Transcript phase 2

An investigation
into the stability
and solubility of
amorphous solid
dispersion of BCS
class II drugs
Shrawan Baghel, WIT
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Manufacturing
Polymer
selection
Crystallization
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Stable ASD
products
An investigation into the crystallization tendency/kinetics of amorphous active pharmaceutical
ingredients: A case study with dipyridamole and cinnarizine
1. Fragility
a. Thermodynamic fragility
b. Dynamic fragility
(i) Extrapolation of configurational entropy to zero
(ii) Heating rate dependence of glass transition temperature
2. Glass forming ability
3. Isothermal crystallization kinetics
4. Non-isothermal crystallization kinetics
5. Stability studies of amorphous solid dispersion
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1. Fragility
a. Thermodynamic fragility (mT)
b. Dynamic fragility
(i) Extrapolation of configurational entropy to zero (mDCE)
(ii) Heating rate dependence of glass transition temperature (mDTg)
Fragility and mean relaxation time of model drugs
*To, TK and Г are Kauzmann temperature, fictive temperature and relaxation time respectively.
m < 100 = Fragile glass
D < 10 = Fragile glass
m > 100 = Strong glass
D > 10 = Strong glass
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2. Glass forming ability
Tred values were found to increase at higher heating rates which suggest that crystallization tendency for both
the model drugs increases with an increase in heating rate. Moreover, at all heating rates, CNZ was found to
have lower GFA as compared to DPM which is in agreement with the molecular mobility based estimation of
crystallization tendency of amorphous model compounds.
FRAGILE GLASSES HAVE POOR GLASS FORMING ABILITY
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3. Isothermal crystallization kinetics
Crystallization temperature (Tc), Avrami constant (K), Avrami exponent (n) and activation energy (Ea) of
amorphous model drugs
Values of Avrami exponent (n) and expected crystallization mechanism
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4. Non-isothermal crystallization kinetics
Effect of heating rate on activation energy of crystallization of amorphous dipyridamole (a) and cinnarizine (b) obtained by fitting nucleation
and diffusion models of different orders. Model-free kinetics for amorphous dipyridamole (a) and cinnarizine (b) calculated by KissingerAkahira-Sunose isoconversional kinetics to identify the most suitable kinetic model; (n=3)
*JMAEK (n=2) (blue), 1D diffusion (red), First order reaction (green), Power law (n=1/2) (purple) and 1D phase boundary reaction (light blue)
CRYSTALLIZATION MECHANISM OF BOTH THE MODEL COMPOUNDS DEPENDS ON THE HEATING
RATE
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5. Stability studies of amorphous solid dispersion
CNZ ASD – Unstable – Highly fragile, poor glass forming ability and low crystallization
activation energy (nucleation based mechanism)
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Theoretical and experimental investigation of drug-polymer interaction and miscibility
1.
2.
3.
4.
5.
Prediction of drug polymer miscibility from solubility parameter approach
Drug-polymer binary interaction parameter from melting point depression data
Phase diagram
Drug-polymer-water ternary interaction parameter
Role of polymers in maintaining and prolonging drug supersaturation in aqueous
medium
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1.Prediction of drug polymer miscibility from solubility parameter approach
Drug/Polymer
Hoftyzer and van Krevelen Fedor method
method (MPa1/2)
(MPa1/2)
Average
Difference
χ (at 25°C)
DPM
CNZ
DPM
CNZ
DPM
28.57
29.57
29.07
CNZ
21.00
21.10
21.05
PVP K30
26.28
23.75
25.02
