudiesPreformulation Studies

Dr. Jigar ShahInstitute of Pharmacy

Preformulation studyPreformulation study is the first step in the is the first step in the rational development of dosage forms of a rational development of dosage forms of a drug substance.drug substance.

It can be defined as an investigation of physical It can be defined as an investigation of physical and chemical properties of a drug substance - and chemical properties of a drug substance - alonealone and when and when combined combined with excipients.with excipients.

The overall objective of The overall objective of preformulation studypreformulation study is is to generate information useful to the formulator to generate information useful to the formulator in developing in developing stable stable and and bioavailable bioavailable dosage dosage forms which can be forms which can be mass-produced.mass-produced.

During the early development of a new drug substance, During the early development of a new drug substance, the synthetic chemist, alone or in cooperation with the synthetic chemist, alone or in cooperation with specialists in other disciplines (including specialists in other disciplines (including preformulation), may record some data which can be preformulation), may record some data which can be appropriately considered as preformulation data.appropriately considered as preformulation data.

This early data collection may include such information This early data collection may include such information as as - gross particle size, - gross particle size, - melting point, - melting point, - infrared analysis, - infrared analysis, - thin-layer chromatographic purity, - thin-layer chromatographic purity, - and other such characterizations of different - and other such characterizations of different

laboratory-scale batches.laboratory-scale batches. These data are useful in guiding, and becoming part of, These data are useful in guiding, and becoming part of,

the main body of preformulation work.the main body of preformulation work.

Steps in Preformulation Process Pharmaceutical ResearchSteps in Preformulation Process Pharmaceutical Research1. Stability1. Stability i. Solubilityi. Solubility

a. Solid Statea. Solid State (1) Water and Other Solvents (1) Water and Other Solvents (1) Temperature(1) Temperature (2) pH-Solubility Profile (2) pH-Solubility Profile (2) Light(2) Light (3) Salt Forms (3) Salt Forms (3) Humidity(3) Humidity (4) Cosolvents (4) Cosolventsb. Solutionb. Solution (5) Complexation (5) Complexation (1) Solvent(1) Solvent (6) Prodrug (6) Prodrug (2) pH(2) pH j. Effect of pH on UV Spectraj. Effect of pH on UV Spectra (3) Light(3) Light k. Ionization Constantk. Ionization Constant

2, Solid State Compatibility2, Solid State Compatibility l. Volatilityl. Volatilitya. TLC Analysisa. TLC Analysis m. Optical Activity m. Optical Activity b. DRS Analysisb. DRS Analysis n. Polymorphism Potentialn. Polymorphism Potential

3. Physico-chemical Properties3. Physico-chemical Properties o. Solvate Formationo. Solvate Formationa. Molecular Structure and Weight a. Molecular Structure and Weight 4. Physico-mechanical Properties4. Physico-mechanical Propertiesb. Colorb. Color a. Bulk and Tapped Density a. Bulk and Tapped Densityc. Odorc. Odor b. Compressibility b. Compressibilityd. Particle size, Shape, and Crystallinityd. Particle size, Shape, and Crystallinity c. Photomicrographc. Photomicrographe. Melting Pointe. Melting Point 5. In Vitro Availability Properties5. In Vitro Availability Propertiesf. Thermal Analysis Profilef. Thermal Analysis Profile a. Dissolution of Drug Crystal Per sea. Dissolution of Drug Crystal Per se (1) DTA(1) DTA b. Dissolution of Pure Drug Pelletb. Dissolution of Pure Drug Pellet (2) DSC(2) DSC c. Dissolution Analysis of Pure Drugc. Dissolution Analysis of Pure Drug (3) TGA(3) TGA d. Rat Everted Gut Techniqued. Rat Everted Gut Techniqueg. Hygroscopicity Potentialg. Hygroscopicity Potential 6. Other Studies6. Other Studiesh. Absorbance Spectrah. Absorbance Spectra a. Plasma Protein Bindinga. Plasma Protein Binding (1) UV(1) UV b. Effect of Compatible Excipientsb. Effect of Compatible Excipients (2) IR(2) IR on Dissolutionon Dissolution

c. Kinetic Studies of Solutionc. Kinetic Studies of Solution DegradationDegradation d. Use of Radio-labeled Drugd. Use of Radio-labeled Drug

The formal preformulation study should start at the The formal preformulation study should start at the point after point after biological screeningbiological screening, when a decision is , when a decision is made for further development of the compound in made for further development of the compound in clinical trialsclinical trials..

