Workshop V

Chemical Principles Applicable to Formulation Developments

Shaukat Ali, Ph.D.Technical Service Manager

Ledgewood, NJ 07852

ExcipientFestSan Juan, Puerto Rico

April 23, 2009

Chemistry 101 for Non-Chemists

Part II

Chemical Principles Applicable to Formulation Developments (primarily Solid Oral Dosage Forms):

Formulation development requires a balance between physical andchemical properties. This session will continue to elaborate on basic chemical principles that need to be taken into consideration to achievewhat is normally referred to in the industry as a robust formulation. Concepts such as excipient selection (binders and disintegrants), possible API and excipient interactions, and how to achieve the desired physical and bioequivalent results will be addressed. A basic explanation on pharmaceutical coatings, their chemistry and corresponding functionality will also be covered.

The Drug Formulation Balance

API

DeliveryForm

Excipients

Manuf.Processing

Safety &Efficacy

Highly Regulated

Environment

FDA

Excipient Role

FORMULATION IS A BALANCING ACT!No one right answer - it depends (balancing tradeoffs)!

INPUT + Formulation & Processing = OUTPUTPhysicalChemicalFunctional

Excipients:a) Fillersb) Bindersc) Disintegrantsd) Lubricantse) Glidantsf) Solubilizers

Physical Tablet Characteristics:a) Weight (running weight variability)b) Dimensionsc) Hardness (breaking strength)d) Friabilitye) Disintegration Time

Manuf. Process / Operations: - Weighing - Sizing - Blending / Granulation - Compression / Encapsulation - Coating - Packaging

Delivery Form:

API

Excipients

Characteristics

Chemically inert carriers in the formulation

Present in significantly large quantity in a dosage

Properties dependent upon formulation or delivery systems

Enhance the functions to the dosages

Requires less stringent qualification criteria

Safety and toxicological profiles well understood

Robust methods to characterize them

Meet Pharmacopeial specifications (USP, EP, or JPE)

Type of Excipients

SweetenersBinders

Disintegrants

Lubricants

Glidants

Preservatives

Suspending agents

Film formers/coatings

Pigments

Print Inks

Fillers

Flavors

Compression aids Opacifiers

IPEC brings the transparency between suppliers and drug manufacturers

Role in Pharmaceutical Dosage

Tablets and Pellets

Fillers, binders, superdisintegrants, glidants, and solubilizers

Functional coatings

Instant release, sustained release or enteric release

Moisture barrier

Influence dissolution and release profile

Influence stability of the dosage form

Characterization

Density (bulk, tapped, true)

Viscosity

Degree of substitution

Molecular weight

Peroxides

Others

Particle Size distribution

Porosity

Moisture level

Surface area

Flowability

API-Excipient Interactions

ComplexationMetalsPhOH (Phenol)

DimerizationOxygenRCH2SH (Sulfhydryl)

OxidationOxygenRCH2OH (alcohol)

Salt formationBasesR-CO2H (carboxylic acid)

Aldehyde-amine, Schiff baseAmine, carbohydrates

R-C(O)H (aldehyde)

Hydrogen bondingSilanolR-C(O)R (carbonyl)

Hydrolysis, ring openingBasic pHR-COOR’ (esters, lactones)

Amine-aldehyde, amine-acetal

Mono- and disaccharides

R-NH2 (amine)

Possible InteractionIncompatibilityFunctional group

API-Excipient Interactions…contd.

Epinephrine/sod. Bisulfite, isomerization of Vit. B12

Undesirable pH conditionsDrug-buffer interaction

Benzocain/Polyvinylacetate phthalate, Norfloxacin/Mg stearate amide

Enzymetic condition, pH controlled

Trans-esterification

Gelatin capsules/PEG400 cross-linkage with aldehyde

Amines react with aldehydesSchiff base formation

Ceronapril/lactose, Isoniazid/lactose, Fluoxetine HCl/lactose

Amines with reducing sugars, alkaline microenvironment

Maillard reaction

Ceronapril/Dicalcium Phosphate,

Raloxifen/PVP/crospovidone

Peroxides, dye excipients, metal ions

Oxidation

Aspirin/excipients, Lansoprazole/excipients

Changes in the microenvironmentHydrolysis

CaCO3/tetracycline, Diclofenacsodium/polymethacrylic acid copolymer, Oxazolam/MCC, Ibuprofen or Aspirin/Mg stearate

