product development and experimental design of solid dosage forms

PRODUCT DEVELOPMENT PRODUCT DEVELOPMENT AND EXPERIMENTAL AND EXPERIMENTAL

DESIGN OF SOLID DESIGN OF SOLID DOSAGE FORMSDOSAGE FORMS



NARONG SARISUTA, Ph.D.NARONG SARISUTA, Ph.D.

DEPARTMENT OF MANUFACTURING PHARMACYDEPARTMENT OF MANUFACTURING PHARMACY

FACULTY OF PHARMACY, MAHIDOL UNIVERSITYFACULTY OF PHARMACY, MAHIDOL UNIVERSITY

1.1. Preformulation TestingPreformulation Testing1.1. Organoleptic propertiesOrganoleptic properties2.2. ImpurityImpurity3.3. Particle size, shape, and surface areaParticle size, shape, and surface area4.4. Solubility, salt forms, and solubilizationSolubility, salt forms, and solubilization5.5. DissolutionDissolution6.6. Parameters affecting absorptionParameters affecting absorption

2.2. Product Development and Experimental Product Development and Experimental Designs Designs

1.1. Accelerated stability studies of pure drug sAccelerated stability studies of pure drug substanceubstance

2.2. Drug-excipient compatibility studiesDrug-excipient compatibility studies3.3. Experimental formulation screeningExperimental formulation screening

1. ORGANOLEPTIC PROPERTIES1. ORGANOLEPTIC PROPERTIES

1.1.11 Color Color Level of unsaturationLevel of unsaturation Chromophores -NH2 , -NO2 , >CChromophores -NH2 , -NO2 , >C=O=O Trace of impuritiesTrace of impurities Degradation productsDegradation products Discoloration in sterile productsDiscoloration in sterile products

APHA Color StandardsAPHA Color Standards(The American Public Health Association)(The American Public Health Association)

0

0.1

0.2

0.3

0.4

0 20 40 60 80 100

1

400

Ab

s or b

an

ce(

c m)

at

nm

% Certified APHA Color Standard (500 units)

125

250

375

500

0

AP

HA

Colo

r Nu

mb

er

400Typicalvisibleabsorbancer eadi ngs at nmf or cer t i fi ed APHA col or 400Typicalvisibleabsorbancer eadi ngs at nmf or cer t i fi ed APHA col or aa aaaaaaa aaaaaaaaa aaaaaa aaaa aaaaa aaaaaa(500 ) aa aaaaaaa aaaaaaaaa aaaaaa aaaa aaaaa aaaaaa(500 )

1.1.22 Odor Odor

Functional groupsFunctional groups Sulfides, sulfoxides, sulfhydrylSulfides, sulfoxides, sulfhydryl

sulfurous acid or garlic odorsulfurous acid or garlic odor

prone to oxidationprone to oxidation AminesAmines

ammonia odorammonia odor

prone to Mellard reactionprone to Mellard reaction SolventSolvent

1.3 Taste1.3 Taste

Unpalatable Unpalatable use of less soluble chemical use of less soluble chemical formform (bioavailability not (bioavailability not

compromised!)compromised!)

suppressed by suppressed by

- flavors excipients- flavors excipients

- coating- coating

Flavors, dyes, excipients used Flavors, dyes, excipients used stability, bioavailability stability, bioavailability

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

Oxidation of ranitidineOxidation of ranitidine

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) USP Impurity IndexUSP Impurity Index defined as a ratio of defined as a ratio of

responses due to impurities to that response due responses due to impurities to that response due to a defined concentration of a standard of the to a defined concentration of a standard of the main component. (using TLC)main component. (using TLC)

General limitGeneral limit 2 % impurities2 % impurities

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 substances.- Chemical and physical properties of drug substances.- Bioavailability of drug substances (griseofulvin, - Bioavailability of drug substances (griseofulvin, chlorpropamide).chlorpropamide).- Flow and mixing efficiency of powders and granules - Flow and mixing efficiency of powders and granules in making tablets.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, and , heat, light, humidity, and interacting excipients than coarse materials. (Table 2)interacting excipients than coarse materials. (Table 2)

Table 2. Influence of Particle Size on Reaction of Sulfacetamide Table 2. Influence of Particle Size on Reaction of Sulfacetamide with Phthalic anhydride in 1:2 Molar Compacts after 3 hr at 95 with Phthalic anhydride in 1:2 Molar Compacts after 3 hr at 95 ooCC

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

((m)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

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 requires - But for quantitative size determination requires counting large number of particles.counting large number of particles.

- For size ~ 1 - For size ~ 1 m upward (magnification x400).m upward (magnification x400).

- Suspending material in nondissolving fluid (water - Suspending material in nondissolving fluid (water or mineral oil)or mineral oil)

- Polarizing lens to observe birefringence => change - Polarizing lens to observe birefringence => change in amorphous state after grinding?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 m 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 m:m:

- Blockage of electrical conductivity path - Blockage of electrical conductivity path (Coulter counter)(Coulter counter)

- Light blockage (HIAC) [adopted by USP] - Light blockage (HIAC) [adopted by USP]

- Light scattering (Royco)- Light scattering (Royco)

- Laser scattering (Malvern)- Laser scattering (Malvern)

4. SOLUBILITY, SALT FORMS AND SOLUBILIZATION4. SOLUBILITY, SALT FORMS AND SOLUBILIZATION

Solubility > 1 % w/v Solubility > 1 % w/v

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

may exhibit good absorptionmay 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

Solubilities could be overestimated due to the Solubilities could be overestimated due to the presence of soluble impurities presence 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 Many compounds in solution degrade, thus making an accurate determination of solubility difficultan accurate 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 solubility of metastable forms that transform to more stable forms when exposed to solventsmore stable forms when exposed to solvents

2 4 6 8 10 12 14

5

4

3

2

1

Indomethacin(weak acid)

Chlorpromazine(weak base)

Oxytetracycline(amphoteric)

pHpH

Lo

g a

qu

eou

s so

lub

ility

(L

og

aq

ueo

us

solu

bili

ty ( m

ol)

mo

l) pH-Solubility ProfilepH-Solubility Profile

Solubility of Salt FormsSolubility of Salt Forms

DDiclofenac (free acid)iclofenac (free acid) : 0.8 x 10 : 0.8 x 10 -5-5 M (25 M (25 ooC)C)

DDiclofenac sodiumiclofenac sodium :: 24.5 mg/ml (37 24.5 mg/ml (37 ooC)C)

Ciprofloxacin (Free base) : < 0.1 mg/ml (25 Ciprofloxacin (Free base) : < 0.1 mg/ml (25 ooC)C)

Ciprofloxacin lactate : > 100 mg/ml (25 Ciprofloxacin lactate : > 100 mg/ml (25 ooC)C)

SolubilizationSolubilizationDrug 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 saltcharacter not amendable to the formation of a stable salt Use more soluble metastable polymorphUse more soluble metastable polymorph Use of complexation (eg. Benzocaine-caffeine complex) Use of complexation (eg. Benzocaine-caffeine complex) Use of high-energy coprecipitates that are mixtures of solid Use of high-energy coprecipitates that are mixtures of solid

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

in PEG 4000 and 20,000 -> supersaturated solutionsin PEG 4000 and 20,000 -> supersaturated solutions

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

Use of suitable surfactantUse of suitable surfactant

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

- - -cyclodextrin-cyclodextrin

C, Vc

Xc

D Xg

kd ka ke

Absorption site(gi-tract)

Central compartment(blood circulation)

Dissolution Absorption Elimination

Diagram showing dissolution and absorption of Diagram showing dissolution and absorption of solid dosage form into blood circulationsolid dosage form into blood circulation

5. 5. DissolutionDissolution

kd << ka => “dissolution rate-limited”

Intrinsic dissolution rate (mg/cmIntrinsic dissolution rate (mg/cm22/min)/min) is is characteristics of each solid compound in a characteristics of each solid compound in a given solvent under fixed hydrodynamic given solvent under fixed hydrodynamic conditionsconditions

Intrinsic dissolution rateIntrinsic dissolution rate helps in predicting if helps in predicting if absorption would be absorption would be dissolution rate-limiteddissolution rate-limited

> > 1 mg/cm1 mg/cm22/min/min --> not likely to present --> not likely to present dissolution rate-limited absorption problemsdissolution rate-limited absorption problems

< < 0.1 mg/cm0.1 mg/cm22/min/min --> usually exhibit dissolution --> usually exhibit dissolution rate-limited absorption rate-limited absorption

0.1 - 1.0 mg/cm0.1 - 1.0 mg/cm22/min/min --> more information is --> more information is needed before making any predictionneeded before making any prediction