Before embarking upon a formal program, the Before embarking upon a formal program, the preformulation scientist must consider the following:preformulation scientist must consider the following:

1. The available physicochemical data (including 1. The available physicochemical data (including chemical structure, different salts available)chemical structure, different salts available)

2. The therapeutic class of the compound and anticipated 2. The therapeutic class of the compound and anticipated dosedose

3. The supply situation and the development schedule 3. The supply situation and the development schedule (i.e., the time available)(i.e., the time available)

4. The availability of a stability-indicating assay4. The availability of a stability-indicating assay5. The nature of the information the formulator should 5. The nature of the information the formulator should

have or would like to havehave or would like to have

1. ORGANOLEPTIC PROPERTIES1. ORGANOLEPTIC PROPERTIES1.1 Color1.1 Color

Unappealing to the eye ==> instrumental methods or Unappealing to the eye ==> instrumental methods or variable from variable from batch to batch batch to batch

Record of early batches ==> establishing “specs” is Record of early batches ==> establishing “specs” is very useful very useful for later production for later production

Undesirable or Undesirable or ==>==> incorporation of a dye variable incorporation of a dye variable colorcolor in the body or coating in the body or coating

1.2 Odor and Taste1.2 Odor and TasteUnpalatable ==> use of less soluble chemical formUnpalatable ==> use of less soluble chemical form

(bioavailability not compromised!)(bioavailability not compromised!)

==> suppressed by - flavors==> suppressed by - flavors - excipients - excipients - coating - coating

Drug substancesDrug substancesirritating to skinirritating to skin ==> handling precautions==> handling precautions or or sternutatory sternutatory (sneezing)(sneezing)

Flavors, dyes, excipients used ==> stability Flavors, dyes, excipients used ==> stability bioavailabilitybioavailability

Table 1. Suggested Terminology to Describe Table 1. Suggested Terminology to Describe Organoleptic Properties of Pharmaceutical Organoleptic Properties of Pharmaceutical PowdersPowders

ColorColor OdorOdor TasteTaste

Off-whiteOff-white PungentPungent AcidicAcidicCream yellowCream yellow SulfurousSulfurous BitterBitterTanTan FruityFruity BlandBlandShinyShiny AromaticAromatic intenseintense

OdorlessOdorless SweetSweetTastelessTasteless

2. PURITY2. PURITY

Materials with impurities not necessary to be Materials with impurities not necessary to be rejectedrejected

Another control parameter for comparison with Another control parameter for comparison with subsequent batchessubsequent batches

More direct concerns - impurity can affect:More direct concerns - impurity can affect:- Stability: metal contamination in ppm- Stability: metal contamination in ppm- Appearance: off-color -> recrystallized -> white - Appearance: off-color -> recrystallized -> white - Toxic: aromatic amine - Toxic: aromatic amine (p-amino phenol)(p-amino phenol) -> carcinogenic -> carcinogenic

Often remedial action => simple recrystallization Often remedial action => simple recrystallization

Cimetidine-acid hydrolysisCimetidine-acid hydrolysis

OH-

H+

Techniques used for characterizing purity are the Techniques used for characterizing purity are the same as used in preformulation study :same as used in preformulation study :- Thin layer chromatography (TLC)- Thin layer chromatography (TLC)- High-pressure liquid chromatography (HPLC)- High-pressure liquid chromatography (HPLC)- Gas chromatography (GC)- Gas chromatography (GC)

Impurity index (II)Impurity index (II) defined as the ratio of all defined as the ratio of all responses (peak areas) due to components other responses (peak areas) due to components other than the main one to the total area response.than the main one to the total area response.

Homogeneity index (HI)Homogeneity index (HI) defined as the ratio of the defined as the ratio of the response (peak area) due to the main component response (peak area) due to the main component to the total response.to the total response.