Capable of interacting each other through H-bondings or ionization

Complexation

Indomethacin/NaHCO3, Citric acid or tartaric acid/NaHCO3

Capable of donating protons and hydroxyl ions

Acid/base

ExampleConditionType of reaction

Excipient Selection Criteria

Prior knowledge on the function of excipients

Expert systems, predictive tools and analytical methods

Formulation dosages or delivery system

Drug-excipient compatibility by selecting the “smart excipients”in the prototype formulation to alleviate interactions with API

Important to assess certain risks in early stage of formulationdevelopment to avoid any surprises

Process Flow Chart

Formulation Optimization

Stability Evaluation

Scale up andValidation

API Excipients

YesPrototype

Formulation,Processing and Characterization

No

No

No

Manufacturing

QbD

Factors Affecting the Formulation Stability

Drug & Excipient

Chemical structureImpurity profilePhysical formMoisture contentParticle sizeSurface areaMorphologyCrystal defects

Drug : Excipient ratio

Processing methodPhysical mixing/

milling or granulationPowder mixing and

packingProbability of

chemical interaction with API

Formulation

TemperatureRelative humidityPackagingLightOxygen

Environment

Stabilization of Formulation

Dosages Instability and Solutions

MoexiprilCaptoprilDrug : Excipient ratio

Study showed decomposition in the present of Mg stearate

High strength (100 mg) tablets with Mg stearate are stable

Low strength (12.5 mg) tablets showed a significant oxidative decomposition

Stabilizes N-Carboxylalkyl dipeptide via aminolysis at pH < 4.5 and ester hydrolysis at pH >10

Excipients are incompatible in dry state, but in wet granulations, alkaline agents retards API degradation due to presence of moisture

Stabilization by salt formation

Stabilization of Formulation…contd.

Dosages Instability and Solutions

Enalapril Ibuprofen

MCC incompatible with API due to adsorption and dissociation of amine maleate of drug

Ca-Phosphate compatible with API, no adsorption

Forms eutectic in presence of Mg stearatewhich vaporizes

Film coating of tablets eliminates this problem

Stabilization of Formulation

Basic Requirements and Solutions

Minimizing the level of moisture in formulation

Altering the properties of solid drug

SOLUTIONS

Increasing melting point

Choosing a non-hygroscopic form (crystal or salt form)

Reducing solubility by choosing a less soluble salt

Micellar inclusion

Complexation

Engineering of the particles (shape)

SOLUTIONS

Choice of excipients

Co-solvents

Manufacturing conditions

Storage conditions

Packaging

Stabilization of Formulation…contd.

Basic Requirements and Solutions

Changing the micro-environment in formulation

Minimizing contact between API & Excipients, and water

SOLUTIONS

Adjusting the pH by using acids, bases, or buffer salts

Incorporating complexation agents to inactivate trace metal ions

Displacing oxygen with nitrogen or argon

Incorporating antioxidants

SOLUTIONS

Coating with polymers/ microencapsulation

Multi-layer particles in capsule/tablet

Tablet in a tablet or capsule

Excipient and API Incompatibility

Excipients under different %RH

Gonnissen et la., Eur. J. Pharm. Biopharm. 2007, 67, 220-226

0

2

4

6

8

10

Moi

stur

e U

ptak

e, %

(w/w

)

32 52 65 75 85

Relative Humidity (% w/w)

MaltodextrinLactoseMannitol

Maltodextrin poses a compressibility challengeLactose is often used in the formulations (eg. Zyrtec OTC, etc.)Mannitol is low hygroscopic of all three (e.g. ODT)

Formulation Dosage Stability

Aspirin: Impact of moisture absorption

Moisture absorption decreases in the order:

Dicalcium phosphate > MCC > Lactose

DCP has more impact on instability of drug due to increase in internal pH resulting from moisture uptake

0

20

40

60

80

100

Deg

rada

tion,

%

Avicel Calc. Phos. HPMC Lactose MgStearate

PVP K-30 Primojel

Excipient

10 %RH

75 %RH

Wyttenbach et al., Pharm Dev and Tech., 2005, 10, 499.