Nelson Constant Surface MethodNelson Constant Surface Method

RotatingPaddle

Tablet surfaceHarden waxor paraffin

Dissolutionmedium

Effect of particle size of phenacetin on Effect of particle size of phenacetin on dissolution rate of the drug from granulesdissolution rate of the drug from granules

Time (min)Time (min)

Am

ou

nt

Dis

solv

ed (

mg

in 5

00

ml)

Am

ou

nt

Dis

solv

ed (

mg

in 5

00

ml) 0.11 – 0.15 0.11 – 0.15 mmmm

0.15 – 0.21 0.15 – 0.21 mmmm

0.21 – 0.30 0.21 – 0.30 mmmm0.30 – 0.50 0.30 – 0.50 mmmm

0.50 – 0.71 0.50 – 0.71 mmmm

(Finholt)

Means of enhancing the slow dissolution:Means of enhancing the slow dissolution:

in absence of more soluble physical or chemical in absence of more soluble physical or chemical form of the drug -form of the drug -

Particle size reduction (most commonly used).Particle size reduction (most commonly used). Enhanced surface area by adsorbing the drug Enhanced surface area by adsorbing the drug

on an inert excipient with a high surface area, on an inert excipient with a high surface area, i.e., fumed silicon dioxide.i.e., fumed silicon dioxide.

Comelting, coprecipitating, or triturating the Comelting, coprecipitating, or triturating the drug with some excipients.drug with some excipients.

Incorporation of suitable surfactant.Incorporation of suitable surfactant.

6. Parameter Affecting Absorption6. Parameter Affecting Absorption

The absorption of drugs administered The absorption of drugs administered orally as solids consists of 2 consecutive orally as solids consists of 2 consecutive processes: processes:

1. The process of dissolution, followed by1. The process of dissolution, followed by

2. The transport of the dissolved materials 2. The transport of the dissolved materials across gi membranes into systemic across gi membranes into systemic circulationcirculation

The rate-determining step in the overall absorption The rate-determining step in the overall absorption process:process:

For relatively insoluble compoundsFor relatively insoluble compounds

-> rate of dissolution -> rate of dissolution

(can be altered via physical intervention)(can be altered via physical intervention)

For relatively soluble compounds For relatively soluble compounds

-> rate of permeation across biological -> rate of permeation across biological membrane membrane

(is dependent on size, relative aqueous and lipid (is dependent on size, relative aqueous and lipid solubilities, and ionic charge of the solute molecules)solubilities, and ionic charge of the solute molecules)

(can be altered, in the majority of cases, only (can be altered, in the majority of cases, only through molecular modification)through molecular modification)

In making a judgement concerning the In making a judgement concerning the absorption potential of a new drug entity, absorption potential of a new drug entity, the preformulation scientist must the preformulation scientist must undertake studies to delineate its undertake studies to delineate its dissolution as well as permeation behavior.dissolution as well as permeation behavior.

Characterization of the permeation behavior of a Characterization of the permeation behavior of a new drug must be performed at an early stage of new drug must be performed at an early stage of drug development-primarily to help avoid drug development-primarily to help avoid mistaken efforts to improve its absorption by mistaken efforts to improve its absorption by improving dissolution, when in reality the improving dissolution, when in reality the absorption is permeability-limited.absorption is permeability-limited.

Permeability studies are of even greater Permeability studies are of even greater importance when analogs of the compound having importance when analogs of the compound having similar pharmacological attributes are availablesimilar pharmacological attributes are available

Permeability studies then would aid in the Permeability studies then would aid in the selection of the compound with the greatest selection of the compound with the greatest absorption potential.absorption potential.

Partition CoefficientPartition Coefficient

Like biological membrane in general, the gi Like biological membrane in general, the gi membranes are largely lipoidal in character.membranes are largely lipoidal in character.

The rate and extent of absorption decreased The rate and extent of absorption decreased with the increasing polarity of molecules.with the increasing polarity of molecules.

Partition coefficient (distribution coefficient):Partition coefficient (distribution coefficient): the ratio in which a solute distributes itself the ratio in which a solute distributes itself between the two phases of two immiscible between the two phases of two immiscible liquids that are in contact with each other liquids that are in contact with each other (mostly n-octanol/water).(mostly n-octanol/water).

Comparison Between Colonic Absorption and Lipid/Water Comparison Between Colonic Absorption and Lipid/Water Partition of the Un-ionized forms of BarbituratesPartition of the Un-ionized forms of Barbiturates

Chloroform/waterChloroform/waterBarbiturateBarbiturate % Absorbed % Absorbed partition coefficientpartition coefficient

BarbitalBarbital 12 12 ++ 2 2 0.7 0.7AprobarbitalAprobarbital 17 17 ++ 2 2 4.0 4.0PhenobarbitalPhenobarbital 20 20 ++ 3 3 4.8 4.8Allylbarbituric acidAllylbarbituric acid 23 23 ++ 3 3 10.510.5ButethalButethal 24 24 ++ 3 3 11.711.7CyclobarbitalCyclobarbital 24 24 ++ 3 3 18.018.0PentobarbitalPentobarbital 30 30 ++ 2 2 23.023.0SecobarbitalSecobarbital 40 40 ++ 3 3 50.750.7HexethalHexethal 44 44 ++ 3 3 > 100.0 > 100.0(Schanker)(Schanker)

1. Accelerated Stability Studies of 1. Accelerated Stability Studies of Pure Drug SubstancePure Drug Substance

Effects of temperature and Effects of temperature and humidityhumidity

Effects of lightEffects of light Effects of oxygenEffects of oxygen Effects of pHEffects of pH

Effects of Temperature and HumidityEffects of Temperature and Humidity

Raw materialRaw material

NN22, Ar, Ar

RefrigeratorRefrigeratorRoom temperatureRoom temperature40 40 ooCC50 50 ooCC60 60 ooCC

Environmental chamberEnvironmental chamber40 40 ooC/ 75 %C/ 75 %RHRH

Effects of LightEffects of Light


Light cabinetLight cabinetfluorescencefluorescence400-500 fc 400-500 fc ((foot-candlesfoot-candles))4 4 weeksweeks

SolidSolid

LiquidLiquid

AmberAmberglass vialglass vial(control)(control)

Petri dish

AmberAmberglass ampulglass ampul

(control)(control)

Clear glass ampul

Effects of OxygenEffects of Oxygen


DarkDarkroom temp.room temp.4 4 weeksweeks

SolidSolid

LiquidLiquid

OO22 Bubbled Bubbled

NN22 Bubbled Bubbled

OO22 Bubbled Bubbled

NN22 Bubbled Bubbled

Effects of pHEffects of pH

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8 9 10

pHpH

PercentPercentRecoveredRecovered

Accelerated Stability Studies of Pure Drug Accelerated Stability Studies of Pure Drug SubstanceSubstance

Accelerated Stability Studies of Pure Drug Accelerated Stability Studies of Pure Drug SubstanceSubstance

Solid StateSolid State Exposure ConditionExposure Condition Container Container DurationDuration TemperatureTemperature 50 50 ooCC Tightly sealed vials Tightly sealed vials 4 weeks 4 weeks

LightLight Fluorescent 400 fc Fluorescent 400 fc 1. Clear glass bottles 1. Clear glass bottles 4 weeks 4 weeks 2. Amber glass bottles2. Amber glass bottles

HumidityHumidity 75 % RH, 40 75 % RH, 40 ooCC Clear vials, lids off Clear vials, lids off 4 weeks 4 weeks

Solution State - Drug Dissolved in the Following SolutionsSolution State - Drug Dissolved in the Following Solutions1. Standard pH 3 buffer1. Standard pH 3 buffer2. Standard pH 5 buffer2. Standard pH 5 buffer3. Standard pH 7 buffer3. Standard pH 7 buffer4. Standard pH 10 buffer4. Standard pH 10 buffer

Exposure ConditionExposure Condition Container Container DurationDuration TemperatureTemperature 50 50 ooCC Glass bottlesGlass bottles 4 weeks 4 weeks LightLight 1. Fluorescent 400 fc 1. Fluorescent 400 fc Glass bottlesGlass bottles 4 weeks 4 weeks

2. Dark2. Dark Glass bottles covered inGlass bottles covered in Al foil; placed in Al foil; placed in

cabinetcabinet

OxygenOxygen 1. O 1. O22 bubbled for 1 hr bubbled for 1 hr Sealed glass ampulesSealed glass ampules 4 weeks 4 weeks