Example:Example:Main component - retention time:Main component - retention time: 4.39 min4.39 min

- area response:- area response: 46204620ImpuritiesImpurities - 7 minor peaks- 7 minor peaks

- total area response :- total area response : 251251Impurity indexImpurity index = 251/(4620 + 251) = 251/(4620 + 251)

= 0.0515= 0.0515Homogeneity indexHomogeneity index = 1 - 0.0515= 1 - 0.0515

= 0.9485= 0.9485

USP Impurity IndexUSP Impurity Index defined as a ratio of responses defined as a ratio of responses due to impurities to that response due to a defined due to impurities to that response due to a defined concentration of a standard of the main component. concentration of a standard of the main component. (using TLC)(using TLC)General limitGeneral limit 2 % impurities2 % impurities

All All IIII, , HIHI, , USP IIUSP II are not absolute measures of are not absolute measures of impurity since the specific response (molecular impurity since the specific response (molecular absorbances or extinction coefficient) due to each absorbances or extinction coefficient) due to each impurity is assumed to be the same as that of the impurity is assumed to be the same as that of the main component.main component.

More accurate analysis - identification of each More accurate analysis - identification of each individual impurity followed by preparation of individual impurity followed by preparation of standards for each one of them.standards for each one of them.

Other useful tools in assessment of Other useful tools in assessment of impurity:impurity:- - Differential Thermal Analysis (DTA)Differential Thermal Analysis (DTA)- Thermogravimetric Analysis (TGA)- Thermogravimetric Analysis (TGA)- Differential Scanning Calorimetry (DSC)- Differential Scanning Calorimetry (DSC)- Powder X-Ray Diffraction (PXRD)- Powder X-Ray Diffraction (PXRD)

acyclovir

Ethylcellulose film

DSC thermograms of pure acyclovir and pure ethylcellulose films

DSC thermograms of ethylcellulose film containing 12.8 % acyclovir with 15 % propylene glycol and 10 % Tween 80

CimetidineCimetidine

3. PARTICLE SIZE, SHAPE, AND SURFACE AREA3. PARTICLE SIZE, SHAPE, AND SURFACE AREA

Effects of particle size distribution and shape on:Effects of particle size distribution and shape on:- Chemical and physical properties of drug - Chemical and physical properties of drug substances.substances.- Bioavailability of drug substances (griseofulvin, - Bioavailability of drug substances (griseofulvin, chlorpropamide).chlorpropamide).- Flow and mixing efficiency of powders and - Flow and mixing efficiency of powders and granules in making tablets.granules in making tablets.- Fine materials tend to require more amount of - Fine materials tend to require more amount of granulating liquid (cimetidine).granulating liquid (cimetidine).- Stability, fine materials relatively more open to - Stability, fine materials relatively more open to attack from atmospheric Oattack from atmospheric O22, heat, light, humidity, , heat, light, humidity, and interacting excipients than coarse materials. and interacting excipients than coarse materials. (Table 2)(Table 2)

Table 2. Influence of Particle Size on Reaction of Table 2. Influence of Particle Size on Reaction of Sulfacetamide with Phthalic anhydride in 1:2 Molar Sulfacetamide with Phthalic anhydride in 1:2 Molar

Compacts after 3 hr at 95 Compacts after 3 hr at 95 ooCC

Particle size ofParticle size of % Conversion% Conversionsulfacetamidesulfacetamide ++ SD SD

((µµm)m)

128128 21.54 21.54 ++ 2.74 2.74164164 19.43 19.43 ++ 3.25 3.25214214 17.25 17.25 ++ 2.88 2.88302302 15.69 15.69 ++ 7.90 7.90387387 9.34 9.34 ++ 4.41 4.41

Weng and ParrottWeng and Parrott

Very fine materials are difficult to handle, overcome Very fine materials are difficult to handle, overcome by creating solid solution in a carrier (water-soluble by creating solid solution in a carrier (water-soluble polymer).polymer).

Important to decide, maintain, and control a desired Important to decide, maintain, and control a desired size range.size range.

Safest - grind most new drugs with particle diameter Safest - grind most new drugs with particle diameter > 100 > 100 µµm (~ 140 mesh) down to ~ 10 - 40 m (~ 140 mesh) down to ~ 10 - 40 µµm (~ 325 m (~ 325 mesh).mesh).

Particles with diameter Particles with diameter << 30 30 µµm (~ 400 mesh), m (~ 400 mesh), grindinggrinding is unnecessary except needle-like => is unnecessary except needle-like => improve flow.improve flow.

