K/H
Yuejie Chen1, Chengyu Liu1 , Zhen Chen1 , Ching Su2, Michael Hageman2 , Munir Hussain2 , Roy Haskell2 , Kevin Stefanski2 , Feng Qian1 1 Dept.
Pharmacology and Pharmaceutical Sciences School of Medicine, Tsinghua University, Beijing, China 2 Bristol-Myers Squibb Company, New Jersey, USA (AAPS Annual Meeting, Nov 2014) 1
Introduction
Risks of amorphous solid
dispersions Physical stability In vitro and in vivo
performance Crystallization over time
Amorphous solid or glass CH3 O
O
O
N
*
CH C H2
*
O
C H2
n
H
OR
OR
H
H
H
H H
R=
O CH2OR
H CH3 COCH3
O
m
CH2OR O H OR
H
H
OR
H
n
CH2CHCH3 OCOCH3 CH2CHCH3
COCH2CH2COOH CH2CH(OH)CH3
OCOCH2COOH
Crowley, Zografi, Thermochimica Acta 380 (2001) 79-93 Ediger, Angell, Nagel J. Phys. Chem. (1996), 100, 13200 Hancock, Shamblin, Zografi, Pharm. Res. 12 (1995) 799 Qian, et al., Pharm Res. 29 (2012) 2766-2776
Questions: What are the key attributes of a well performing amorphous solid dispersion? Is there a simple in vitro assay that might be able to predict the in vitro and in vivo performance? 2
Dissolution of amorphous solid dispersion Goal: to achieve the best
dissolution performance, i.e., F of free drug ~1
Dissolution performance parameter, F =
AUCactual AUCtheoretical
Polymer Drug-polymer complex?
Dissolving SDD
Free drug
Potential controlling factors: Crystallization tendency of the drug Drug-polymer interaction with/without water Ability of polymer to maintain solution drug supersaturation Polymer dissolution kinetics … Fundamentally: drug-polymer-
Crystalline drug
water interaction 3
Model drugs and polymers
Solid dispersions of 20%, 40% and 60% drug loadings were prepared by spray drying; Factors that could influence dissolution were investigated; In vitro dissolution kinetics of both the drug and the polymer at different dose levels were obtained Evaporative light scattering detector (ELSD) method developed to measure polymer concentration 4
Crystallization kinetics of amorphous drugs in FaSSIF
Note: Felodipine did not crystallize after 2 hours Rank order of drug crystallization rate by this assay: griseofulvin ( felodipine (2-4 hours) > ketoconazole (>4 hours) 5
Determine the Flory-Huggins interaction parameters between drug, polymer and water • Drug-polymer FH interaction parameter (1)
(2)
αd: drug activity, T: temperature , Tm: melting temperature of drug, x: molar volume ratio, △Hm: molar heat of fusion of pure drug,, Фp: volume fraction of polymer, χ: drug–polymer interaction parameter.
• ASD-water and polymer-water FH interaction parameter
αw: vapor activity, Φp: polymer volume fraction, χ: interaction parameter, R: gas constant, T: temperature.
Sun, Y., et al. Journal of Pharmaceutical Science, Vol. 99, No. 9, September 2010 Beck, M. I.; Tomka, I. J. Macromol. Sci. Phys. 1997, B36, 19-39
6
A summary of Flory-Huggins interaction parameters between drug, polymer, and water χ
PVP-VA (P)
HPMC-AS (H)
Griseofulvin (G)
-0.14
0.26
Felodipine (F)
-1.9
-0.21
Ketoconazole (K)
-0.43
-1.68
Strong interaction
between F-P, K-H Confirmed by IR and
NMR
χASD-water vs. drug loading: Nonlinear for F-P and KH; linear for G-H, F-H, KP ASDs Compared with physical blends: F-P interaction decreased the hydrophobicity, while K-H interaction increased the hydrophobicity of ASDs 7
Specific drug-polymer interaction by
13C
NMR
Chemical shift (ppm)
Carbon Pure felodipine (δa)
F-P (δb)
δa-δb
F-H (δb)
δa-δb
C5a
168.038
168.018
-0.02
168.002
-0.036
C3a
167.550
167.525
-0.025
167.507
-0.043
C1 ’
148.252
148.338
0.086
148.249
-0.003
C6
144.434
144.604
0.17
144.314
-0.12
C2
144.332
144.504
0.172
144.213
-0.119
C3 ’
132.858
132.785
-0.073
132.894
0.036
C6 ’
131.062
131.004
-0.058
131.119
0.057
C2 ’
129.785
129.770