2. N2. N22 bubbled for 1 hr bubbled for 1 hr Sealed glass ampulesSealed glass ampules

Effects of Temperature, Light, Oxygen, and pH Effects of Temperature, Light, Oxygen, and pH on Stability of a Pure Drug Substanceon Stability of a Pure Drug Substance

Percent Degradation after 4 weeksPercent Degradation after 4 weeks

Fluorescent LightFluorescent Light

pHpH Buffer System Buffer System 50 50 ooCC Clear Bottle Amber Bottle Oxygen NitrogenClear Bottle Amber Bottle Oxygen Nitrogen

33 Phthalate-HCl Phthalate-HCl < 1< 1 30 30 4 4 < 1 < 1 < 1 < 1

55 Citrate-Phosphate Citrate-Phosphate < 1< 1 28 28 4 4 1 1 1 1

77 Phosphate Phosphate 7 7 63 63 10 10 3 3 4 4

1010 Borate-NaOH Borate-NaOH 53 53 78 78 40 40 28 28 28 28

Conclusion of Conclusion of Pure DrugPure Drug Stability Stability Less effect fromLess effect from temperature and humidity temperature and humidity

Hydrolysis or photochemical decomposition, but not Hydrolysis or photochemical decomposition, but not oxidationoxidation

Significant effect fromSignificant effect from light light Photochemical decompositionPhotochemical decomposition

Less effect from Less effect from oxygenoxygen No oxidationNo oxidation

Significant Significant eeffect ffect fromfrom pH pH higher than 7higher than 7 Alkaline hydrolysisAlkaline hydrolysis

Drug decomposed by alkaline pH and lightDrug decomposed by alkaline pH and light Use pH < 7 and protect from light, but no need to add Use pH < 7 and protect from light, but no need to add

antioxidant antioxidant

Drug-Excipient Binary MixturesDrug-Excipient Binary Mixtures

- Stress condition and analysis for drug- Stress condition and analysis for drugdrug + fillerdrug + filler - Differential Scanning Calorimetry - Differential Scanning Calorimetry (DSC)(DSC)drug + binderdrug + binder - Fourier Transform Infrared Spectroscopy drug - Fourier Transform Infrared Spectroscopy drug + disintegrant + disintegrant (FTIR)(FTIR)drug + lubricantdrug + lubricant - Diffuse Reflectance Infrared Fourier - Diffuse Reflectance Infrared Fourier

etc. etc. Transform Spectroscopy (DRIFT) Transform Spectroscopy (DRIFT) - Powder X-Ray Diffraction (PXRD)- Powder X-Ray Diffraction (PXRD)- Nuclear Magnetic Resonance- Nuclear Magnetic Resonance

Spectroscopy (NMR) Spectroscopy (NMR)

2. Drug-Excipient Compatibility Studies2. Drug-Excipient Compatibility Studies

Amount ofAmount ofmixture drugmixture drug Variables Variables aa

PercentPercentTrial (mg)Trial (mg) XX11 X X22 X X33 X X44 X X55 X X66 X X77 X X88 X X99 X X1010 X X1111 Recovery Recovery

1 501 50 + ++ + - - + + ++ + + - - -- - - + + - - 8383 2 502 50 ++ - - + + ++ + + - - -- - - + + - - ++ 8787 3 503 50 -- + + ++ + + - - -- - - ++ - - + ++ + 8989 4 504 50 + + ++ + + -- - - - - ++ - - + ++ + -- 8484 5 505 50 + ++ + - -- - - - + + - - + ++ + - - ++ 8484 6 506 50 + + - - -- - - ++ -- + ++ + - - + ++ + 9191 7 507 50 - - -- - - ++ - - + ++ + - - + + ++ + + 8181 8 508 50 - -- - + + -- + ++ + - - + + ++ + + - - 7474 9 509 50 - - ++ -- + ++ + -- + + ++ + + - -- - 8585 10 5010 50 ++ -- + ++ + - - + + ++ + + - - -- - - 6565 11 5011 50 - - + ++ + -- + + ++ + + - - -- - - ++ 7777 12 5012 50 - - - -- - - - - - - - - - - - - - - - - - 8888Sum +Sum + 494 502 476 490 497 464 483 488 495 502 509 494 502 476 490 497 464 483 488 495 502 509Sum - Sum - 494 486 512 498 491 524 505 500 493 486 479 494 486 512 498 491 524 505 500 493 486 479Average effect: 0.0 2.7 -6.0Average effect: 0.0 2.7 -6.0c c -1.3 1.0 -10.0-1.3 1.0 -10.0b b -3.7 -2.0 0.33 2.7 5.0-3.7 -2.0 0.33 2.7 5.0

aa See the text for an explanation of + and - See the text for an explanation of + and -bb Significant effect Significant effectcc Borderline effect Borderline effect

Plackett-Burman Design in the Study of the Effect of Excipients on Plackett-Burman Design in the Study of the Effect of Excipients on Stability of Drug After Storage at 75 Stability of Drug After Storage at 75 ooC for 2 WeeksC for 2 Weeks

Average Effect for XAverage Effect for X22 = (502 - 486)/6 = 16/6 = 2.7 = (502 - 486)/6 = 16/6 = 2.7

Standard deviation of the factor effect SStandard deviation of the factor effect SFEFE

SSFEFE == (-3.7)(-3.7)22 + (-2.0) + (-2.0)22 + (0.33) + (0.33)22 + (2.7) + (2.7)22 + (5.0) + (5.0)22

55

== 3.163.16

Minimum significant factor effect EMinimum significant factor effect Emsms = t.S = t.SFEFE

at 90 % confidence level, degree of freedom = 5,at 90 % confidence level, degree of freedom = 5,

from Student’s t-distribution table: t = 2.02from Student’s t-distribution table: t = 2.02

EEmsms == (2.02)(3.16)(2.02)(3.16)

== 6.46.4

Amount ofAmount ofmixture drugmixture drug Variables Variables aa

PercentPercentTrial (mg)Trial (mg) XX11 X X22 X X33 X X44 X X55 X X66 X X77 X X88 X X99 X X1010 X X1111 Recovery Recovery

1 501 50 + ++ + - - + + ++ + + - - -- - - + + - - 8383 2 502 50 ++ - - + + ++ + + - - -- - - + + - - ++ 8787 3 503 50 -- + + ++ + + - - -- - - ++ - - + ++ + 8989 4 504 50 + + ++ + + -- - - - - ++ - - + ++ + -- 8484 5 505 50 + ++ + - -- - - - + + - - + ++ + - - ++ 8484 6 506 50 + + - - -- - - ++ -- + ++ + - - + ++ + 9191 7 507 50 - - -- - - ++ - - + ++ + - - + + ++ + + 8181 8 508 50 - -- - + + -- + ++ + - - + + ++ + + - - 7474 9 509 50 - - ++ -- + ++ + -- + + ++ + + - -- - 8585 10 5010 50 ++ -- + ++ + - - + + ++ + + - - -- - - 6565 11 5011 50 - - + ++ + -- + + ++ + + - - -- - - ++ 7777 12 5012 50 - - - -- - - - - - - - - - - - - - - - - - 8888Sum +Sum + 494 502 476 490 497 464 483 488 495 502 509 494 502 476 490 497 464 483 488 495 502 509Sum - Sum - 494 486 512 498 491 524 505 500 493 486 479 494 486 512 498 491 524 505 500 493 486 479Average effect: 0.0 2.7 -6.0Average effect: 0.0 2.7 -6.0c c -1.3 1.0 -10.0-1.3 1.0 -10.0b b -3.7 -2.0 0.33 2.7 5.0-3.7 -2.0 0.33 2.7 5.0

aa See the text for an explanation of + and - See the text for an explanation of + and -bb Significant effect Significant effectcc Borderline effect Borderline effect

Plackett-Burman Design in the Study of the Effect of Excipients on Plackett-Burman Design in the Study of the Effect of Excipients on Stability of Drug After Storage at 75 Stability of Drug After Storage at 75 ooC for 2 WeeksC for 2 Weeks

acyclovir

Ethylcellulose film

DSC thermograms of DSC thermograms of pure acyclovir and purpure acyclovir and pure ethylcellulose filmse ethylcellulose films

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

DSC thermograms of DSC thermograms of (1)(1) ranitidine HCl , ranitidine HCl , (2)(2) 1:1 ranitidine HCl-lactose mixture 1:1 ranitidine HCl-lactose mixture (3)(3) lactose.lactose.

