Peptides in parenteral formulations
Christina Avanti
Department of Pharmaceutics
University of Surabaya,
Surabaya, Indonesia
Assoc. Prof. Christina Avanti, PhD
Dean of Faculty of Pharmacy in University of Surabaya
G ra d ua te d in Pha rma c y a t the Unive rsity o f Sura b a ya , she wo rke d a t
Sa nd o z Bio c he mie Fa rma Ind o ne sia a nd d id he r Ma ste r Pro g ra m in
C o sme tic Fo rmula tio n a t the De p a rtme nt o f Pha rma c e utic s Airla ng g a
Unive rsity. She d id he r PhD a t the De p a rtme nt o f Pha rma c e utic a l
Te c hno lo g y Unive rsity o f G ro ning e n, The Ne the rla nd s. She wo rke d
within the Dutc h To p Institute Pha rma Pro je c t e ntitle d “ Bre a king The
C o ld C ha in o f Po lyp e p tid e -Ba se d Me d ic ine ” . She is no w wo rking a s a
Se nio r Re se a rc he r a nd te a c hing Physic a l Pha rma c y, Fo rmula tio n,
Te c hno lo g y, a nd Bio p ha rma c y a t The Sc ho o l o f Pha rma c y Unive rsity
o f Sura b a ya . The o ve ra ll a im o f he r wo rk is to a c hie ve a sta b le
p e p tid e / p ro te in fo rmula tio n to b e tra nsp o rte d , sto re d , a nd use d
p a rtic ula rly in tro p ic a l d e ve lo p ing c o untrie s.
(Pa te nt: (W O /2010/030180) PEPTIDE FO RMULA TIO NS A ND USES THEREO F)
•
La te st public a tio n:
Sta b ility o f lyso zyme in a q ue o us e xtre mo lyte so lutio ns d uring he a t
sho c k a nd a c c e le ra te d the rma l c o nd itio ns. Plo s O ne Jo urna l,
Ja nua ry 2014, Vo lume 9, Issue 1, e 86244
•
The fo rma tio n o f o xyto c in d ime rs is sup p re sse d b y the zinc a sp a rta te -o xyto c in c o mp le x. J. Pha rm . Sc i., 2013, DO I
10.1002/ jp s.23546 (e a rly p ub lishe d o nline )
•
Asp a rta te b uffe r a nd d iva le nt me ta l io ns a ffe c t o xyto c in in
a q ue o us so lutio n a nd p ro te c t it fro m d e g ra d a tio n. Int. J. Pha rm ,
2013 , 444(1-2):139-45
Outline
Introduction
Peptide
instability
and the
possible
causes of
degradation
Strategies to
improve
peptide
stability in
liquid
formulations
Conclusion
Introduction
• Peptides as potential drugs:
Successful chemical synthesis of oxytocin by
duVigneaud in 1953
• over a hundred peptide drug candidates are in
development for a wide variety of diseases
• Peptides differ from proteins:
smaller and typically lack a defined tertiary structure
What is peptide and peptide bond ?
• Amino acids linked to each other by peptide bonds
• Peptide bond occurs when nitrogen atom on one amino
acid binds to the carboxyl group of another amino acid.
Definition of Peptide
• Malavolta (2011)
Peptides are molecules containing fewer than 40
amino acid residues, while proteins contain 50
residues or more
• Lee (1991)
Amino acids joined together in chains of 50 amino
acids or less are defined as peptides, 50-100
amino acids are defined as polypeptides, and over
100 amino acids are defined as proteins
Amino Acid Building Block
Tyr
Arg
Lys
Ser
Glu
Trp
Gln
Asp
Met
Purposes of Peptides
• A number of hormones, enzymes, antitumor
agents, antibiotics and neurotransmitters are
peptides.
• Peptides regulate many physiological processes,
acting at some sites as endocrine or paracrine
signals and at other sites as neurotransmitters or
growth factors.