4.06
3.97
2.39
2.07
PAA
27.00
28.73
27.87
1.21
6.82
0.21
6.11
Solubility parameter difference < 7 MPa1/2 = Miscible System
Solubility parameters differing by more than 10 MPa1/2 = Immiscible system
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2. Drug-polymer binary interaction parameter from melting point depression data
Based on Flory-Huggins model
1. Solubility parameter approach
𝝌=
𝑽𝒎
𝑹𝑻
𝜹𝒅𝒓𝒖𝒈 − 𝜹𝒑𝒐𝒍𝒚𝒎𝒆𝒓
𝟐
2. Melting-point depression method
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𝟏
𝑻𝒎
−
𝟏
𝑻𝒐𝒎
=
−𝑹
𝜟𝑯𝒇
𝒍𝒏𝜱𝒅 + 𝟏 −
3. Phase diagram
(a) DPM-PVP; (b) DPM-PAA; (c) (CNZ-PVP and (d) CNZPAA
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Antiplasticization effect:
Phase diagram predicted unstability for Systems at higher drug
loading
However DPM-PVP, DPM-PAA and CNZ-PAA are found to be stable up
to 65% (w/w) drug loading
This could be explained from antiplasticization effect of polymer on
drug within dispersion
Positive deviation = Strong heteronuclear interactions
Negative deviation = Strong homonuclear interactions
Only CNZ-PVP systems shows negative deviation which explains its
crystallization at higher drug loading (50 and 65 % w/w)
PAA is found to be more effective in stabilizing model drugs compared
to PVP
FT-IR studies further confirmed the presence of stronger drugpolymer interaction within DPM-PVP, DPM-PAA and CNZ-PAA systems
whereas CNZ-PVP spectra does reveal any significant interaction
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(a) DPM-PVP; (b) DPM-PAA; (c) (CNZ-PVP and (d) CNZ-PAA
Blue line indicates Tg values predicted from Gordon-Taylor
Equation; Red dots are experimentally obtained values
4. Drug-polymer-water ternary interaction parameter (ternary Flory-Huggins theory)
ln
𝑝
𝑝𝑜
= 𝑙𝑛𝛷1 + 1 −
1
𝜒12
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𝛷2 + 𝜒12 𝛷22 ln
𝑝
𝑝𝑜
= 𝑙𝑛𝛷1 𝛷2 + 𝛷3 −
𝑉2
𝜒12
−
𝑉3
𝜒13
+ 𝜒12 𝛷12 + 𝜒13 𝛷13 𝑉2 +
5. Role of polymers in maintaining and prolonging drug supersaturation in aqueous
medium
𝑺𝒖𝒑𝒆𝒓𝒔𝒂𝒕𝒖𝒓𝒂𝒕𝒊𝒐𝒏 𝒑𝒂𝒓𝒂𝒎𝒆𝒕𝒆𝒓
𝑨𝒓𝒆𝒂𝑪 𝑪𝒏𝒐 𝒑𝒐𝒍𝒚 𝑪𝒑𝒐𝒍𝒚
𝒊 𝒇
𝒇
=
𝑨𝒓𝒆𝒂𝑪 𝑪𝒏𝒐 𝒑𝒐𝒍𝒚 𝑪′
𝒊 𝒇
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𝒊
The value of SP for different drug-polymer systems used in this study are
found to be 0.17, 0.98, 0.06 and 0.94 for DPM-PVP, DPM-PAA, CNZ-PVP and
CNZ-PAA systems, respectively. Thus DPM-PAA system performed best in
maintaining and prolonging drug supersaturation in aqueous medium
which was attributed to the drug’s low crystallization tendency, the strong
DPM-PAA interaction, the robustness of this interaction against water and
the ability of PAA in maintaining DPM supersaturation.
DPM --- F-H interaction parameter with PVP and PAA are -1.45 and -3.08 --- hydrophobic nature (log P = 3.71)
prevents its interaction with water to retard crystallization --- Both situations may lead to a strong adsorption
of polymers to the drug surface
CNZ --- forms strong h-bond with PAA and thus its supersaturation is maintained in PAA solution --Hydrophobic nature (log P = 5.71) could also favours its interaction with PAA in the solution state. Although,
the physical interaction between CNZ and PVP (-1.11) is nearly equal to that between CNZ and PAA (-1.51),
the more hydrophilic nature of PVP and lack of H-bonding could reduce its interaction with hydrophobic CNZ,
thus negates its ability to prevent CNZ crystallization and maintain its supersaturation in solution.
The initial significantly higher concentration of CNZ in PVP solution compared to solution without PVP may
be attributed to retardation in crystallization due to increase in fluid viscosity surrounding solubilised drug.
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Dr. Niall O’Reilly
Dr. Helen Fox
Thank you for your time. Any questions?
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