(1) ranitidine HCl(1) ranitidine HCl

(2) 1:1 ranitidine HCl-(2) 1:1 ranitidine HCl-lactose mixturelactose mixture

(3) lactose(3) lactose


- Stress condition and analysis for drug- Stress condition and analysis for drugdrug + fillerdrug + filler - Differential Scanning Calorimetry - Differential Scanning Calorimetry (DSC)(DSC)drug + binderdrug + binder - Fourier Transform Infrared Spectroscopy- Fourier Transform Infrared Spectroscopy drug drug + disintegrant + disintegrant (FTIR)(FTIR)drug + lubricantdrug + lubricant - Diffuse Reflectance Infrared Fourier - Diffuse Reflectance Infrared Fourier




FTIR spectra of pure acyclovir, pure ethylcellulose film andFTIR spectra of pure acyclovir, pure ethylcellulose film and12.8 % 12.8 % acyclovir-ethylcellulose filmacyclovir-ethylcellulose film

AcyclovirAcyclovir

Ethylcellulose filmEthylcellulose film

Acyclovir-ethylcellulose filmAcyclovir-ethylcellulose film

FTIR spectra of erythromycin-Eudragit LFTIR spectra of erythromycin-Eudragit L100100 mixture mixturea. erythromycin after being heateda. erythromycin after being heatedb. erythromycin powder recrystallized from b. erythromycin powder recrystallized from 1:1-1:1-isopropanol:acetoneisopropanol:acetonec. erythromycin-polymer mixturec. erythromycin-polymer mixtured. polymer pure powderd. polymer pure powder

DRIFTS spectra of DRIFTS spectra of (1)(1) ranitidine HClranitidine HCl(2)(2) 1:1 ranitidine HCl-Eudragit E1001:1 ranitidine HCl-Eudragit E100 mixture mixture(3)(3) Eudragit E100Eudragit E100

Diltiazem HCl

50 % w/w diltiazem HCl in ethylcellulose 10 cps

25 % w/w diltiazem HCl in ethylcellulose 10 cps

Ethylcellulose 10 cps

Some Examples of Drug-Excipient InteractionsSome Examples of Drug-Excipient InteractionsDrugDrug ExcipientExcipient

AcetaminophenAcetaminophen Ascorbic acidAscorbic acidAmine drugsAmine drugs LactoseLactoseAminophyllineAminophylline LactoseLactoseAmpicillin trihydrateAmpicillin trihydrate SucroseSucroseAspirinAspirin Magnesium stearateMagnesium stearateBenzocaineBenzocaine Polyethylene glycol seriesPolyethylene glycol seriesBromhexine hydrochlorideBromhexine hydrochloride AvicelAvicelCeftazidimeCeftazidime Sodium carbonateSodium carbonateCephradineCephradine N-methylglucamineN-methylglucamine

Trisodium phosphate Trisodium phosphate dodecahydratedodecahydrate

TromethamineTromethamineDexamethasoneDexamethasone Cellulose acetate phthalateCellulose acetate phthalateDiazepamDiazepam Starch 1500Starch 1500

AvicelAvicelEmcompressEmcompress

Diphenhydramine hydrochlorideDiphenhydramine hydrochloride Magnesium stearateMagnesium stearateFurosemideFurosemide Magnesium stearateMagnesium stearateGriseofulvinGriseofulvin PolyvinylpyrrolidonePolyvinylpyrrolidoneHydrochlorothiazideHydrochlorothiazide PolyvinylpyrrolidonePolyvinylpyrrolidoneIbuprofenIbuprofen Sodium carboxymethylcelluloseSodium carboxymethylcellulose

Some Examples of Drug-Excipient InteractionsSome Examples of Drug-Excipient Interactions DrugDrug ExcipientExcipient

IndomethacinIndomethacin LactoseLactoseIsoniazidIsoniazid LactoseLactoseKetoprofenKetoprofen LactoseLactoseNaproxenNaproxen Magnesium stearateMagnesium stearateNitrazepamNitrazepam EmcompressEmcompressNorfloxacinNorfloxacin Potato starchPotato starchOxazolamOxazolam AvicelAvicelOxytetracycline hydrochlorideOxytetracycline hydrochloride Starch 1500Starch 1500Phenylephrine hydrochloridePhenylephrine hydrochloride LactoseLactosePhenylpropanolaminePhenylpropanolamine LactoseLactosePrednisolonePrednisolone PolyvinylpyrrolidonePolyvinylpyrrolidoneReserpineReserpine PolyvinylpyrrolidonePolyvinylpyrrolidoneRifampicinRifampicin Avicel PH101Avicel PH101SulfamethoxazoleSulfamethoxazole Cellulose acetate phthalateCellulose acetate phthalate

TalcumTalcumTetracyclineTetracycline Magnesium stearateMagnesium stearateTolbutamideTolbutamide Sodium chlorideSodium chlorideVitamin B1Vitamin B1 Microcrystalline celluloseMicrocrystalline celluloseVitamin CVitamin C SucroseSucrose

ตั�วยาสำาคั�ญตั�วยาสำาคั�ญ สำารโพลิ�เมอร�สำารโพลิ�เมอร�Acyclovir*Acyclovir* Ethylcellulose Ethylcellulose CarbamazCarbamazepine epine

HPMCHPMC

Carteolol Carteolol Eudragit L30D Eudragit L30D Diltiazem Diltiazem HCl*HCl*

Ethylcellulose Ethylcellulose

Ephedrine Ephedrine HClHCl

HPMC, polyvinyl HPMC, polyvinyl alcoholalcohol

ErythromyErythromycincin

Eudragit L100, Eudragit L100, Shellac Shellac

FurosemidFurosemide* e*

Eudragit RL, Eudragit RL, Eudragit RS Eudragit RS

IndomethaIndomethacin cin

PVPPVPChitosanChitosan

Ibuprofen*Ibuprofen* PVPPVPChitosanChitosan

Morphine Morphine Eudragit L30D Eudragit L30D

ตั�วยาสำาคั�ญตั�วยาสำาคั�ญ สำารโพลิ�เมอร�สำารโพลิ�เมอร�KetoprofeKetoprofen n

HPMCHPMCPVPPVP

Piroxicam* Piroxicam* Eudragit E Eudragit E PropranolPropranolol ol

Eudragit L Eudragit L

Ranitidine Ranitidine HClHCl

Eudragit EEudragit E

Salicylic Salicylic acid*acid*

Eudragit RL, Eudragit RL, Eudragit RSEudragit RSChitosanChitosan

Sulindac*Sulindac* PVP K30PVP K30TheophylliTheophylline*ne*

Eudragit L100Eudragit L100Chitosan-Chitosan-alginatealginate

Triptolide*Triptolide* Poly(D,L-lactic Poly(D,L-lactic acid) acid)

Verapamil Verapamil HClHCl

Eudragit L Eudragit L

Xanthone*Xanthone* Poly(lactic-Poly(lactic-glycolic acid) glycolic acid)

3. Experimental Formulation Screening3. Experimental Formulation Screening

Fractional-Order Randomized Block DesignFractional-Order Randomized Block Design5 variables [ 5 variables [ 2 levels2 levels (5 variables)(5 variables) = 32 ] = 32 ]

A- A+

B- B-B+ B+

C- C+ C- C+ C- C+ C- C+

D-

D+

E-

E-

E+

E+

1

2 1

1

1

1

1

1

12

2

2

2

2

2

2

Fractional-Order Randomized Block DesignFractional-Order Randomized Block Design

4 variables4 variables 3 variables3 variables

A- A+

B- B-B+ B+

C-

C+

D-

D-

D+

D+

2

2

2

2

2

2

2

2

1

1

1

1

1

1

1

1

A- A+

B- B-B+ B+

C-

C+

Design of Tablet FormulationDesign of Tablet Formulation

Norfloxacin Norfloxacin : 100 mg: 100 mg ToolingTooling

: 3/8” standard flat-faced punches: 3/8” standard flat-faced punches Tablet pressTablet press : single punch tablet machine: single punch tablet machine

Fette Model Exacta IFette Model Exacta I Tablet weightTablet weight : 300 mg: 300 mg HardnessHardness : 5 - 7 kg: 5 - 7 kg ProcessProcess : Direct compression: Direct compression

SluggingSlugging

Wet granulationWet granulation


4 variables4 variables

A-A- A+A+

B-B- B-B-B+B+ B+B+

C-C-

C+C+

D-D-

D-D-

D+D+

D+D+

VV

VIVI

VIIVII

VIIIVIII

II

IIII

IIIIII

IVIV

A = filler A = filler A- = lactoseA- = lactoseA+ = mannitolA+ = mannitol

B = disintegrantB = disintegrantB- = ExplotabB- = ExplotabB+ = Ac-di-solB+ = Ac-di-sol