• Nowadays, peptides are used as therapeutic
agents against diverse disease areas such as
neurological, endocrinological and hematological
disorders
Table 1 Several peptide-based parenteral
products in the market in 2010-2013
Generic
name
Trade name
Supplier
Thyrotropine releasing hormones
TRH/TRF
Relefact TRH® SanoviAventis
Antibiotic peptides
Daptomycin
Cubicin®
Novartis
Teicoplanin
Targocid®
SanofiAventis
Dosage form
Shelf-life
pH
and storage
temp.
Liquid inj.
2 yr 1525°C
Powder for inj. 3 yr, 2°C –
8°C
Powder for inj. 4 yr, 2-8°C
6.5
4-5
Platelet aggregates inhibitors
Eptifibatide
Integrilin®
GlaxoSmithKl Liquid for
ine
infusion
3 yr, 2-8°C
5.35
Table 1 Several peptide-based parenteral
products in the market in 2010-2013
Generic name Trade name
Supplier
Somatostatin analog
Octreotide
Sandostatin® Novartis
acetate
Vasopressins and analogs
Desmopressin DDAVP®
Ferring
Octostim®
Ferring
Minrin®
Felypressin
Ferring
Citanest 3% Densply
Octapressin®
Dosage form Shelf-life
pH
and storage
temp.
Liquid inj.
3 yr, 2-8°C
4.2
Liquid inj.
Liquid inj.
4 yr, 2-8°C
4 yr, 2-8°C
4-5
Liquid inj.
4 yr, 2-8°C
4
Liquid inj.
3 yr, 15-25°C 3.55.2
4
Table 1 Several peptide-based parenteral
products in the market in 2010-2013
Generic
name
Trade name
Oxytocins
Oxytocin
Syntocinon®
Carbetocin Pabal®
Oxytocin antagonist
Atosiban
Tractocile®
Tractocile®
Supplier
Dosage form
Shelf-life
pH
and storage
temp.
Defiante
Ferring
Liquid inj.
Liquid inj.
4 yr, 2-8°C
2 yr, 2-8°C
4
3.8
Ferring
Ferring
Liquid inj.
Liquid inj.
4yr, 2-8°C
4 yr 2-8°C
4.5
4.5
Table 1 Several peptide-based parenteral
products in the market in 2010-2013
Generic
name
Trade name
GNRH/LHRH agonists
Goserelin
Zoladex®
Gonadorelin Relefact
LH-RH®
Decapeptyl Triptorelin
CR®
Supplier
Dosage form
Shelf-life
pH
and storage
temp.
Div
SanofiAventis
Ipsen
Liquid inj.
Liquid inj.
3 yr, < 25°C
15-25°C
Powder and
solv. for sol for
inj.
Liquid nasal
spray
Powder and
solv. for sol for
inj.
Powder for inj.
3 yr, 2-8°C
Nafarelin
Synarel®
Pfizer
Leuprolide
Eligard ®
SanofiAventis
Cetrorelix
Cetrotide®
Serono
2 yr, < 25°C
2 yr, 2-8°C
3 yr, 1525°C
5-7
Table 1 Several peptide-based parenteral
products in the market in 2010-2013
Generic
name
Trade name
Supplier
Non-NSAID analgesic
Ziconotide
Prialt®
Elan
Calcitonins
Salmon
Calcitonin Novartis
Calcitonin
Sandoz®
Human parathyroid hormone [hPTH (1–34)]
Teriparatide Forsteo®
Eli Lily
Fusion inhibitor of HIV-1 with CD4 cells
Enfuvirtide Fuzeon®
Roche
ACTH and derivatives
CRH/CRF/
CRH Corticorelin Ferring®
Ferring
Dosage form
Shelf-life
pH
and storage
temp.
Liquid inj.
3 yr, 2-8°C
4-5
Liquid inj.
5 yr, 2-8°C
3-5
Liquid inj.