Drawbacks to grinding:Drawbacks to grinding:- material losses- material losses- static charge build-up- static charge build-up- aggregation - aggregation => increase hydrophobicity=> increase hydrophobicity => lowering dissolution rate=> lowering dissolution rate

- polymorphic or chemical transformations- polymorphic or chemical transformations

3.1 General Techniques For Determining3.1 General Techniques For DeterminingParticle SizeParticle Size

3.1.1 Microscopy 3.1.1 Microscopy - Most rapid technique.- Most rapid technique.- But for quantitative size determination - But for quantitative size determination requires counting large number of particles.requires counting large number of particles.- For size ~ 1 - For size ~ 1 µµm upward (magnification x400).m upward (magnification x400).- Suspending material in nondissolving fluid - Suspending material in nondissolving fluid (water or mineral oil)(water or mineral oil)- Polarizing lens to observe birefringence => - Polarizing lens to observe birefringence => change in amorphous state after grinding?change in amorphous state after grinding?

KetoprofenKetoprofen

Eudragit L100Eudragit L100

3.1.2 Sieving3.1.2 Sieving- Quantitative particle size distribution analysis. - Quantitative particle size distribution analysis. - For size > 50 - For size > 50 µµm upward.m upward.- Shape has strong influence on results.- Shape has strong influence on results.

3.1.3 Electronic means3.1.3 Electronic meansTo encompass most pharmaceutical To encompass most pharmaceutical

powders ranging in size 1 - 120 powders ranging in size 1 - 120 µµm:m:- Blockage of electrical conductivity path - Blockage of electrical conductivity path (Coulter)(Coulter)- Light blockage (HIAC) [adopted by USP] - Light blockage (HIAC) [adopted by USP] - Light scattering (Royco)- Light scattering (Royco)- Laser scattering (Malvern)- Laser scattering (Malvern)

3.1.4 Other techniques3.1.4 Other techniques- Centrifugation- Centrifugation- Air suspension- Air suspension- Sedimentation (Adreasen pipet, - Sedimentation (Adreasen pipet, recording balance)recording balance)Disfavor now because of their tedious Disfavor now because of their tedious

nature.nature.

Table 3. Common Techniques for Measuring Fine Particles of Table 3. Common Techniques for Measuring Fine Particles of Various Sizes Various Sizes

TechniqueTechnique Particle size (Particle size (µµm)m)

MicroscopicMicroscopic 1 - 1001 - 100SieveSieve > 50 > 50SedimentationSedimentation > 1 > 1ElutriationElutriation 1 - 501 - 50CentrifugalCentrifugal < 50 < 50PermeabilityPermeability > 1 > 1Light scatteringLight scattering 0.5 - 500.5 - 50

(Parrott)(Parrott)

(Undersize)

(Undersize)

3.2 Determination of Surface Area3.2 Determination of Surface Area Surface areas of powders Surface areas of powders

-> increasing attention in recent years: reflect the particle size -> increasing attention in recent years: reflect the particle size Grinding operation:Grinding operation:

particle size particle size ==>==> surface area. surface area. Brunauer-Emmett-Teller (BET)Brunauer-Emmett-Teller (BET) theory of adsorption theory of adsorption

Most substances will adsorb a monomolecular layer of a gas Most substances will adsorb a monomolecular layer of a gas under certain conditions of partial pressure (of the gas) and under certain conditions of partial pressure (of the gas) and temperature. temperature. Knowing the monolayer capacity of an adsorbent (i.e., the Knowing the monolayer capacity of an adsorbent (i.e., the

quantity of adsorbate that can be accommodated as a quantity of adsorbate that can be accommodated as a monolayer on the surface of a solid, the adsorbent) and the monolayer on the surface of a solid, the adsorbent) and the area of the adsorbate molecule, the surface area can, in area of the adsorbate molecule, the surface area can, in principle be calculated.principle be calculated.

Most commonly, nitrogen is used as the adsorbate at a Most commonly, nitrogen is used as the adsorbate at a specific partial pressure established by mixing it with an inert gas, specific partial pressure established by mixing it with an inert gas, typically helium. The adsorption process is carried out at liquid typically helium. The adsorption process is carried out at liquid nitrogen temperature (-195 nitrogen temperature (-195 ooC).C).