C = binderC = binderC- = Starch 1500C- = Starch 1500C+ = PVP K30C+ = PVP K30

D = lubricantD = lubricantD- = Magnesium stearateD- = Magnesium stearateD+ = AerosilD+ = Aerosil

PRODUCT NAME: PRODUCT NAME: Norfloxacin tablets 100 mgNorfloxacin tablets 100 mg BATCH SIZE: BATCH SIZE: Per tabletPer tabletMETHOD: METHOD: Wet granulation methodWet granulation method

RxRx II IIII IIIIII IVIV VV VIVI VIIVII VIIIVIII

IngredientIngredient mgmg mgmg mgmg mgmg mgmg mgmg mgmg mgmg

NorfloxacinNorfloxacin 100100 100100 100100 100100 100100 100100 100100 100100

LactoseLactose 171.5 174.3171.5 174.3 173173 163163

MannitolMannitol 167167 168.6168.6 177.5177.5 167.5167.5

Explotab 15 Explotab 15 1515 1515 15 15

Ac-Di-SolAc-Di-Sol 99 9 9 9 9 9 9

Starch 1500 6Starch 1500 6 6 6 6 6 6 6

PVP K30PVP K30 9.29.2 10.410.4 1010 10 10

Mg stearate 1.5Mg stearate 1.5 1.51.5 1.51.5 1.5 1.5

AerosilAerosil 6 6 6 6 6 6 6 6

TalcumTalcum 66 66 6 6 6 6 6 6 6 6 6 6 6 6

Tablet weightTablet weight 300.0300.0 300.0300.0 300.0300.0 300.0300.0 300.0300.0 300.0300.0 300.0300.0300.0300.0

PRODUCT NAME: PRODUCT NAME: Norfloxacin tablets 100 mgNorfloxacin tablets 100 mg BATCH SIZE: BATCH SIZE: 300 tablets300 tabletsMETHOD: METHOD: Wet granulation methodWet granulation method

RxRx II IIII IIIIII IVIV VV VIVI VIIVII VIIIVIIIIngredientIngredient gg gg gg gg gg g g g g g g

Norfloxacin 30 30 30 30 30 30 30 30Norfloxacin 30 30 30 30 30 30 30 30

LactoseLactose 51.45 52.3 51.45 52.3 51.9 48.9 51.9 48.9

Mannitol 50.1 50.58Mannitol 50.1 50.58 53.25 50.25 53.25 50.25

Explotab 4.5 Explotab 4.5 4.54.5 4.54.5 4.54.5

Ac-Di-SolAc-Di-Sol 2.72.7 2.72.7 2.72.7 2.72.7

Starch 1500 1.8Starch 1500 1.8 1.8 1.8 1.81.8 1.81.8

PVP K30PVP K30 2.772.77 3.12 3.12 3 3 3 3

Mg stearate 0.45Mg stearate 0.450.450.45 0.450.45 0.450.45

AerosilAerosil 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8

TalcumTalcum 1.8 1.8 1.81.8 1.81.8 1.81.8 1.81.8 1.81.8 1.81.8 1.8 1.8

การเตัร�ยมยาเม�ด การเตัร�ยมยาเม�ด Norfloxacin Norfloxacin โดยโดยว�ธี� ว�ธี� Wet Granulation Wet Granulation

1. 1. ผสำมผงยา ผสำมผงยา norfloxacin norfloxacin ก�บสำารเพ��มปร�มาณ ก�บสำารเพ��มปร�มาณ ((lactose lactose หร!อ หร!อ mannitol)mannitol) แลิะสำารช่%วยแตักตั�ว แลิะสำารช่%วยแตักตั�ว ((ถ้'าในตัาร�บใช่' ถ้'าในตัาร�บใช่' Ac-Di-Sol Ac-Di-Sol ใสำ%เพ�ยงคัร*�งหน*�งของใสำ%เพ�ยงคัร*�งหน*�งของตัาร�บตัาร�บ แตั%ถ้'าใช่' แตั%ถ้'าใช่' Explotab Explotab ให'ใสำ%ทั้�-ให'ใสำ%ทั้�-งง หมด เน!�องจาก หมด เน!�องจาก

เป/น เป/น superdisintegrantsuperdisintegrant ) ) ให'เข'าก�นด�ใน ให'เข'าก�นด�ใน dry dry mixer mixer นาน นาน 10 10 นาทั้�นาทั้�

2. 2. เตัร�ยมสำารลิะลิายย*ดเกาะของ เตัร�ยมสำารลิะลิายย*ดเกาะของ PVP K30PVP K30 10 % 10 % ใน ในalcohol alcohol โดยโปรย โดยโปรย PVP K30 PVP K30 ลิงใน ลิงใน alcohol alcohol คันจนได'สำารลิะลิายใสำคันจนได'สำารลิะลิายใสำ 3. 3. เตั�มสำารลิะลิายย*ดเกาะลิงใน เตั�มสำารลิะลิายย*ดเกาะลิงใน 1. 1. แตั%ถ้'าใช่' แตั%ถ้'าใช่' Starch Starch 15001500 ให'ผสำม ให'ผสำม Starch 1500 Starch 1500 ด'วยในข�-น ด'วยในข�-น 1. 1. แลิ'วแลิ'วจ*งคั%อยๆ เตั�มน-าทั้��อ2ณหภู4ม�ห'องลิงทั้��ลิะน'อย บดผสำมให'จ*งคั%อยๆ เตั�มน-าทั้��อ2ณหภู4ม�ห'องลิงทั้��ลิะน'อย บดผสำมให'เข'าก�นด�จนได' เข'าก�นด�จนได' damp massdamp mass

การเตัร�ยมยาเม�ด การเตัร�ยมยาเม�ด Norfloxacin Norfloxacin โดยโดยว�ธี� ว�ธี� Wet Granulation Wet Granulation

4. 4. นา นา damp mass damp mass ทั้��ได'ไปผ%านแร%งขนาด ทั้��ได'ไปผ%านแร%งขนาด 14 14

meshmesh อบแกรน4ลิทั้��ได' ทั้��อ2ณหภู4ม� อบแกรน4ลิทั้��ได' ทั้��อ2ณหภู4ม� 50 50 ooC C นาน นาน 6 6ช่มช่ม.. 5. 5. นาแกรน4ลิแห'งไปผ%านแร%งขนาด นาแกรน4ลิแห'งไปผ%านแร%งขนาด 18 18meshmesh แลิ'วแลิ'วผสำมก�บ ผสำมก�บ Ac-Di-SolAc-Di-Sol ทั้��เหลิ!อคัร*�งหลิ�งทั้��เหลิ!อคัร*�งหลิ�ง,, talcum, talcum, Aerosil Aerosil หร!อ หร!อ magnesium stearatemagnesium stearate ใน ใน dry dry mixer mixer นาน นาน 10 10 นาทั้� นาทั้� ((สำาหร�บ สำาหร�บ Aerosil Aerosil แลิะ แลิะ magnesium stearate magnesium stearate ให'ผ%านแร%งขนาด ให'ผ%านแร%งขนาด 80 80 mesh mesh ก%อนช่��งก%อนช่��ง))

6. 6. ตัอกยาเม�ดด'วยเคัร!�องตัอก ตัอกยาเม�ดด'วยเคัร!�องตัอก single punch single punchFetteFette ใช่'ช่2ดสำากแลิะแม%พ�มพ�ขนาด ใช่'ช่2ดสำากแลิะแม%พ�มพ�ขนาด 3/8”3/8”

7. 7. ประเม�นผลิยาเม�ดทั้��ได' ได'แก% น-าหน�ก คัวามแข�ง ประเม�นผลิยาเม�ดทั้��ได' ได'แก% น-าหน�ก คัวามแข�ง คัวามกร%อน การแตักตั�ว แลิะการลิะลิาย คัวามกร%อน การแตักตั�ว แลิะการลิะลิาย

Physicochemical Properties of Prepared Norfloxacin TabletsPhysicochemical Properties of Prepared Norfloxacin Tablets

I 305.0 4.0 5.7 0.6 0.72 7.46 2.75

II 303.0 5.0 5.7 0.5 1.17 10.44 2.74

III 299.0 7.0 6.0 0.6 1.22 12.00 5.00

IV 298.0 4.0 5.8 0.8 0.81 2.25 0.39

V 306.0 4.0 5.0 0.5 0.80 4.25 2.50

VI 304.0 3.0 6.1 0.3 1.26 3.30 0.26

VII 297.0 12.0 5.5 1.7 1.07 1.91 0.31

VIII 301.0 4.0 6.2 0.6 1.14 8.00 3.00

Rx Weight (mg)Rx Weight (mg) Hardness (kg)Hardness (kg) % Friability Disintegration % Friability Disintegration