2 yr, 2-8°C
Powder and
solv. solution
for inj.
4 yr, 2-8°C
Powder for inj. 3 yr, < 25°C
Pharmaceutical peptides:
Challenge
• The sensitivity to enzymatic breakdown
• The poor ability to pass absorbing membranes
typically results in a poor bioavailability
following non-parenteral administration.
• The lack of physical and chemical stability lead
to significant degradation during processing
and storage of the (aqueous) formulations
Non-invasive routes for peptide
drug administration
• buccal,
• rectal,
• vaginal,
• percutaneous,
• ocular,
• transdermal,
• nasal,
• pulmonary
many of these routes of administration are still under
investigation and they may be insufficiently efficient,
especially when a rapid effect is desired.
Intravenous administration is the most
efficient way to deliver peptide drugs
directly into the systemic circulation
most peptide drugs have to be stored
and transported at low temperatures
Peptide Degradation
Pathways
Chemical degradation pathways
• hydrolysis,
• oxidation,
• deamidation .
Physical degradation:
• adsorption
• aggregation
problem in the
development as active
pharmaceuticals
Need
better understanding of the underlying mechanisms of instability of a
certain peptide to design rational strategies in the development
process of pharmaceuticals to optimize the stability of the peptide in
the final formulation
Peptide instability and the
possible causes of degradation
• Hydrolytic pathways
– Chain cleavage of the peptide backbone
– Deamidation of Asn and Gln residues
– Isomerization of Asp residues
• Oxidation pathways
– Autoxidation
– Metal-catalyzed oxidation
– Light-induced oxidation
• β-elimination reactions
• Disulfide exchange reactions
• Dimerization, aggregation, and precipitation
Deamidation pathways of Asn residue via
A. direct hydrolysis and B. succinimide mediation
Selected oxidation reactions of Met and His. (A): methionine oxidation by peroxide to
methionine sulfoxide in acidic solution (HA=acid). (B): 2-oxo-His, Asn and Asp
(adapted from Li, et. al, 1995).
Oxytocin degradation pathways
Strategies to improve peptide stability in
liquid formulations
Ta b le 2 De g ra d a tio n p a thwa ys a nd p o ssib le sta b iliza tio n stra te g ie s fo r p e p tid e s
inc lud ing a mino a c id re sid ue s invo lve d in the d e g ra d a tio n.
Degradation pathway
Chemical Instability
Acid/base catalyzed
hydrolysis
Deamidation
β-elimination
Stabilization strategy
Amino acid
residue(s)
involved
pH
buffer species
co-solvents
Ser
Trp
Asn-Pro
Asn-Tyr
Asn, Gln
pH 3-5
increased solvent viscosity
Buffer species
divalent metal ions
Cys-Cys
Ta ble 2 De g ra da tio n pa thwa ys a nd po ssible sta biliza tio n stra te g ie s fo r pe ptide s
inc luding a mino a c id re sidue s invo lve d in the de g ra da tio n, c o ntinue d
Degradation pathway
Chemical Instability
Oxidation
Light induced oxidation
Metal induced oxidation
Disulfide exchange
Stabilization strategy
Amino acid
residue(s)
involved
pH < 7
air exclusion
antioxidants
Protect from light
Chelating agents
Polyols
Surfactans
Polyols and sugars
Buffer and divalent metal ions
Trp, Met, Cys,
Tyr, His
Trp
His, Cys, Arg, Pro,
Met
Cys-Cys
Ta ble 2 De g ra da tio n pa thwa ys a nd po ssible sta biliza tio n stra te g ie s fo r pe ptide s
inc luding a mino a c id re sidue s invo lve d in the de g ra da tio n, c o ntinue d
Degradation pathway
Physical Instability
Dimerization and further
aggregation
Adsorption
Stabilization strategy
Amino acid
residue(s)
involved
Lower concentration
minimal mechanical stress
organic solvents
alkyl saccharide
alkyl polyglycoside
surfactans
polymers
Cys-Cys
Tyr-Tyr
His
Arg
Conclusion
• In a q ue o us so lutio ns p e p tid e s a re o fte n unsta b le .