Aspirin degradation @ Varied %RH

Formulation Dosage Stability…contd.

Indomethacin: Impact of moisture absorption

Water acts as a plasticizer and lower Tg of the excipient and alters the physico- chemical properties of API by increasing the molecular mobility that leads to phase separation and crystallization

0

30

60

90

120

150

180

Tg (o

C)

0 15 35 45 55 65 70

Relative Humidity (%)

Stubberud et al., Int. J. Pharm., 1996, 134, 79-88.0

2

4

6

8

10

kobs

x10

4

50 70 80 90

Relative Humidity (%)

IND decomposition

Stubberud et al., Int. J. Pharm., 1996, 134, 79-88.

Rate constant is correlated with amount of moisture

IND crystallizes under high %RH

Cartensen and Rhodes, Drug Stability, 3rd, Ed.

PVP K-25

30%

Moisture Uptake5%

Influence of Excipients on the Dissolution of an APICarbamazepine (CBZ) and PVP w/wo Solubilizers

0

0.04

0.08

0.12

0.16

0.2

Intr

insi

c D

isso

lutio

nra

te (m

g/m

in/c

m2)

CBZ CBZ-K30 (1:5) CBZ-K-30-Gelucire 44/14

(1:4:1)

CBZ-K-30-TPGS (1:4:1)

CBZ/Excipient

Sethia and Sequillante, Int. J. Pharm. 2004, 272, 1-10

Dissolution rate:

PVP K-30 > Vit. E-TPGS > Gellucire 44/14

Influence of Excipients on the Dissolution of an APICBZ in Different Dissolution Media

Tian et al., J. Pharm. Sci., 2007, 96, 584-594

Rate of CBZ dissolution: Water > PEG > HPMC

Faster dissolution of CBZ Dihydrate was due to increased surface area

CBZ

500 μm

H2O

PEG

H2O

HPMC

150 min

Excipient-API Incompatibility

Excipient’s Particle size on Aspirin Stability

Ahlneck et al (1988)

Aspirin degradation in presence of microcrystalline and microfine-cellulose (55°C/75% RH)

Stability decreased with increasing amount of cellulose presumably due to the catalytic effect

Dosages Stability – Functional Coating

Aspirin Stability (6 months)Tablet wt. 301.5 mg, API 100 mg, Coating level 3.7 wt%

0

0.4

0.8

1.2

Salic

ylic

aci

d, %

KollicoatProtect:Kaolin:Talc

(60:25:15)

KollicoatProtect:Kaolin:Talc

(40:40:20)

PVA based Competitor Product

Coated Aspirin Tablets

25 oC/60%RH

PVA-co-PEG is an effective moisture barrier polymer

Effect of Binders on Dissolution of API

Ibuprofen

Dissolution properties dependent on the binder selectionPossible interaction of Ibuprofen with DCP

Superdisintegrants in Performance of Phenacetin TabletsDisintegrant @5%

0

20

40

60

80

100

Dis

solu

tion,

%

Crospovidone CroscarmelloseSodium

Carboxymethystarch L-HPC

Superdisintegrants

Dissolution @15 min

Crospovidone ≥ Croscarmellose Sodium > Carboxymethylstarch > L-HPC

Functional coating with Polyvinylacetate dispersion 30%Effects of pore formers on Theophylline release

30% PVP K-90

30% PVA-co-PEG

30% PVP K-30

15% PVP K-90

15% PVA-co-PEG

no pore former

30% PVP K-90

30% PVA-co-PEG

30% PVP K-30

Theophylline release from the pellets coated with Kollicoat SR 30D with and without pore-formers