(20 tablets)(20 tablets) (10 tablets)(10 tablets) (20 tablets) Time (min) (20 tablets) Time (min)

XX SDSD X X SD SD X X SD SD


4 variables4 variables

A-A- A+A+

B-B- B-B-B+B+ B+B+

C-C-

C+C+

D-D-

D-D-

D+D+

D+D+

VV(4.25)(4.25)

VIVI(3.30)(3.30)

VIIVII(1.91)(1.91)

VIIIVIII(8.00)(8.00)

II(7.46)(7.46)

IIII(10.44)(10.44)

IIIIII(15.00)(15.00)

IVIV(2.25)(2.25)

A- = 7.46 + 4.25 + 10.44 + 3.30 = 25.45A- = 7.46 + 4.25 + 10.44 + 3.30 = 25.45A+ = 1.91 + 15.00 + 8.00 + 2.25 = 27.16A+ = 1.91 + 15.00 + 8.00 + 2.25 = 27.16

B- = 7.46 + 3.30 + 15.00 + 8.00 = 33.76B- = 7.46 + 3.30 + 15.00 + 8.00 = 33.76B+ = 4.25 + 10.44 + 1.91 + 2.25 = 18.85B+ = 4.25 + 10.44 + 1.91 + 2.25 = 18.85

C- = 7.46 + 1.91 + 4.25 + 15.00 = 28.62C- = 7.46 + 1.91 + 4.25 + 15.00 = 28.62C+ = 3.30 + 10.44 + 8.00 + 2.25 = 23.99C+ = 3.30 + 10.44 + 8.00 + 2.25 = 23.99

D- = 7.46 + 1.91 + 10.44 + 8.00 = 27.81D- = 7.46 + 1.91 + 10.44 + 8.00 = 27.81D+ = 4.25 + 15.00 + 3.30 + 2.25 = 24.80D+ = 4.25 + 15.00 + 3.30 + 2.25 = 24.80

In conclusion: In conclusion: A-A- , , B+B+ , , C+C+ , , D+D+ Excipients to be chosen:Excipients to be chosen: Filler Filler LactoseLactose Disintegrant Disintegrant Ac-di-solAc-di-sol Binder Binder PVP K30PVP K30 LubricantLubricant AerosilAerosilIXIX

Disintegration time (min)Disintegration time (min)

Recommended Norfloxacin Tablet Recommended Norfloxacin Tablet Formulation:Formulation:

Rx IXRx IX

NorfloxacinNorfloxacin 100.00 100.00 mgmg

LactoseLactose 169.00169.00 mgmg

Ac-Di-SolAc-Di-Sol 9.00 9.00 mgmg

PVP K30PVP K30 10.00 10.00 mgmg

AerosilAerosil 6.00 6.00 mgmg

TalcumTalcum 6.00 6.00 mgmg

Tablet weight =Tablet weight = 300.00300.00 mgmg

Formulations of Norfloxacin Tablets to Undergo Formulations of Norfloxacin Tablets to Undergo Dissolution TestDissolution Test

IngredientIngredient mg/tabmg/tab

Rx VRx V NorfloxacinNorfloxacin 100 mg100 mgLactoseLactose 173 mg173 mgAc-Di-SolAc-Di-Sol 9 mg 9 mgStarch 1500 6 mgStarch 1500 6 mgAerosilAerosil 6 mg 6 mgTalcumTalcum 6 mg 6 mg

Rx VIRx VI NorfloxacinNorfloxacin 100 mg100 mgLactoseLactose 163 mg163 mgExplotabExplotab 15 mg 15 mgPVP K30PVP K30 10 mg 10 mgAerosilAerosil 6 mg 6 mgTalcumTalcum 6 mg 6 mg

IngredientIngredient mg/tabmg/tab

Rx IXRx IX NorfloxacinNorfloxacin 100 mg100 mgLactoseLactose 169 mg169 mgAc-Di-SolAc-Di-Sol 9 mg 9 mgPVP K30PVP K30 10 mg 10 mgAerosilAerosil 6 mg 6 mgTalcumTalcum 6 mg 6 mg

Physicochemical Properties of Prepared Norfloxacin TabletsPhysicochemical Properties of Prepared Norfloxacin Tablets

V 306.0 4.0 5.0 0.5 0.80 4.25 2.50

VI 304.0 3.0 6.1 0.3 1.26 3.30 0.26

IX 301.0 2.0 7.3 1.2 0.62 1.45 0.67

Rx Weight (mg) Hardness (kg) % Friability Disintegration (20 tablets) (10 tablets) (20 tablets) Time (min)

X SD X SD X SD

0

10

20

30

40

50

60

70

80

90

100

0 min 2 min 5 min 10 min 20 min 30 min

Rx V

Rx VI

Rx IX

Time

% D

rug

Dis

solv

ed

Design of Indomethacin Tablet Design of Indomethacin Tablet FormulationFormulation

Indomethacin: 20 mgIndomethacin: 20 mg Tooling:Tooling: 0.635 cm standard 0.635 cm standard

flat-faced punch tipflat-faced punch tip Tablet Press:Tablet Press: Diaf single punch Model TM 20 H Diaf single punch Model TM 20 H Tablet weight: 120 mgTablet weight: 120 mg Hardness:Hardness: 5 - 7 kg 5 - 7 kg Process:Process: Wet granulation Wet granulation

FormulatioFormulationn

Diluent RatioDiluent Ratio

DisintegrantDisintegrantLactoseLactose DCPDCP

11 00 100100

Ac-Di-Sol 4 %Ac-Di-Sol 4 %

22 2020 8080

33 4040 6060

44 6060 4040

55 8080 2020

66 100100 00

77 2020 8080

Corn starch 8 %Corn starch 8 %88 4040 6060

99 6060 4040

1010 8080 2020

1111 100100 00

PRODUCT NAME: PRODUCT NAME: Indomethacin tablets 20 mgIndomethacin tablets 20 mg BATCH SIZE: BATCH SIZE: Per tabletPer tabletMETHOD: METHOD: Wet granulation methodWet granulation method

Rx 1 2 3 4 5 6 7 8 9 10 11Rx 1 2 3 4 5 6 7 8 9 10 11

IngredientIngredient mg mg mg mg mg mg mg mgmg mg mg mg mg mg mg mg mg mg mg mg mgmg

Indomethacin 20Indomethacin 20 20 20 20 20 20 2020 20 20 20 20 20 20 20 20 20 20 20 20 20

LactoseLactose 18.3 18.3 36.6 55.0 73.3 91.6 36.6 55.0 73.3 91.6 17.4 17.4 34.7 52.1 69.4 34.7 52.1 69.4 86.886.8

DCP 91.6 73.3 55.0 36.6 18.3 DCP 91.6 73.3 55.0 36.6 18.3 69.4 69.4 52.1 34.7 17.4 52.1 34.7 17.4

Ac-Di-SolAc-Di-Sol 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8

Corn starchCorn starch 9.6 9.6 9.6 9.6 9.6 9.6 9.6 9.6 9.6 9.6

Starch paste 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8Starch paste 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8

10 %w/w10 %w/w

Stearic acid Stearic acid 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.81.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8

Tablet Tablet 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120120

weightweight

การเตัร�ยมยาเม�ด การเตัร�ยมยาเม�ด IndomethIndomethacin acin โดยว�ธี� โดยว�ธี� Wet Granulation Wet Granulation

1. 1. นาผงยา นาผงยา indomethacin indomethacin แลิะสำ%วนประกอบแลิะสำ%วนประกอบทั้�-งหมดในตัาร�บ มาผ%านแร%ง ทั้�-งหมดในตัาร�บ มาผ%านแร%ง 80 mesh80 mesh 2. 2. ผสำมผงยา ผสำมผงยา indomethacin indomethacin ก�บสำารเพ��มก�บสำารเพ��มปร�มาณ ปร�มาณ ((lactose lactose แลิะแลิะ//หร!อ หร!อ DCP)DCP) แลิะสำารแลิะสำารช่%วยแตักตั�ว ช่%วยแตักตั�ว - - (Ac Di Sol- - (Ac Di Sol หร!อ หร!อ corn starch) corn starch)((ใสำ%เพ�ยงคัร*�งหน*�งของตัาร�บใสำ%เพ�ยงคัร*�งหน*�งของตัาร�บ ) ) ให'เข'าก�นด�ใน ให'เข'าก�นด�ใน dry dry mixer mixer นาน นาน 10 10 นาทั้�นาทั้�

3. 3. เตัร�ยมสำารลิะลิายย*ดเกาะของ เตัร�ยมสำารลิะลิายย*ดเกาะของ starch paste starch paste10 %w/w 10 %w/w 4. 4. เตั�มสำารลิะลิายย*ดเกาะลิงใน เตั�มสำารลิะลิายย*ดเกาะลิงใน 2. 2. บดผสำมให'เข'าบดผสำมให'เข'าก�นด�จนได' ก�นด�จนได' damp massdamp mass

การเตัร�ยมยาเม�ด การเตัร�ยมยาเม�ด Indomethacin Indomethacin โดยว�ธี� โดยว�ธี� Wet Granulation Wet Granulation

5. 5. นา นา damp mass damp mass ทั้��ได'ไปผ%านแร%งขนาด ทั้��ได'ไปผ%านแร%งขนาด 14 14

meshmesh 6. 6. อบแกรน4ลิทั้��ได' ทั้��อ2ณหภู4ม� อบแกรน4ลิทั้��ได' ทั้��อ2ณหภู4ม� 50 50 ooC C นาน นาน 8 8 ช่มช่ม.. 7. 7. นาแกรน4ลิแห'งไปผ%านแร%งขนาด นาแกรน4ลิแห'งไปผ%านแร%งขนาด 20 20meshmesh แลิ'วแลิ'วผสำมก�บสำารช่%วยแตักตั�วทั้��เหลิ!อคัร*�งหลิ�งผสำมก�บสำารช่%วยแตักตั�วทั้��เหลิ!อคัร*�งหลิ�ง แลิะ แลิะstearic acidstearic acid ใน ใน dry mixer dry mixer นาน นาน 10 10 นาทั้� นาทั้�

8. 8. ตัอกยาเม�ดด'วยเคัร!�องตัอก ตัอกยาเม�ดด'วยเคัร!�องตัอก single punch single punchDiafDiaf ใช่'ช่2ดสำากแลิะแม%พ�มพ�หน'าเร�ยบขนาด ใช่'ช่2ดสำากแลิะแม%พ�มพ�หน'าเร�ยบขนาด 0.635 0.635 cm cm ให'ได'น-าหน�ก ให'ได'น-าหน�ก 120 mg 120 mg แลิะคัวามแข�ง แลิะคัวามแข�ง - 5 7 - 5 7

kgkg9. 9. ประเม�นผลิยาเม�ดทั้��ได' ได'แก% น-าหน�ก คัวามแข�ง ประเม�นผลิยาเม�ดทั้��ได' ได'แก% น-าหน�ก คัวามแข�ง

คัวามกร%อน การแตักตั�ว แลิะการลิะลิาย คัวามกร%อน การแตักตั�ว แลิะการลิะลิาย

Physicochemical Properties of Prepared Indomethacin TabletsPhysicochemical Properties of Prepared Indomethacin Tablets

Rx Diluent Hardness (kg) % Friability Disintegration

Ratio (10 tablets) (20 tablets) Time (sec)

Lactose DCP X SD X SD


11 0 100 6.83 0.95 0 100 6.83 0.95 0.320.32 13.17 13.17 2.142.14

22 20 20 80 80 6.12 6.12 0.36 0.36 0.280.28 49.17 49.17 4.964.96

33 40 40 60 60 5.54 5.54 0.77 0.77 0.350.35 45.66 45.66 6.026.02

44 60 60 40 40 5.65 5.65 0.76 0.76 0.450.45 25.00 25.00 4.204.20

55 80 80 20 20 6.99 6.99 0.83 0.83 0.300.30 66.83 66.83 9.919.91

66 100 100 0 0 5.56 5.56 0.88 0.88 0.240.24 31.33 31.33 1.911.91

Corn starch 8 %Corn starch 8 %

77 20 20 80 80 7.34 7.34 0.87 0.87 0.250.25 63.17 63.17 3.823.82

88 40 40 60 60 5.23 5.23 1.14 1.14 0.320.32 17.33 17.33 2.072.07

99 60 60 40 40 5.84 5.84 0.70 0.70 0.380.38 34.33 34.33 8.418.41

1010 80 80 20 20 5.39 5.39 0.80 0.80 0.280.28 31.83 31.83 4.924.92

1111 100 100 0 0 6.18 6.18 1.02 1.02 0.200.20 31.33 31.33 5.245.24

0102030405060708090

100

0 5 10 15 20 25 30 40 60

0/100

20/80

40/60

60/40

80/20

100/0

Time (min)

Cu

mu

lati

ve %

Dis

solv

ed

Lactose:DCP

Dissolution profiles of indomethacin from tablets with lactose-DCPDissolution profiles of indomethacin from tablets with lactose-DCPmixtures at various ratios as fillers and Ac-Di-Sol as a disintegrant.mixtures at various ratios as fillers and Ac-Di-Sol as a disintegrant.

0102030405060708090

100

0 5 10 15 20 25 30 40 60

20/80

40/60

60/40

80/20

100/0

Time (min)

Cu

mu

lati

ve %

Dis

solv

ed

Lactose:DCP

Dissolution profiles of indomethacin from tablets with lactose-DCPDissolution profiles of indomethacin from tablets with lactose-DCPmixtures at various ratios as fillers and corn starch as a disintegrant.mixtures at various ratios as fillers and corn starch as a disintegrant.






11 0 100 6.83 0.95 0 100 6.83 0.95 0.320.32 13.17 13.17 2.142.14

22 20 20 80 80 6.12 6.12 0.36 0.36 0.280.28 49.17 49.17 4.964.96

33 40 40 60 60 5.54 5.54 0.77 0.77 0.350.35 45.66 45.66 6.026.02

44 60 60 40 40 5.65 5.65 0.76 0.76 0.450.45 25.00 25.00 4.204.20

55 80 80 20 20 6.99 6.99 0.83 0.83 0.300.30 66.83 66.83 9.919.91

66 100 100 0 0 5.56 5.56 0.88 0.88 0.240.24 31.33 31.33 1.911.91

Corn starch 8 %Corn starch 8 %

77 20 20 80 80 7.34 7.34 0.87 0.87 0.250.25 63.17 63.17 3.823.82

88 40 40 60 60 5.23 5.23 1.14 1.14 0.320.32 17.33 17.33 2.072.07

99 60 60 40 40 5.84 5.84 0.70 0.70 0.380.38 34.33 34.33 8.418.41

1010 80 80 20 20 5.39 5.39 0.80 0.80 0.280.28 31.83 31.83 4.924.92

1111 100 100 0 0 6.18 6.18 1.02 1.02 0.200.20 31.33 31.33 5.245.24





Ac-Di-Sol 4 % + SLS 0.2 %Ac-Di-Sol 4 % + SLS 0.2 %

1212 40 60 7.95 0.57 40 60 7.95 0.57 0.270.27 46.17 46.17 0.98 0.98

1313 80 80 20 20 6.64 6.64 0.60 0.60 0.280.28 66.17 66.17 12.7412.74

1414 100 100 0 0 6.56 6.56 0.63 0.63 0.220.22 102.50 102.50 11.9611.96

Corn starch 8 % + SLS 0.2 %Corn starch 8 % + SLS 0.2 %

1515 20 20 80 80 5.94 5.94 0.40 0.40 0.300.30 64.33 64.33 2.25 2.25

1616 60 60 40 40 4.60 4.60 0.50 0.50 0.280.28 41.67 41.67 6.06 6.06

1717 80 80 20 20 7.91 7.91 0.87 0.87 0.300.30 88.50 88.50 7.34 7.34

1818 100 100 0 0 6.74 6.74 0.54 0.54 0.230.23 96.67 96.67 20.9320.93

0

20

40

60

80

100

120

0 5 10 15 20 25 30 40 60

40/60

80/20

100/0

Time (min)

Cu

mu

lati

ve %

Dis

solv

ed

Lactose:DCP

Dissolution profiles of indomethacin from tablets with lactose-DCPDissolution profiles of indomethacin from tablets with lactose-DCPmixtures at various ratios as fillers, Ac-Di-Sol as a disintegrant,mixtures at various ratios as fillers, Ac-Di-Sol as a disintegrant,

and 0.2 % SLS (intragranular).and 0.2 % SLS (intragranular).

0102030405060708090

100

0 5 10 15 20 25 30 40 60

20/80

60/40

80/20

100/0

Time (min)

Cu

mu

lati

ve %

Dis

solv

ed

Lactose:DCP

Dissolution profiles of indomethacin from tablets with lactose-DCPDissolution profiles of indomethacin from tablets with lactose-DCPmixtures at various ratios as fillers, corn starch as a disintegrant,mixtures at various ratios as fillers, corn starch as a disintegrant,

and 0.2 % SLS (intragranular).and 0.2 % SLS (intragranular).