It has been demonstrated that, at a partial pressure of nitrogen It has been demonstrated that, at a partial pressure of nitrogen attainable when it is in a 30 % mixture with an inert gas and at -195 attainable when it is in a 30 % mixture with an inert gas and at -195 ooC, a monolayer is adsorbed onto most solids.C, a monolayer is adsorbed onto most solids.

Apparently, under these conditions the polarity of nitrogen is Apparently, under these conditions the polarity of nitrogen is sufficient for van de Waals forces of attraction between the sufficient for van de Waals forces of attraction between the adsorbate and the adsorbents to be manifest.adsorbate and the adsorbents to be manifest.

The kinetic energy present under these conditions The kinetic energy present under these conditions overwhelms the intermolecular attraction between nitrogen atoms. overwhelms the intermolecular attraction between nitrogen atoms. However, it is not sufficient to break the bonding between the However, it is not sufficient to break the bonding between the nitrogen and dissimilar atoms. The latter are most often more nitrogen and dissimilar atoms. The latter are most often more polar and prone to van de Waals forces of attractionpolar and prone to van de Waals forces of attraction..

The nitrogen molecule does not readily enter into chemical The nitrogen molecule does not readily enter into chemical combinations, and thus its binding is of a nonspecific nature (I.e., it combinations, and thus its binding is of a nonspecific nature (I.e., it enters into a physical adsorption); consequently , the nitrogen enters into a physical adsorption); consequently , the nitrogen molecule is well suited for this role.molecule is well suited for this role.

Brunauer-Emmett-Teller (BET)Brunauer-Emmett-Teller (BET) adsorption isothermadsorption isotherm

11 == C - 1C - 1 P + P + 11 (1)(1)λλ(P(Poo/P - 1)/P - 1) λλmmCC P Poo λλmmCC

λ λ == g of adsorbate per g of adsorbentg of adsorbate per g of adsorbentλλmm = = maximum value of that maximum value of that λλ ratio for a monolayer ratio for a monolayerP P = = partial pressure of the adsorbate gaspartial pressure of the adsorbate gasPPoo = = vapor pressure of the pure adsorbate gasvapor pressure of the pure adsorbate gasCC = = constantconstant

P, PP, Poo, and C are temperature-dependent, and C are temperature-dependent

The values of The values of λλ (g of adsorbate/g of adsorbent) (g of adsorbate/g of adsorbent) at at various various P values (partial pressure of the P values (partial pressure of the adsorbate gas)adsorbate gas) could be obtained from the could be obtained from the experiment through instrument.experiment through instrument.

PPoo (vapor pressure of the pure adsorbate gas) (vapor pressure of the pure adsorbate gas) can be obtained from the literature.can be obtained from the literature.

Plotting the term Plotting the term 1/[1/[λλ(P(Poo/P - 1)]/P - 1)] against against P/PP/Poo will will obtain a straight line with obtain a straight line with slope = (C - 1)/slope = (C - 1)/λλmmC C

intercept = 1/intercept = 1/λλmmCC The termThe term C C and and λλmm can readily be obtained can readily be obtained

Dynamic Method of Gas AdsorptionDynamic Method of Gas Adsorption Accurately weighing the sample into an appropriate Accurately weighing the sample into an appropriate

containercontainer Immersing the container in liquid nitrogenImmersing the container in liquid nitrogen Passing the gas over the samplePassing the gas over the sample Removing the liquid nitrogen when the adsorption is Removing the liquid nitrogen when the adsorption is

complete (as signaled by the instrument)complete (as signaled by the instrument) Warming the sample to about the room temperatureWarming the sample to about the room temperature Measuring (via the instrument) the adsorbated gas Measuring (via the instrument) the adsorbated gas

released (column 3 of Table 5) released (column 3 of Table 5) Performing the calibration by injecting known amounts Performing the calibration by injecting known amounts

of adsorbated gas into the proper instrument port of adsorbated gas into the proper instrument port (column 4 and 5 of Table 5)(column 4 and 5 of Table 5)

P is the product of the fraction of NP is the product of the fraction of N22 in the gas mixture in the gas mixture (column 1 of Table 5) and the ambient pressure(column 1 of Table 5) and the ambient pressure

At relatively large diameters, the specific At relatively large diameters, the specific surface area is insensitive to an increase in surface area is insensitive to an increase in diameterdiameter

At very small diameters the surface area is At very small diameters the surface area is comparatively very sensitive.comparatively very sensitive.