-0.015
129.817
0.032
C4 ’
128.329
128.25
-0.079
128.357
0.028
C5 ’
127.121
127.076
-0.045
127.137
0.016
C3
103.921
103.763
-0.158
104.051
0.13
C5
103.510
103.349
-0.161
103.639
0.129
3b
59.974
59.877
-0.097
59.994
0.02
5b
50.991
50.913
-0.078
51.014
0.023
4
38.702
38.645
-0.057
38.717
0.015
2a
19.600
19.471
-0.129
19.713
0.113
6a
19.541
19.414
-0.127
19.657
0.116
14.417
0.023
3c
14.394
14.367
-0.027
Carbon number 2
Pure PVP-VA (δa) 175.433
175.390
-0.043
1
170.739
170.831
0.1
Note: Felodipine systems are listed as an example
• Drugs were dissolved in non-polar solvent and its 13C NMR spectra were collected before and after polymer addition; • The affected chemical shifts were analyzed to assist identification of type and strength of drug-polymer interaction
ASD
Drug-polymer interaction
G/P
No interaction
G/H
No interaction
F/P
Strong H-bonding
F/H
Weak dipole interaction
K/P
Medium dipole interaction H-bonding & strong dipole interaction
K/H
8
Specific drug-polymer interaction investigated by FT-IR, before and after moisture exposure
carbonyl region, no interaction
carbonyl region, drug-polymer interaction disrupted by moisture
-NH region, drug-polymer interaction resistant to moisture
carbonyl region, drug-polymer interaction resistant to moisture
9
The ability of polymers to maintain solution drug supersaturation
Drug/ polymer
[C]drug in FaSSIF with/without pre-dissolved PVP-VA or HPMC-AS, polymer concentration: 0.3 mg and 3 mg/mL
Supersaturation parameters 0.2mg/mL [drug] 1mg/mL [drug] [Polymer] (mg/mL) 0.3 3 0.3 3
G/P
0.27
0.22
0.03
0.10
G/H
0.17
0.41
0.05
0.10
F/P
0.51
0.73
0.04
0.35
F/H
0.40
0.73
0.07
0.41
K/P
0.36
0.30
0.27
0.17
K/H
0.57
0.65
0.23
0.49
10 10
In vitro dissolution performance of drug and polymer
Dissolution performance parameter, F =
ASD
F (dissolution performance parameter) 0.5mg/ml ASD 5mg/ml ASD Drug loading (%) 20 40 60 20 40 60
G/P
0.75 0.23 0.14 0.05 0.02 0.01
G/H
0.73 0.29 0.21 0.09 0.04 0.02
F/P
0.33 0.31 0.20 0.29 0.11 0.07
F/H
0.62 0.37 0.18 0.48 0.13 0.06
K/P
0.85 0.28 0.15 0.38 0.13 0.04
K/H
0.95 0.97 0.80 0.82 0.31 0.15 11
0.5 mg/mL SDD in FaSSIF
5 mg/mL SDD in FaSSIF
AUCactual AUCtheoretical
Summary of the findings A summary of key physiochemical characteristics, different interactions in ASDs, and the corresponding ASD dissolution performance. Supersaturation parameter of
Drug-polymer interaction in solid state Crystallization ASD
tendency in
FH
solution/solida
interaction, χb
G/P G/H F/P
polymers
Disruption of H-bonding
Drug-polymer
drug-polymer
formation
interaction
interaction by
by FT-IR
by NMR
water?
(Y/N)
0.2 mg/ml drug
1 mg/ml drug
Dissolution performance parameter 0.5 mg/ml ASD
Polymer concentration
5 mg/ml ASD
Drug loading (%)
0.3
3
0.3
3
mg/ml
mg/ml
mg/ml
mg/ml
20
40
60
20
40
60
H/(Calss I)
W
N
No interaction
N/A
0.27
0.22
0.03
0.10
0.75
0.23
0.14
0.05
0.02
0.01
H/(Calss I)
W
N
No interaction
N/A
0.17
0.41
0.05
0.10
0.73
0.29
0.21
0.09
0.04
0.02
M/(Calss III)
S
Y
H-bonding
N
0.51
0.73
0.04
0.35
0.33
0.31
0.20
0.29
0.11
0.07
F/H
M/(Calss III)
M
N
Y
0.40
0.73
0.07
0.41
0.62
0.37
0.18
0.48
0.13
0.06
K/P
L/(Calss III)
Y
0.36
0.30
0.27
0.17
0.85
0.28
0.15
0.38
0.13
0.04
N
0.57
0.65
0.23
0.49
0.95
0.97
0.80
0.82
0.31
0.15
Dipole complex (W) Dipole complex
M
N
(M) H-bonding &
K/H
L/(Calss III)
S
Y
Dipole complex (S)
a
Classification of crystallization tendency of amorphous drug in FaSSIF: High if drug crystallized within 30 minutes, low if drug did not crystallize within 4 hours, and
medium if drug crystallized between 30 minutes to 4 hours. Crystallization tendency in solid state is classified according to Baird et al.37. b
χ< -1 is defined as strong, -1 -0.2 is defined as weak.