0

20

40

60

80

100

120

0 5 10 15 20 25 30 40 60

No SLS

0.2 % SLS

Time (min)

Cu

mu

lati

ve %

Dis

solv

ed

Dissolution profiles of indomethacin from tablets with lactose-DCPDissolution profiles of indomethacin from tablets with lactose-DCPmixtures at 100:0 ratio as a filler and Ac-Di-Sol as a disintegrant.mixtures at 100:0 ratio as a filler and Ac-Di-Sol as a disintegrant.

0102030405060708090

100

0 5 10 15 20 25 30 40 60

No SLS

0.2 % SLS

Time (min)

Cu

mu

lati

ve %

Dis

solv

ed

Dissolution profiles of indomethacin from tablets with lactose-DCPDissolution profiles of indomethacin from tablets with lactose-DCPmixtures at 100:0 ratio as a filler and corn starch as a disintegrant.mixtures at 100:0 ratio as a filler and corn starch as a disintegrant.

Practical Approaches to improve Practical Approaches to improve the Dissolution Rate of Tablets:the Dissolution Rate of Tablets:

Water soluble diluentsWater soluble diluents Acid/base bufferingAcid/base buffering Addition of SurfactantAddition of Surfactant Complex formingComplex forming Solid dispersionSolid dispersion

เอกสำารอ'างอ�งเอกสำารอ'างอ�ง1 .1 . ณรงคั� สำาร�สำ2ตัณรงคั� สำาร�สำ2ตั. . การศึ*กษาก%อนการตั�-งตัาร�บแลิะแนวทั้างการตั�-งตัาร�บยาการศึ*กษาก%อนการตั�-งตัาร�บแลิะแนวทั้างการตั�-งตัาร�บยา

ปราศึจากเช่!-อปราศึจากเช่!-อ. . ในใน: : มนตั�ช่2ลิ� น�ตั�พน แลิะ ณ�ฐน�นทั้� สำ�นช่�ยพาน�ช่มนตั�ช่2ลิ� น�ตั�พน แลิะ ณ�ฐน�นทั้� สำ�นช่�ยพาน�ช่, , บรรณาธี�การบรรณาธี�การ. . เทั้คัโนโลิย�สำาหร�บยาปราศึจากเช่!-อเทั้คัโนโลิย�สำาหร�บยาปราศึจากเช่!-อ. . กร2งเทั้พฯกร2งเทั้พฯ: : คัณะคัณะเภูสำ�ช่ศึาสำตัร� มหาว�ทั้ยาลิ�ยมห�ดลิเภูสำ�ช่ศึาสำตัร� มหาว�ทั้ยาลิ�ยมห�ดลิ, 2542: 159-190., 2542: 159-190.

2.2. ณรงคั� สำาร�สำ2ตัณรงคั� สำาร�สำ2ตั. . ระบบนาสำ%งยาในร4ปแบบทั้��เป/นของแข�งระบบนาสำ%งยาในร4ปแบบทั้��เป/นของแข�ง. . ในใน: : การประช่2มการประช่2มว�ช่าการ คัร�-งทั้�� ว�ช่าการ คัร�-งทั้�� 2 2 เร!�อง เทั้คัโนโลิย�เภูสำ�ช่กรรมทั้�นย2คัแลิะการว�จ�ยเก��ยว“เร!�อง เทั้คัโนโลิย�เภูสำ�ช่กรรมทั้�นย2คัแลิะการว�จ�ยเก��ยว“ก�บงานเภูสำ�ช่กรรม ขอนแก%น”ก�บงานเภูสำ�ช่กรรม ขอนแก%น” : : ภูาคัว�ช่าเภูสำ�ช่กรรมเทั้คัโนโลิย� คัณะภูาคัว�ช่าเภูสำ�ช่กรรมเทั้คัโนโลิย� คัณะเภูสำ�ช่ศึาสำตัร� มหาว�ทั้ยาลิ�ยขอนแก%นเภูสำ�ช่ศึาสำตัร� มหาว�ทั้ยาลิ�ยขอนแก%น, 27-28 , 27-28 ก2มภูาพ�นธี� ก2มภูาพ�นธี� 2545:1-22.2545:1-22.

3.3. ณรงคั� สำาร�สำ2ตัณรงคั� สำาร�สำ2ตั. . หลิ�กเกณฑ์�การทั้ดสำอบคัวามคังตั�วของยา ในหลิ�กเกณฑ์�การทั้ดสำอบคัวามคังตั�วของยา ใน: : การการทั้ดสำอบคัวามคังตั�วของยาทั้ดสำอบคัวามคังตั�วของยา. . กร2งเทั้พฯกร2งเทั้พฯ: : ฝ่<ายทั้ดสำอบคัวามคังตั�วของยา ฝ่<ายทั้ดสำอบคัวามคังตั�วของยา กองว�เคัราะห�ยา กรมว�ทั้ยาศึาสำตัร�การแพทั้ย�กองว�เคัราะห�ยา กรมว�ทั้ยาศึาสำตัร�การแพทั้ย�, 2534: 1-103., 2534: 1-103.

4.4. ณรงคั� สำาร�สำ2ตัณรงคั� สำาร�สำ2ตั. . ป=จจ�ยทั้��ม�ผลิคัวามคังตั�วของยา ในป=จจ�ยทั้��ม�ผลิคัวามคังตั�วของยา ใน: : การทั้ดสำอบคัวามการทั้ดสำอบคัวามคังตั�วของยาคังตั�วของยา. . กร2งเทั้พฯกร2งเทั้พฯ: : ฝ่<ายทั้ดสำอบคัวามคังตั�วของยา กองว�เคัราะห�ฝ่<ายทั้ดสำอบคัวามคังตั�วของยา กองว�เคัราะห�ยา กรมว�ทั้ยาศึาสำตัร�การแพทั้ย�ยา กรมว�ทั้ยาศึาสำตัร�การแพทั้ย�, 2534: 104-116., 2534: 104-116.

5.5. ณรงคั� สำาร�สำ2ตัณรงคั� สำาร�สำ2ตั. . คัวามคังตั�วก�บการกาหนดสำ4ตัรตัาร�บคัวามคังตั�วก�บการกาหนดสำ4ตัรตัาร�บ. . ในใน: : ไกรสำ�ห� อ�มไกรสำ�ห� อ�มพรายน�พรายน�, , บรรณาธี�การบรรณาธี�การ. . การศึ*กษาคัวามคังตั�วของเภูสำ�ช่ภู�ณฑ์�การศึ*กษาคัวามคังตั�วของเภูสำ�ช่ภู�ณฑ์�. . กร2งเทั้พฯกร2งเทั้พฯ: : ศึ4นย�บร�การเทั้คัโนโลิย�เภูสำ�ช่อ2ตัสำาหกรรม คัณะเภูสำ�ช่ศึาสำตัร� จ2ฬาลิงกรณ�ศึ4นย�บร�การเทั้คัโนโลิย�เภูสำ�ช่อ2ตัสำาหกรรม คัณะเภูสำ�ช่ศึาสำตัร� จ2ฬาลิงกรณ�มหาว�ทั้ยาลิ�ยมหาว�ทั้ยาลิ�ย, 2534: 161-183., 2534: 161-183.

6.6. ณรงคั� สำาร�สำ2ตัณรงคั� สำาร�สำ2ตั. . คัวามคังตั�วของยาคัวามคังตั�วของยา. . ในใน: : ทั้�ดทั้รง ทั้��วทั้�พย�ทั้�ดทั้รง ทั้��วทั้�พย�, , บรรณาธี�การบรรณาธี�การ. . ยาเม�ดยาเม�ด. . กร2งเทั้พฯกร2งเทั้พฯ: : คัณะเภูสำ�ช่ศึาสำตัร� มหาว�ทั้ยาลิ�ยมห�ดลิคัณะเภูสำ�ช่ศึาสำตัร� มหาว�ทั้ยาลิ�ยมห�ดลิ, 2534:, 2534: 117-189. 117-189.





NARONG SARISUTA, Ph.D.NARONG SARISUTA, Ph.D.

DEPARTMENT OF MANUFACTURING PHARMACYDEPARTMENT OF MANUFACTURING PHARMACY

FACULTY OF PHARMACY, MAHIDOL UNIVERSITYFACULTY OF PHARMACY, MAHIDOL UNIVERSITY

product development and experimental design of solid dosage forms

Documents

experimental designs1

preformulation testing

product development

certified apha color

apha color number

color recrystallized

particle size

surface area