Far less porous

Less porous

Far more porous

FASTERDissolution

SLOWERDissolution

Coating Excipients in the Performance of ProductsTablets versus Pellets

0

20

40

60

80

100

0 1 2 3 4 5

Time, Hr

Rel

ease

d, %

Aspirin TabletAscorbic Acid Pellets

Enteric Effect

Achieve a similar release (0-2 Hr) from both coatings Provide more flexibilityEasy manufacturing

Multi-layeredpellets

Enteric coated tablets

Enteric Copolymer

Methylacrylic acid-ethyl acrylate co-polymer

Sustained release

Polyvinylacetate 30%

Drug Approval Process

Brand Rx vs. Generic Rx

Years

Bioequivalency of a Drug Product

Definition

Brand Rx Generic Rx

Pharmaceutical EquivalentProducts

Therapeutic Equivalence(Same dissolution spec., PK profile)

Possible Differences

Drug particle size,

Flowability..

Excipients

Manufacturing process

Equipments

Site of manufacturing

Batch size ….

Same Active

Conc

entra

tion

Time

Determine the Bioequivalency

Comparison of PK Profiles in Plasma

Food and Drug Administration Web site.

Generic Rx

Brand Rx The AUC and Cmax of the generic Rx must meet 80% - 125% of the brand Rx in order to be deemed BE

Tmax

Cmax

AUC

Bioequivalency of Brand Rx vs. Generic RxFDA Requirements

125%100%80%

Product ABioequivalent

Brand Rx (Reference Drug)

Product BNot Bioequivalent

Pharmacokinetic (PK)Reference Range

Food and Drug Administration Web site

Product A is BE to Brand RxProduct B is not BE

Achieving the Bioequivalency

Dissolution profiles of Generic Rx to Brand Rx

0

20

40

60

80

100

120

0 4 8 12 16 20 24

Time, hr

Rel

ease

d, %

Brand RxGeneric Rx

Dissolution profiles of brand Rx and generic Rx very close

Achieving the Bioequivalency

PK profiles of Brand Rx and Generic Rx

SRx-502 meets bioequivalencecriteria of Topamax forboth Cmaxand AUC

The PK data of SRx-502 supports approval based on bioequivalence

Source: Spherics

SRx-501(Levodopa-Carbidopa XR)

The fluctuationindex is identicalin both Brand Rx and Generic Rx

Efficacy and Bioavailability-PK Profiles

Effects of excipients on highly and poorly permeable drugs

Theophylline serum concentration profiles

Fassihi et al., Int. J. Pharm. 1991, 72, 175-178

Highly Permeable Drug

About 10 grams of sorbitol had no (minimal) effect on bioavailability (Cmax and AUC) of theophylline

WaterSorbitol

Efficacy and Bioavailability-PK Profiles…contd.Effects of excipients on highly and poorly permeable drugs

Adkin et al., J. Pharm. Sci. 1995, 84, 1405-1409

Sucrose solution

Chewable Sucrose tablet

Mannitol SolutionChewable mannitol tablet

Cimetidine serum concentration profile

Poorly Permeable Drug

2.3 grams of mannitol in a chewable tablet reduced bioavailability of cimetidine compared to a tablet containing the same amount of sucrose

Bioavailability of a Class III Drug

PK profiles of Ranitidine

Time (hours)0 2 4 6 8 10 12

Plas

ma

Con

c. (n

g/m

L)

0

100

200

300

400

500

Sucrose Sorbitol

Ranitidine: 150 mgSucrose: 5 gSorbitol: 5 g

Hussain, A., AAPS 2000

Sucrose metabolizes to glucose and fructose, and both show complete absorption

Ranitidine (poorly permeable drug)

LnCmax 44%-54%

LnAUCi 53%-62%

Concluding Remarks

Selection of the API

Selection of the excipients and compatibility in formulation

Development of analytical methods, method validation and testing

Product manufacturing processes and robustness

Stability, storage and packaging conditions

Safety and toxicological profiles

A comprehensive knowledge of APIs and Excipients is required to minimize any late stage development surprises!!

Success in Formulation Design

Thomas Edison

Many of life's failures are people who did not realize how close they were to success when they gave up.

Perseverance…