Best performing ASD (K/H) appears have: slow crystallizing drug; strong drug-polymer interaction that is resistant to moisture and makes solid dispersion more hydrophobic; fast polymer release kinetics (not in F/P); a polymer that maintain drug supersaturaiton 12
Summary of the findings (con’t) K/H solid disperision
The χASD-water vs. drug loading plot: Could be conveniently obtained by DVS, and appears to have
implication on:
The existence of strong and moisture resistant drug-polymer interaction? The relative hydrophobicity of the ASD? The drug dissolution performance?
Further validation of this plot is undergoing
13
Summary of the findings (con’t) • For fast crystallizers that do not interact with polymers, ASD only works if both the drug dose and ASD drug loading are low; • Strong drug-polymer interaction may be helpful in maintaining supersaturation but did not demonstrate clear correlation with dissolution performance of ASDs; • For ASDs evaluated in this study: HPMC-AS doesn’t always outperform PVP-VA in maintaining drug supersaturation, but most HPMC-AS ASDs do seem to outperform PVP-VA ASDs in dissolution study, which could due to the relatively hydrophilic nature and gelling of the PVP-VA ASDs, and possibly faster drug crystallization within the PVP-VA ASDs • Introduced “supersaturation parameter” and “dissoluton performance parameter” to quantify and simplify the performance evaluation • Further investigation of more ASD systems to validate the above observation, and in vivo data will be obtained to support the 14 conclusion
Acknowledgment • Bristol-Myers Squibb Company • Center for Life Sciences at Tsinghua and Peking Universities • China Recruitment Program of Global Experts • Prof. Lian Yu (University of Wisconsin, Madison)
15 15
Department of Pharmacology and Pharmaceutical Sciences School of Medicine, Tsinghua University
16
Pharmacology and Pharmaceutical Sciences School of Medicine, Tsinghua University, Beijing, China 2 Bristol-Myers Squibb Company, New Jersey, USA (AAPS Annual Meeting, Nov 2014) 1
Introduction
Risks of amorphous solid
dispersions Physical stability In vitro and in vivo
performance Crystallization over time
Amorphous solid or glass CH3 O
O
O
N
*
CH C H2
*
O
C H2
n
H
OR
OR
H
H
H
H H
R=
O CH2OR
H CH3 COCH3
O
m
CH2OR O H OR
H
H
OR
H
n
CH2CHCH3 OCOCH3 CH2CHCH3
COCH2CH2COOH CH2CH(OH)CH3
OCOCH2COOH
Crowley, Zografi, Thermochimica Acta 380 (2001) 79-93 Ediger, Angell, Nagel J. Phys. Chem. (1996), 100, 13200 Hancock, Shamblin, Zografi, Pharm. Res. 12 (1995) 799 Qian, et al., Pharm Res. 29 (2012) 2766-2776
Questions: What are the key attributes of a well performing amorphous solid dispersion? Is there a simple in vitro assay that might be able to predict the in vitro and in vivo performance? 2
Dissolution of amorphous solid dispersion Goal: to achieve the best
dissolution performance, i.e., F of free drug ~1
Dissolution performance parameter, F =
AUCactual AUCtheoretical
Polymer Drug-polymer complex?
Dissolving SDD
Free drug
Potential controlling factors: Crystallization tendency of the drug Drug-polymer interaction with/without water Ability of polymer to maintain solution drug supersaturation Polymer dissolution kinetics … Fundamentally: drug-polymer-
Crystalline drug
water interaction 3
Model drugs and polymers
Solid dispersions of 20%, 40% and 60% drug loadings were prepared by spray drying; Factors that could influence dissolution were investigated; In vitro dissolution kinetics of both the drug and the polymer at different dose levels were obtained Evaporative light scattering detector (ELSD) method developed to measure polymer concentration 4
Crystallization kinetics of amorphous drugs in FaSSIF
Note: Felodipine did not crystallize after 2 hours Rank order of drug crystallization rate by this assay: griseofulvin ( felodipine (2-4 hours) > ketoconazole (>4 hours) 5
Determine the Flory-Huggins interaction parameters between drug, polymer and water • Drug-polymer FH interaction parameter (1)
(2)
αd: drug activity, T: temperature , Tm: melting temperature of drug, x: molar volume ratio, △Hm: molar heat of fusion of pure drug,, Фp: volume fraction of polymer, χ: drug–polymer interaction parameter.