• Pe p tid e s ha ve uniq ue struc ture s tha t the sid e c ha in
o f ne a rly a ll o f the a mino a c id re sid ue s a re fully
so lve nt e xp o se d , a llo wing ma xima l c o nta c t with
so lve nts
• the d e g ra d a tio n ra te s a p p e a r to c o rre la te with the
d e g re e o f so lve nt e xp o sure .
• Ba se d o n kno wle d g e o f the p e p tid e ’ s struc ture a nd
a n und e rsta nd ing o f the p re d o mina nt d e g ra d a tio n
p a thwa ys, the stra te g ie s ma y b e d e ve lo p e d to
a c hie ve a d e q ua te sta b ility o f the fo rmula tio n.
Conclusion
• The d e g ra d a tio n p a thwa ys o f p e p tid e s a re
ma inly d e p e nd e nt o n the a mino a c id se q ue nc e .
• The mo st p ro mine nt d e g ra d a tio n p a thwa ys fo r
p e p tid e s a re hyd ro lysis, o xid a tio n, a nd
d ime riza tio n.
• Fo rmula ting p e p tid e s in a sp e c ific p H with a
sp e c ific b uffe r, a vo id ing o xyg e n re a c tive sp e c ie s,
a nd minimizing so lve nt e xp o sure e limina te
c he mic a l d e g ra d a tio n.
• Inc re a sing so lutio n visc o sity b y using sug a rs o r
p o lyme rs re d uc e s p e p tid e mo b ility a nd furthe r
d e c e le ra te s p hysic a l d e g ra d a tio n.
Instability is the most stable
characteristic of
a dissolved peptide
Christina Avanti, 2011
Instabilities are a natural way to
achieve thermodynamic equilibrium
Christina Avanti, 2012
Department of Pharmaceutics
University of Surabaya,
Surabaya, Indonesia
Assoc. Prof. Christina Avanti, PhD
Dean of Faculty of Pharmacy in University of Surabaya
G ra d ua te d in Pha rma c y a t the Unive rsity o f Sura b a ya , she wo rke d a t
Sa nd o z Bio c he mie Fa rma Ind o ne sia a nd d id he r Ma ste r Pro g ra m in
C o sme tic Fo rmula tio n a t the De p a rtme nt o f Pha rma c e utic s Airla ng g a
Unive rsity. She d id he r PhD a t the De p a rtme nt o f Pha rma c e utic a l
Te c hno lo g y Unive rsity o f G ro ning e n, The Ne the rla nd s. She wo rke d
within the Dutc h To p Institute Pha rma Pro je c t e ntitle d “ Bre a king The
C o ld C ha in o f Po lyp e p tid e -Ba se d Me d ic ine ” . She is no w wo rking a s a
Se nio r Re se a rc he r a nd te a c hing Physic a l Pha rma c y, Fo rmula tio n,
Te c hno lo g y, a nd Bio p ha rma c y a t The Sc ho o l o f Pha rma c y Unive rsity
o f Sura b a ya . The o ve ra ll a im o f he r wo rk is to a c hie ve a sta b le
p e p tid e / p ro te in fo rmula tio n to b e tra nsp o rte d , sto re d , a nd use d
p a rtic ula rly in tro p ic a l d e ve lo p ing c o untrie s.
