Workshop V

Chemical Principles Applicable to

Formulation Developments

Shaukat Ali, Ph.D.

Technical Service Manager
Ledgewood, NJ 07852

ExcipientFest
San 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 and

chemical properties. This session will continue to elaborate on basic
chemical principles that need to be taken into consideration to achieve
what 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
Highly FDA
Regulated
Environment

Manuf. Safety & Delivery

Processing Efficacy Form

Excipients
Excipient Role

API

Delivery Form:
Excipients: Manuf. Process / Operations:
Physical Tablet Characteristics:
a) Fillers a) Weight (running weight variability) - Weighing
- Sizing
b) Binders b) Dimensions
c) Hardness (breaking strength) - Blending / Granulation
c) Disintegrants d) Friability - Compression / Encapsulation
d) Lubricants e) Disintegration Time - Coating
e) Glidants - Packaging
f) Solubilizers
FORMULATION IS A BALANCING ACT!
No one right answer - it depends (balancing tradeoffs)!

INPUT + Formulation & Processing = OUTPUT

Physical
Chemical
Functional
Excipients

Characteristics

9 Chemically inert carriers in the formulation

9 Present in significantly large quantity in a dosage

9 Properties dependent upon formulation or delivery systems

9 Enhance the functions to the dosages

9 Requires less stringent qualification criteria

9 Safety and toxicological profiles well understood

9 Robust methods to characterize them

9 Meet Pharmacopeial specifications (USP, EP, or JPE)

Type of Excipients

Fillers Suspending agents

Compression aids Opacifiers

Binders Sweeteners

Disintegrants Flavors

Lubricants Film formers/coatings

Glidants Pigments

Preservatives Print Inks

9 IPEC brings the transparency between suppliers and drug manufacturers

Role in Pharmaceutical Dosage

‰ Tablets and Pellets

9 Fillers, binders, superdisintegrants, glidants, and solubilizers

9 Functional coatings

9 Instant release, sustained release or enteric release

9 Moisture barrier

‰ Influence dissolution and release profile

‰ Influence stability of the dosage form

Characterization

9 Particle Size distribution 9 Density (bulk, tapped, true)

9 Porosity 9 Viscosity

9 Moisture level 9 Degree of substitution

9 Surface area 9 Molecular weight

9 Flowability 9 Peroxides

9 Others
API-Excipient Interactions

Functional group Incompatibility Possible Interaction

R-NH2 (amine) Mono- and Amine-aldehyde, amine-
disaccharides acetal
R-COOR’ (esters, lactones) Basic pH Hydrolysis, ring opening
R-C(O)R (carbonyl) Silanol Hydrogen bonding
R-C(O)H (aldehyde) Amine, Aldehyde-amine, Schiff base
carbohydrates
R-CO2H (carboxylic acid) Bases Salt formation
RCH2OH (alcohol) Oxygen Oxidation
RCH2SH (Sulfhydryl) Oxygen Dimerization
PhOH (Phenol) Metals Complexation
API-Excipient Interactions…contd.
Type of reaction Condition
Acid/base Capable of donating protons and
hydroxyl ions
Complexation Capable of interacting each other
through H-bondings or ionization
Hydrolysis Changes in the microenvironment
Oxidation Peroxides, dye excipients, metal
ions
Maillard reaction Amines with reducing sugars,
alkaline microenvironment
Schiff base formation Amines react with aldehydes
Drug-buffer interaction Undesirable pH conditions
Trans-esterification Enzymetic condition, pH
controlled
Example
Indomethacin/NaHCO3, Citric acid or
tartaric acid/NaHCO3
CaCO3/tetracycline, Diclofenac
sodium/polymethacrylic acid
copolymer, Oxazolam/MCC, Ibuprofen
or Aspirin/Mg stearate
Aspirin/excipients,
Lansoprazole/excipients
Ceronapril/Dicalcium Phosphate,
Raloxifen/PVP/crospovidone
Ceronapril/lactose, Isoniazid/lactose,
Fluoxetine HCl/lactose
Gelatin capsules/PEG400 Æ cross-
linkage with aldehyde
Epinephrine/sod. Bisulfite,
isomerization of Vit. B12
Benzocain/Polyvinylacetate phthalate,
Norfloxacin/Mg stearate Æamide
Excipient Selection Criteria