Relatively high surface area most often Relatively high surface area most often reflects a relatively small particle size, except reflects a relatively small particle size, except porous or strongly agglomerated massporous or strongly agglomerated mass

Small particles (thus of high surface area) Small particles (thus of high surface area) agglomerate more readily, and often to render agglomerate more readily, and often to render the inner pores and surfaces inaccessible to the inner pores and surfaces inaccessible to dissolution mediumdissolution medium

4. SOLUBILITY4. SOLUBILITY Solubility > 1 % w/v Solubility > 1 % w/v

=> no dissolution-related absorption problem=> no dissolution-related absorption problem Highly insoluble drug administered in small Highly insoluble drug administered in small

doses may exhibit good absorptiondoses may exhibit good absorption Unstable drug in highly acidic environment of Unstable drug in highly acidic environment of

stomach, high solubility and consequent rapid stomach, high solubility and consequent rapid dissolution could result in a decreased dissolution could result in a decreased bioavailabilitybioavailability

The solubility of every new drug must be The solubility of every new drug must be determined as a function of pH over the determined as a function of pH over the physiological pH range of 1 - 8physiological pH range of 1 - 8

4.1 Determination of Solubility4.1 Determination of Solubility

Solvent(fixed volume)

Adding solute in smallincremental amounts

Vigorously shaking

Undissolvedsolute particles ?

Examinevisually

YesNo

Total amountadded up

Estimated solubility

4.1.1 Semiquantitative determination:

““LAW OF MASS ACTION”LAW OF MASS ACTION”

4.1.2 Accurately Quantitative determination:4.1.2 Accurately Quantitative determination:

Excess drug powder150 mg/ml (15 %)+ solvent

Ampul/vial(2-5 ml)

Shaking at constant temperature (25 or 37 oC)

2 - 8 oC ?

Membrane filter0.45 µm

Determine the drugconcentration in the

filtrate

Determine the drugconcentration in the

filtrate

Determine the drugconcentration in the

filtrate

Membrane filter0.45 µm

Membrane filter0.45 µm

Sameconcentration ?

The first few ml’s of the filtrates should be discarded due to possible filter adsorption

Solubility

48 hr

72 hr

? hr

4.1.3 Unique Problems in Solubility 4.1.3 Unique Problems in Solubility Determination of Poorly Soluble CompoundsDetermination of Poorly Soluble Compounds

Solubilities could be overestimated due to the presence Solubilities could be overestimated due to the presence of soluble impurities of soluble impurities

Saturation solubility is not reached in a reasonable Saturation solubility is not reached in a reasonable length of time unless the amount of solid used is length of time unless the amount of solid used is greatly in excess of that needed to saturationgreatly in excess of that needed to saturation

Many compounds in solution degrade, thus making an Many compounds in solution degrade, thus making an accurate determination of solubility difficultaccurate determination of solubility difficult

Difficulty is also encountered in the determination of Difficulty is also encountered in the determination of solubility of metastable forms that transform to more solubility of metastable forms that transform to more stable forms when exposed to solventsstable forms when exposed to solvents

4.2 pH-Solubility Profile4.2 pH-Solubility Profile

Excess drugpowder

Stir in beakerwith distilled

water

Continuousstirring of

suspension

Addacid/base

MeasurepH of

suspension

Determine theconcentration

of drug in the filtrate

SOLUBILITY pH

Filter Stirring

2 4 6 8 10 12 14

5

4

3

2

1

Indomethacin(weak acid)

Chlorpromazine(weak base)

Oxytetracycline(amphoteric)

pHpH

Log

aque

ous

solu

bilit

y (

Log

aque

ous

solu

bilit

y ( µµ

mol

)m

ol)

Poorly-soluble weakly-acidic drugs:Poorly-soluble weakly-acidic drugs:

pHpH == pKpKaa + log [(S + log [(Stt - S - Soo)/S)/Soo]] (2) (2)

Poorly-soluble weakly-basic drugs:Poorly-soluble weakly-basic drugs:

pHpH == pKpKaa + log [S + log [Soo/(S/(Stt - S - Soo)])] (3) (3)

wherewhereSSoo = solubility of unionized free acid or base= solubility of unionized free acid or baseSStt = total solubility (unionized + ionized)= total solubility (unionized + ionized)