(Pa te nt: (W O /2010/030180) PEPTIDE FO RMULA TIO NS A ND USES THEREO F)
•
La te st public a tio n:
Sta b ility o f lyso zyme in a q ue o us e xtre mo lyte so lutio ns d uring he a t
sho c k a nd a c c e le ra te d the rma l c o nd itio ns. Plo s O ne Jo urna l,
Ja nua ry 2014, Vo lume 9, Issue 1, e 86244
•
The fo rma tio n o f o xyto c in d ime rs is sup p re sse d b y the zinc a sp a rta te -o xyto c in c o mp le x. J. Pha rm . Sc i., 2013, DO I
10.1002/ jp s.23546 (e a rly p ub lishe d o nline )
•
Asp a rta te b uffe r a nd d iva le nt me ta l io ns a ffe c t o xyto c in in
a q ue o us so lutio n a nd p ro te c t it fro m d e g ra d a tio n. Int. J. Pha rm ,
2013 , 444(1-2):139-45
Outline
Introduction
Peptide
instability
and the
possible
causes of
degradation
Strategies to
improve
peptide
stability in
liquid
formulations
Conclusion
Introduction
• Peptides as potential drugs:
Successful chemical synthesis of oxytocin by
duVigneaud in 1953
• over a hundred peptide drug candidates are in
development for a wide variety of diseases
• Peptides differ from proteins:
smaller and typically lack a defined tertiary structure
What is peptide and peptide bond ?
• Amino acids linked to each other by peptide bonds
• Peptide bond occurs when nitrogen atom on one amino
acid binds to the carboxyl group of another amino acid.
Definition of Peptide
• Malavolta (2011)
Peptides are molecules containing fewer than 40
amino acid residues, while proteins contain 50
residues or more
• Lee (1991)
Amino acids joined together in chains of 50 amino
acids or less are defined as peptides, 50-100
amino acids are defined as polypeptides, and over
100 amino acids are defined as proteins
Amino Acid Building Block
Tyr
Arg
Lys
Ser
Glu
Trp
Gln
Asp
Met
Purposes of Peptides
• A number of hormones, enzymes, antitumor
agents, antibiotics and neurotransmitters are
peptides.
• Peptides regulate many physiological processes,
acting at some sites as endocrine or paracrine
signals and at other sites as neurotransmitters or
growth factors.
• Nowadays, peptides are used as therapeutic
agents against diverse disease areas such as
neurological, endocrinological and hematological
disorders
Table 1 Several peptide-based parenteral
products in the market in 2010-2013
Generic
name
Trade name
Supplier
Thyrotropine releasing hormones
TRH/TRF
Relefact TRH® SanoviAventis
Antibiotic peptides
Daptomycin
Cubicin®
Novartis
Teicoplanin
Targocid®
SanofiAventis
Dosage form
Shelf-life
pH
and storage
temp.
Liquid inj.
2 yr 1525°C
Powder for inj. 3 yr, 2°C –
8°C
Powder for inj. 4 yr, 2-8°C
6.5
4-5
Platelet aggregates inhibitors
Eptifibatide
Integrilin®
GlaxoSmithKl Liquid for
ine
infusion
3 yr, 2-8°C
5.35
Table 1 Several peptide-based parenteral
products in the market in 2010-2013
Generic name Trade name
Supplier
Somatostatin analog
Octreotide
Sandostatin® Novartis
acetate
Vasopressins and analogs
Desmopressin DDAVP®
Ferring
Octostim®
Ferring
Minrin®
Felypressin
Ferring
Citanest 3% Densply
Octapressin®
Dosage form Shelf-life
pH
and storage
temp.
Liquid inj.
3 yr, 2-8°C
4.2
Liquid inj.
Liquid inj.
4 yr, 2-8°C
4 yr, 2-8°C
4-5
Liquid inj.
4 yr, 2-8°C
4
Liquid inj.
3 yr, 15-25°C 3.55.2
4
Table 1 Several peptide-based parenteral
products in the market in 2010-2013
Generic
name
Trade name
Oxytocins
Oxytocin
Syntocinon®
Carbetocin Pabal®
Oxytocin antagonist
Atosiban
Tractocile®
Tractocile®
Supplier
Dosage form
Shelf-life
pH
and storage
temp.
Defiante
Ferring
Liquid inj.