9 Prior knowledge on the function of excipients

9 Expert systems, predictive tools and analytical methods

9 Formulation dosages or delivery system

9 Drug-excipient compatibility by selecting the “smart excipients”

in the prototype formulation to alleviate interactions with API

9 Important to assess certain risks in early stage of formulation

development to avoid any surprises
Process Flow Chart

API Excipients

Prototype
Yes Formulation, No
Processing and
Characterization

Formulation Stability No
Optimization Evaluation
QbD

Scale up and No
Validation

Manufacturing
Factors Affecting the Formulation Stability

Drug & Excipient Formulation Environment

9 Chemical structure 9 Drug : Excipient 9 Temperature

9 Impurity profile ratio 9 Relative humidity
9 Physical form 9 Processing method 9 Packaging
9 Moisture content 9 Physical mixing/ 9 Light
9 Particle size milling or granulation 9 Oxygen
9 Surface area 9 Powder mixing and
9 Morphology packing
9 Crystal defects 9 Probability of
chemical interaction
with API
Stabilization of Formulation
Dosages Instability and Solutions
Captopril
Drug : Excipient ratio
9 Study showed
decomposition in the
present of Mg stearate
9 High strength (100 mg)
tablets with Mg stearate are
stable
9 Low strength (12.5 mg)
tablets showed a significant
oxidative decomposition
Moexipril
9 Stabilizes N-
Carboxylalkyl dipeptide via
aminolysis at pH < 4.5 and
ester hydrolysis at pH >10
9 Excipients are
incompatible in dry state,
but in wet granulations,
alkaline agents retards API
degradation due to presence
of moisture
9 Stabilization by salt
formation
Stabilization of Formulation…contd.

Dosages Instability and Solutions

Enalapril Ibuprofen

9 MCC incompatible with 9 Forms eutectic in

API due to adsorption and presence of Mg stearate
dissociation of amine which vaporizes
maleate of drug
9 Film coating of tablets
9 Ca-Phosphate
eliminates this problem
compatible with API, no
adsorption
Stabilization of Formulation

Basic Requirements and Solutions

Altering the properties of Minimizing the level of

solid drug moisture in formulation

SOLUTIONS SOLUTIONS
9 Increasing melting 9 Choice of
point excipients
9 Choosing a non- 9 Co-solvents
hygroscopic form (crystal
9 Manufacturing
or salt form)
conditions
9 Reducing solubility by
9 Storage conditions
choosing a less soluble
salt 9 Packaging
9 Micellar inclusion
9 Complexation
9 Engineering of the
particles (shape)
Stabilization of Formulation…contd.

Basic Requirements and Solutions

Changing the micro- Minimizing contact between

environment in formulation API & Excipients, and water

SOLUTIONS SOLUTIONS
9 Adjusting the pH by
9 Coating with
using acids, bases, or
polymers/
buffer salts
microencapsulation
9 Incorporating
complexation agents to 9 Multi-layer particles
inactivate trace metal in capsule/tablet
ions
9 Tablet in a tablet or
9 Displacing oxygen
capsule
with nitrogen or argon
9 Incorporating
antioxidants
Excipient and API Incompatibility

Excipients under different %RH

10 Maltodextrin
Moisture Uptake, %(w/w)

Lactose
Mannitol
8

0
32 52 65 75 85

Relative Humidity (% w/w)

9 Maltodextrin poses a compressibility challenge

9 Lactose is often used in the formulations (eg. Zyrtec OTC, etc.)
9 Mannitol is low hygroscopic of all three (e.g. ODT)

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

Formulation Dosage Stability

Aspirin: Impact of moisture absorption

9 Moisture absorption decreases Aspirin degradation @ Varied %RH

in the order: 100 10 %RH
75 %RH
80

D e g r a d a t io n , %
Dicalcium phosphate > MCC >
60
Lactose
40

20
¾ DCP has more impact on
instability of drug due to 0
Avicel Calc. Phos. HPMC Lactose Mg PVP K-30 Primojel

increase in internal pH Stearate

resulting from moisture Excipient

uptake
Wyttenbach et al., Pharm Dev and Tech., 2005, 10, 499.
Formulation Dosage Stability…contd.

Indomethacin: Impact of moisture absorption

180
PVP K-25
150

5% Moisture Uptake
120

Tg (oC)
90

9 Water acts as a plasticizer and lower 60

30%

Tg of the excipient and alters the 30

0
physico- chemical properties of API 0 15 35 45 55 65 70

Relative Humidity (%)

by increasing the molecular mobility
that leads to phase separation and Stubberud et al., Int. J. Pharm., 1996, 134, 79-88.
crystallization
10 IND decomposition

kobs x104
6

™ Rate constant is correlated with 2

amount of moisture 0
Stubberud et50al., Int. 70
J. Pharm.,
80 1996, 134,
90 79-88.
™ IND crystallizes under high %RH Relative Humidity (%)

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

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

0.2
Intrinsic Dissolution
rate (mg/min/cm2)

0.16

0.12

0.08

0.04

0
CBZ CBZ-K30 (1:5) CBZ-K-30- CBZ-K-30-
Gelucire 44/14 TPGS (1:4:1)
(1:4:1)

CBZ/Excipient

Dissolution rate:

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

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

Influence of Excipients on the Dissolution
of an API
CBZ in Different Dissolution Media
150 min

H2O
H2O

PEG

500 μm

CBZ HPMC

9Rate of CBZ dissolution: Water > PEG > HPMC

9 Faster dissolution of CBZ Dihydrate was due to increased surface area

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

Excipient’s Particle size on Aspirin Stability

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

™ Stability decreased with increasing amount of cellulose Ahlneck et al (1988)

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%

1.2 25 oC/60%RH
Salicylic acid, %

0.8

0.4

0 Kollicoat Kollicoat PVA based

Protect:Kaolin:Talc Protect:Kaolin:Talc Com petitor Product
(60:25:15) (40:40:20)