• ASD-water and polymer-water FH interaction parameter
αw: vapor activity, Φp: polymer volume fraction, χ: interaction parameter, R: gas constant, T: temperature.
Sun, Y., et al. Journal of Pharmaceutical Science, Vol. 99, No. 9, September 2010 Beck, M. I.; Tomka, I. J. Macromol. Sci. Phys. 1997, B36, 19-39
6
A summary of Flory-Huggins interaction parameters between drug, polymer, and water χ
PVP-VA (P)
HPMC-AS (H)
Griseofulvin (G)
-0.14
0.26
Felodipine (F)
-1.9
-0.21
Ketoconazole (K)
-0.43
-1.68
Strong interaction
between F-P, K-H Confirmed by IR and
NMR
χASD-water vs. drug loading: Nonlinear for F-P and KH; linear for G-H, F-H, KP ASDs Compared with physical blends: F-P interaction decreased the hydrophobicity, while K-H interaction increased the hydrophobicity of ASDs 7
Specific drug-polymer interaction by
13C
NMR
Chemical shift (ppm)
Carbon Pure felodipine (δa)
F-P (δb)
δa-δb
F-H (δb)
δa-δb
C5a
168.038
168.018
-0.02
168.002
-0.036
C3a
167.550
167.525
-0.025
167.507
-0.043
C1 ’
148.252
148.338
0.086
148.249
-0.003
C6
144.434
144.604
0.17
144.314
-0.12
C2
144.332
144.504
0.172
144.213
-0.119
C3 ’
132.858
132.785
-0.073
132.894
0.036
C6 ’
131.062
131.004
-0.058
131.119
0.057
C2 ’
129.785
129.770
-0.015
129.817
0.032
C4 ’
128.329
128.25
-0.079
128.357
0.028
C5 ’
127.121
127.076
-0.045
127.137
0.016
C3
103.921
103.763
-0.158
104.051
0.13
C5
103.510
103.349
-0.161
103.639
0.129
3b
59.974
59.877
-0.097
59.994
0.02
5b
50.991
50.913
-0.078
51.014
0.023
4
38.702
38.645
-0.057
38.717
0.015
2a
19.600
19.471
-0.129
19.713
0.113
6a
19.541
19.414
-0.127
19.657
0.116
14.417
0.023
3c
14.394
14.367
-0.027
Carbon number 2
Pure PVP-VA (δa) 175.433
175.390
-0.043
1
170.739
170.831
0.1
Note: Felodipine systems are listed as an example
• Drugs were dissolved in non-polar solvent and its 13C NMR spectra were collected before and after polymer addition; • The affected chemical shifts were analyzed to assist identification of type and strength of drug-polymer interaction
ASD
Drug-polymer interaction
G/P
No interaction
G/H
No interaction
F/P
Strong H-bonding
F/H
Weak dipole interaction
K/P
Medium dipole interaction H-bonding & strong dipole interaction
K/H
8
Specific drug-polymer interaction investigated by FT-IR, before and after moisture exposure
carbonyl region, no interaction
carbonyl region, drug-polymer interaction disrupted by moisture
-NH region, drug-polymer interaction resistant to moisture
carbonyl region, drug-polymer interaction resistant to moisture
9
The ability of polymers to maintain solution drug supersaturation
Drug/ polymer
[C]drug in FaSSIF with/without pre-dissolved PVP-VA or HPMC-AS, polymer concentration: 0.3 mg and 3 mg/mL
Supersaturation parameters 0.2mg/mL [drug] 1mg/mL [drug] [Polymer] (mg/mL) 0.3 3 0.3 3
G/P
0.27
0.22
0.03
0.10
G/H
0.17
0.41
0.05
0.10
F/P
0.51
0.73
0.04
0.35
F/H
0.40
0.73
0.07
0.41
K/P
0.36
0.30
0.27
0.17
K/H
0.57
0.65
0.23
0.49
10 10
In vitro dissolution performance of drug and polymer
Dissolution performance parameter, F =
ASD
F (dissolution performance parameter) 0.5mg/ml ASD 5mg/ml ASD Drug loading (%) 20 40 60 20 40 60
G/P
0.75 0.23 0.14 0.05 0.02 0.01
G/H
0.73 0.29 0.21 0.09 0.04 0.02
F/P
0.33 0.31 0.20 0.29 0.11 0.07
F/H
0.62 0.37 0.18 0.48 0.13 0.06
K/P
0.85 0.28 0.15 0.38 0.13 0.04
K/H
0.95 0.97 0.80 0.82 0.31 0.15 11
0.5 mg/mL SDD in FaSSIF
5 mg/mL SDD in FaSSIF
AUCactual AUCtheoretical
Summary of the findings A summary of key physiochemical characteristics, different interactions in ASDs, and the corresponding ASD dissolution performance. Supersaturation parameter of
Drug-polymer interaction in solid state Crystallization ASD
tendency in
FH
solution/solida
interaction, χb
G/P G/H F/P
polymers
Disruption of H-bonding
Drug-polymer
drug-polymer
formation
interaction
interaction by
by FT-IR
by NMR
water?