Liquid inj.
4 yr, 2-8°C
2 yr, 2-8°C
4
3.8
Ferring
Ferring
Liquid inj.
Liquid inj.
4yr, 2-8°C
4 yr 2-8°C
4.5
4.5
Table 1 Several peptide-based parenteral
products in the market in 2010-2013
Generic
name
Trade name
GNRH/LHRH agonists
Goserelin
Zoladex®
Gonadorelin Relefact
LH-RH®
Decapeptyl Triptorelin
CR®
Supplier
Dosage form
Shelf-life
pH
and storage
temp.
Div
SanofiAventis
Ipsen
Liquid inj.
Liquid inj.
3 yr, < 25°C
15-25°C
Powder and
solv. for sol for
inj.
Liquid nasal
spray
Powder and
solv. for sol for
inj.
Powder for inj.
3 yr, 2-8°C
Nafarelin
Synarel®
Pfizer
Leuprolide
Eligard ®
SanofiAventis
Cetrorelix
Cetrotide®
Serono
2 yr, < 25°C
2 yr, 2-8°C
3 yr, 1525°C
5-7
Table 1 Several peptide-based parenteral
products in the market in 2010-2013
Generic
name
Trade name
Supplier
Non-NSAID analgesic
Ziconotide
Prialt®
Elan
Calcitonins
Salmon
Calcitonin Novartis
Calcitonin
Sandoz®
Human parathyroid hormone [hPTH (1–34)]
Teriparatide Forsteo®
Eli Lily
Fusion inhibitor of HIV-1 with CD4 cells
Enfuvirtide Fuzeon®
Roche
ACTH and derivatives
CRH/CRF/
CRH Corticorelin Ferring®
Ferring
Dosage form
Shelf-life
pH
and storage
temp.
Liquid inj.
3 yr, 2-8°C
4-5
Liquid inj.
5 yr, 2-8°C
3-5
Liquid inj.
2 yr, 2-8°C
Powder and
solv. solution
for inj.
4 yr, 2-8°C
Powder for inj. 3 yr, < 25°C
Pharmaceutical peptides:
Challenge
• The sensitivity to enzymatic breakdown
• The poor ability to pass absorbing membranes
typically results in a poor bioavailability
following non-parenteral administration.
• The lack of physical and chemical stability lead
to significant degradation during processing
and storage of the (aqueous) formulations
Non-invasive routes for peptide
drug administration
• buccal,
• rectal,
• vaginal,
• percutaneous,
• ocular,
• transdermal,
• nasal,
• pulmonary
many of these routes of administration are still under
investigation and they may be insufficiently efficient,
especially when a rapid effect is desired.
Intravenous administration is the most
efficient way to deliver peptide drugs
directly into the systemic circulation
most peptide drugs have to be stored
and transported at low temperatures
Peptide Degradation
Pathways
Chemical degradation pathways
• hydrolysis,
• oxidation,
• deamidation .
Physical degradation:
• adsorption
• aggregation
problem in the
development as active
pharmaceuticals
Need
better understanding of the underlying mechanisms of instability of a
certain peptide to design rational strategies in the development
process of pharmaceuticals to optimize the stability of the peptide in
the final formulation
Peptide instability and the
possible causes of degradation
• Hydrolytic pathways
– Chain cleavage of the peptide backbone
– Deamidation of Asn and Gln residues
– Isomerization of Asp residues
• Oxidation pathways
– Autoxidation
– Metal-catalyzed oxidation
– Light-induced oxidation
• β-elimination reactions
• Disulfide exchange reactions
• Dimerization, aggregation, and precipitation
Deamidation pathways of Asn residue via
A. direct hydrolysis and B. succinimide mediation
Selected oxidation reactions of Met and His. (A): methionine oxidation by peroxide to
methionine sulfoxide in acidic solution (HA=acid). (B): 2-oxo-His, Asn and Asp
(adapted from Li, et. al, 1995).