Coated Aspirin Tablets

9 PVA-co-PEG is an effective moisture barrier polymer

Effect of Binders on Dissolution of API

Ibuprofen

9 Dissolution properties dependent on the binder selection

9 Possible interaction of Ibuprofen with DCP
Superdisintegrants in Performance of
Phenacetin Tablets
Disintegrant @5%

Dissolution @15 min

100

80
Dissolution, %

60

40

20

0
Crospovidone Croscarm ellose Carboxym ethystarch L-HPC
Sodium

Superdisintegrants

Crospovidone ≥ Croscarmellose Sodium > Carboxymethylstarch > L-HPC

Functional coating with Polyvinylacetate
dispersion 30%
Effects of pore formers on Theophylline release
FASTER
Dissolution
30% PVP K-90
30% PVP K-90

Far more porous

30% PVA-co-PEG 30% PVA-co-PEG

15% PVP K-90

15% PVA-co-PEG
Less porous

30% PVP K-30

no pore former 30% PVP K-30

Theophylline release from the pellets coated with Far less porous SLOWER
Kollicoat SR 30D with and without pore-formers
Dissolution
Coating Excipients in the Performance of
Products
Tablets versus Pellets
Enteric Copolymer

Methylacrylic acid-ethyl
acrylate co-polymer
100
Aspirin Tablet Enteric coated tablets
80 Ascorbic Acid Pellets
Released, %

60
Multi-layered
40 Enteric Effect pellets
Sustained release
20
Polyvinylacetate 30%
0
0 1 2 3 4 5
Time, Hr

9 Achieve a similar release (0-2 Hr) from both coatings

9 Provide more flexibility
9 Easy manufacturing
Drug Approval Process

Brand Rx vs. Generic Rx

Years
Bioequivalency of a Drug Product

Definition
Pharmaceutical Equivalent
Products

Brand Rx Generic Rx
Same Active

Possible Differences
9 Drug particle size,
Flowability..
9 Excipients
9 Manufacturing process
9 Equipments
9 Site of manufacturing
9 Batch size ….

Therapeutic Equivalence
(Same dissolution spec., PK profile)
Determine the Bioequivalency
Comparison of PK Profiles in Plasma

Generic Rx
Concentration

Cmax Brand Rx The AUC and Cmax of the generic Rx

must meet 80% - 125% of the brand
Rx in order to be deemed BE

AUC

Tmax

Time
Food and Drug Administration Web site.
Bioequivalency of Brand Rx vs. Generic
Rx
FDA Requirements
Pharmacokinetic (PK)
Reference Range
80% 100% 125%

Product A
Bioequivalent
9 Product A is BE to Brand Rx
9 Product B is not BE

Brand Rx
(Reference Drug)

Product B
Not Bioequivalent

Food and Drug Administration Web site

Achieving the Bioequivalency

Dissolution profiles of Generic Rx to Brand Rx

120
Brand Rx
100 Generic Rx
Released, %

80

60

40

20

0
0 4 8 12 16 20 24
Time, hr

9 Dissolution profiles of brand Rx and generic Rx very close

Achieving the Bioequivalency

PK profiles of Brand Rx and Generic Rx

SRx-501
(Levodopa-Carbidopa XR)

SRx-502 meets
bioequivalence
criteria of
Topamax for
both Cmax
and AUC

9 The fluctuation
index is identical
in both Brand Rx
and Generic Rx

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

Source: Spherics
Efficacy and Bioavailability-PK Profiles

Effects of excipients on highly and poorly permeable drugs

Highly Permeable Drug

Water
Sorbitol

Theophylline serum concentration profiles

About 10 grams of sorbitol had no (minimal)

effect on bioavailability (Cmax and AUC) of
theophylline

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

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

Poorly Permeable Drug

Sucrose solution

Chewable Sucrose tablet

Mannitol Solution
Chewable mannitol tablet

Cimetidine serum concentration profile

2.3 grams of mannitol in a chewable tablet

reduced bioavailability of cimetidine compared to
a tablet containing the same amount of sucrose

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

Bioavailability of a Class III Drug
PK profiles of Ranitidine

Ranitidine (poorly permeable drug)

500
LnCmax 44%-54%

400 LnAUCi 53%-62%

Plasma Conc. (ng/mL)

Sucrose
Sorbitol
300

Ranitidine: 150 mg
200
Sucrose: 5 g
100 Sorbitol: 5 g
0

0 2 4 6 8 10 12
Time (hours)

¾ Sucrose metabolizes to glucose and fructose, and both show complete

absorption
Hussain, A., AAPS 2000
Concluding Remarks

9 Selection of the API

9 Selection of the excipients and compatibility in formulation

9 Development of analytical methods, method validation and

testing

9 Product manufacturing processes and robustness

9 Stability, storage and packaging conditions

9 Safety and toxicological profiles

A comprehensive knowledge of APIs and Excipients is required to minimize

any late stage development surprises!!
Success in Formulation Design

Perseverance… Thomas Edison

Many of life's failures are people who did not

realize how close they were to success
when they gave up.