(Y/N)
0.2 mg/ml drug
1 mg/ml drug
Dissolution performance parameter 0.5 mg/ml ASD
Polymer concentration
5 mg/ml ASD
Drug loading (%)
0.3
3
0.3
3
mg/ml
mg/ml
mg/ml
mg/ml
20
40
60
20
40
60
H/(Calss I)
W
N
No interaction
N/A
0.27
0.22
0.03
0.10
0.75
0.23
0.14
0.05
0.02
0.01
H/(Calss I)
W
N
No interaction
N/A
0.17
0.41
0.05
0.10
0.73
0.29
0.21
0.09
0.04
0.02
M/(Calss III)
S
Y
H-bonding
N
0.51
0.73
0.04
0.35
0.33
0.31
0.20
0.29
0.11
0.07
F/H
M/(Calss III)
M
N
Y
0.40
0.73
0.07
0.41
0.62
0.37
0.18
0.48
0.13
0.06
K/P
L/(Calss III)
Y
0.36
0.30
0.27
0.17
0.85
0.28
0.15
0.38
0.13
0.04
N
0.57
0.65
0.23
0.49
0.95
0.97
0.80
0.82
0.31
0.15
Dipole complex (W) Dipole complex
M
N
(M) H-bonding &
K/H
L/(Calss III)
S
Y
Dipole complex (S)
a
Classification of crystallization tendency of amorphous drug in FaSSIF: High if drug crystallized within 30 minutes, low if drug did not crystallize within 4 hours, and
medium if drug crystallized between 30 minutes to 4 hours. Crystallization tendency in solid state is classified according to Baird et al.37. b
χ< -1 is defined as strong, -1 -0.2 is defined as weak.
Best performing ASD (K/H) appears have: slow crystallizing drug; strong drug-polymer interaction that is resistant to moisture and makes solid dispersion more hydrophobic; fast polymer release kinetics (not in F/P); a polymer that maintain drug supersaturaiton 12
Summary of the findings (con’t) K/H solid disperision
The χASD-water vs. drug loading plot: Could be conveniently obtained by DVS, and appears to have
implication on:
The existence of strong and moisture resistant drug-polymer interaction? The relative hydrophobicity of the ASD? The drug dissolution performance?
Further validation of this plot is undergoing
13
Summary of the findings (con’t) • For fast crystallizers that do not interact with polymers, ASD only works if both the drug dose and ASD drug loading are low; • Strong drug-polymer interaction may be helpful in maintaining supersaturation but did not demonstrate clear correlation with dissolution performance of ASDs; • For ASDs evaluated in this study: HPMC-AS doesn’t always outperform PVP-VA in maintaining drug supersaturation, but most HPMC-AS ASDs do seem to outperform PVP-VA ASDs in dissolution study, which could due to the relatively hydrophilic nature and gelling of the PVP-VA ASDs, and possibly faster drug crystallization within the PVP-VA ASDs • Introduced “supersaturation parameter” and “dissoluton performance parameter” to quantify and simplify the performance evaluation • Further investigation of more ASD systems to validate the above observation, and in vivo data will be obtained to support the 14 conclusion
Acknowledgment • Bristol-Myers Squibb Company • Center for Life Sciences at Tsinghua and Peking Universities • China Recruitment Program of Global Experts • Prof. Lian Yu (University of Wisconsin, Madison)
15 15
Department of Pharmacology and Pharmaceutical Sciences School of Medicine, Tsinghua University
16