Oxytocin degradation pathways
Strategies to improve peptide stability in
liquid formulations
Ta b le 2 De g ra d a tio n p a thwa ys a nd p o ssib le sta b iliza tio n stra te g ie s fo r p e p tid e s
inc lud ing a mino a c id re sid ue s invo lve d in the d e g ra d a tio n.
Degradation pathway
Chemical Instability
Acid/base catalyzed
hydrolysis
Deamidation
β-elimination
Stabilization strategy
Amino acid
residue(s)
involved
pH
buffer species
co-solvents
Ser
Trp
Asn-Pro
Asn-Tyr
Asn, Gln
pH 3-5
increased solvent viscosity
Buffer species
divalent metal ions
Cys-Cys
Ta ble 2 De g ra da tio n pa thwa ys a nd po ssible sta biliza tio n stra te g ie s fo r pe ptide s
inc luding a mino a c id re sidue s invo lve d in the de g ra da tio n, c o ntinue d
Degradation pathway
Chemical Instability
Oxidation
Light induced oxidation
Metal induced oxidation
Disulfide exchange
Stabilization strategy
Amino acid
residue(s)
involved
pH < 7
air exclusion
antioxidants
Protect from light
Chelating agents
Polyols
Surfactans
Polyols and sugars
Buffer and divalent metal ions
Trp, Met, Cys,
Tyr, His
Trp
His, Cys, Arg, Pro,
Met
Cys-Cys
Ta ble 2 De g ra da tio n pa thwa ys a nd po ssible sta biliza tio n stra te g ie s fo r pe ptide s
inc luding a mino a c id re sidue s invo lve d in the de g ra da tio n, c o ntinue d
Degradation pathway
Physical Instability
Dimerization and further
aggregation
Adsorption
Stabilization strategy
Amino acid
residue(s)
involved
Lower concentration
minimal mechanical stress
organic solvents
alkyl saccharide
alkyl polyglycoside
surfactans
polymers
Cys-Cys
Tyr-Tyr
His
Arg
Conclusion
• In a q ue o us so lutio ns p e p tid e s a re o fte n unsta b le .
• Pe p tid e s ha ve uniq ue struc ture s tha t the sid e c ha in
o f ne a rly a ll o f the a mino a c id re sid ue s a re fully
so lve nt e xp o se d , a llo wing ma xima l c o nta c t with
so lve nts
• the d e g ra d a tio n ra te s a p p e a r to c o rre la te with the
d e g re e o f so lve nt e xp o sure .
• Ba se d o n kno wle d g e o f the p e p tid e ’ s struc ture a nd
a n und e rsta nd ing o f the p re d o mina nt d e g ra d a tio n
p a thwa ys, the stra te g ie s ma y b e d e ve lo p e d to
a c hie ve a d e q ua te sta b ility o f the fo rmula tio n.
Conclusion
• The d e g ra d a tio n p a thwa ys o f p e p tid e s a re
ma inly d e p e nd e nt o n the a mino a c id se q ue nc e .
• The mo st p ro mine nt d e g ra d a tio n p a thwa ys fo r
p e p tid e s a re hyd ro lysis, o xid a tio n, a nd
d ime riza tio n.
• Fo rmula ting p e p tid e s in a sp e c ific p H with a
sp e c ific b uffe r, a vo id ing o xyg e n re a c tive sp e c ie s,
a nd minimizing so lve nt e xp o sure e limina te
c he mic a l d e g ra d a tio n.
• Inc re a sing so lutio n visc o sity b y using sug a rs o r
p o lyme rs re d uc e s p e p tid e mo b ility a nd furthe r
d e c e le ra te s p hysic a l d e g ra d a tio n.
Instability is the most stable
characteristic of
a dissolved peptide
Christina Avanti, 2011
Instabilities are a natural way to
achieve thermodynamic equilibrium
Christina Avanti, 2012