4.3 Salt Forms4.3 Salt FormsNSAID’sNSAID’s alclofenac, diclofenac, fenbufen,alclofenac, diclofenac, fenbufen,

ibuprofen, naproxenibuprofen, naproxenWeak acid pKWeak acid pKaa ~ 4, low solubility ~ 4, low solubility

Salt formsSalt forms sodiumsodiumN-(2-hydroxy ethyl) piperaziniumN-(2-hydroxy ethyl) piperaziniumarginiumarginiumN-methylglucosammoniumN-methylglucosammonium

SolubilitySolubilitydiclofenac (free acid) : diclofenac (free acid) : 0.8 x 10 0.8 x 10 -5-5 M (25 M (25 ooC)C)diclofenac sodiumdiclofenac sodium :: 24.5 mg/ml (37 24.5 mg/ml (37 ooC)C)

4.3 Salt Forms (cont.)4.3 Salt Forms (cont.)QuinolonesQuinolones enoxacin, norfloxacin,enoxacin, norfloxacin,

ciprofloxacinciprofloxacin

Salt formsSalt forms lactate, acetate, gluconate,lactate, acetate, gluconate,galacturonate, aspartate,galacturonate, aspartate,glutamate, etc.glutamate, etc.

SolubilitySolubilityFree base : Free base : < 0.1 mg/ml (25 < 0.1 mg/ml (25 ooC)C)Salt forms :Salt forms : > 100 mg/ml (25 > 100 mg/ml (25 ooC)C)

4.4 Solubilization4.4 SolubilizationDrug not an acidic or basic, or the acidic or basic Drug not an acidic or basic, or the acidic or basic

character not amendable to the formation of a stable character not amendable to the formation of a stable saltsalt

Use more soluble metastable polymorphUse more soluble metastable polymorph Use of complexation (eg. Ribloflavin-xanthines Use of complexation (eg. Ribloflavin-xanthines

complex) complex) Use of high-energy coprecipitates that are mixtures of Use of high-energy coprecipitates that are mixtures of

solid solutions and solid dispersions (eg. solid solutions and solid dispersions (eg. Griseofulvin in PEG 4000, 6000, and 20,000)Griseofulvin in PEG 4000, 6000, and 20,000)

in PEG 4000 and 20,000 -> supersaturated in PEG 4000 and 20,000 -> supersaturated solutionssolutions

in PEG 6000 -> bioavailability in human twice > in PEG 6000 -> bioavailability in human twice > micronized drugmicronized drug

Use of suitable surfactantUse of suitable surfactant

4.4.1 Complexation4.4.1 ComplexationComplexation can be analyzed and explained Complexation can be analyzed and explained

on the basis of “law of mass action” as follows:on the basis of “law of mass action” as follows:D (solid)D (solid) D (solution)D (solution) (4)(4)xD + yCxD + yC DDxxCCyy (5)(5)

SStt == [D] + x[D[D] + x[DxxCCyy]] (6)(6)wherewhere

D = drug moleculeD = drug moleculeC = complexing agent (ligand)C = complexing agent (ligand)SStt = total solubility of free drug [D] and the = total solubility of free drug [D] and the

drug in the complex [Ddrug in the complex [DxxCCyy]]

Benzocaine-caffeine complex Benzocaine-caffeine complex

Ligand (Complexing Agents)Ligand (Complexing Agents)- Vitamin K- Vitamin K - Caffeine- Caffeine- Menadione- Menadione - Benzoic acid- Benzoic acid- Cholesterol- Cholesterol - PEG series- PEG series- Cholate salt- Cholate salt - PVP- PVP- - ββ-cyclodextrin-cyclodextrinFormulation point of view:Formulation point of view:1. How much will a specific complexing agent be 1. How much will a specific complexing agent be

used for a certain amount of drug?used for a certain amount of drug?2. How does the resultant complex affect the 2. How does the resultant complex affect the

safety, stability, and therapeutic efficacy of the safety, stability, and therapeutic efficacy of the product?product?

Stoichiometric ratio Stoichiometric ratio = = moles of drug in complexmoles of drug in complex moles of complexing agent in the complexmoles of complexing agent in the complex

(7)(7)x:yx:y == DDTT - R - R (8)(8)

b - ab - aDDTT = Amount of total drug added in excess (than its solubility) to the system = Amount of total drug added in excess (than its solubility) to the system