Discussion topics
Discussion topics Phase and state diagram Drug-polymer interaction Questions to industry Dissolution Accelerated stability studies Crystallization in the glassy state
Polymer properties General questions 1
Phase and state diagram
How does that solubility and miscibility of API and polymer impact ASD stability?
How does intrinsic properties of API such as ‘fast crystallization” impact ASD stability? 2
8. How does that solubility and miscibility of API and polymer impact ASD stability?
Qian et al, J Pharm Sci, 2010
3
Drug-polymer interaction
4
Polymer hydrogen bonding with drug Kothari et al, Mol Pharm 12, 2015,
5
Polymer strongly interacting with drug
6
7
8
Miscibility • Observation of >1 Tg in DSC experiment – red flag! • Determination of 1H Spin-lattice relaxation times by ssNMR (Munson et al Mol Pharm 11, 2014) • Experimentally determining the interaction parameter (using melting-point depression or low molecular weight analog for polymer) and calculating Gibb’s free energy of mixing by Flory-Huggins theory. (Taylor et al. Pharm Res 26(1) 2009) • Microscopic evidence of immiscibility by AFM and TEM (Taylor et al. J. Pharm. Sci 99(1) 2010)
9
Formulation Challenges Spray Drying SD powders typically include:
HME The intermediate appears as
Co-precipitation Powders are usually free-
relatively small particles;
solid strands or films of
flowing with a certain
low bulk density;
Undefined length;
porosity and surface roughness
often show poor flowability
Pelletization, Milling Dry Granulation compression can result in amorphous–amorphous phase separation or increased
crystallinity
The final dense particles, having a high bulk density, enabling capsule filling with a powder blend or direct compression
Milling ?
What are the approaches to perform physical stability prediction? Relaxation / Molecular mobility Enthalpy recovered (J/• g)
2.0
t = 9 days at 66ºC
1.6
1.2 Tg-15ºC 0.8
Tg-25ºC Tg-35ºC
0.4
DH from the Tg
Tg-55ºC
0.0 0
5
10
Aging time (h)
15
20
t = n years at 26ºC
Crystallization time of amorphous solid dispersions by controlling the combined effect of temperature and moisture content
Greco et all. Pharm Res (2012) 29:2792–2805
11
High-throughput screening techniques Using 96-well plates to screen supersaturated state stability Page et al Eur J Pharm Biopharm 84, 2013
12
High-throughput screening techniques Hovione’s Approach
Other examples: Memphis (Evonik); BASF HTS tool 13
High-throughput screening techniques PLM to study crystallization onset time in spin-coated dispersions Taylor et al. Mol Pharm 7(4) 2010
14
Solid state versus solution experiments Early screening of the polymers can be based either on solution experiments like (precipitation inhibition/supersaturation) or on solid state experiments (miscibility, melting point depression etc.) or both. “Which approach is more suitable during early stages of ASD development and what are the advantages of using one approach over the other?” or “Do we need to carry out polymer screening in both solution and solid state simultaneously during early stages of ASDs development?” 15
What is the impact of ASD manufacture method? ASD of a given composition prepared by: • Spray-drying • Hot melt extrusion • Melt quenching Any information in the literature?
This is product dependent and influenced by properties like: melting point; solubility, Tg, candidate formulation, etc. Powder properties will be very different: particles size, porosity, density, etc They also require specific downstream processing. 16
Dissolution
17
Factors influencing ASD dissolution (in vitro)? • • • •
Hydrophobicity of polymers (and drug) pH dependence solubility of the drug and polymer wettability of the dispersion Particle size of ASD (applicable when doing powder dissolution) • drug-polymer interactions in solution • equilibrium solubility and amorphous “solubility” of the drug in dissolution media • Recrystallization kinetics of drug in dissolution media 18
Dissolution (QC) tests for ASDs • What is the best method to test dissolution of ASDs as a QC criteria? • Sticking/gel formation observed in USP apparatus 2
19
What are the effects of surfactants (in vivo) on dissolution behavior of ASD? - Improve wettability - Maintain supersaturation - Comparing the impact of polymer on stabilizing ASD, the influence of surfactant is somewhat more complicated and can go in both directions.
20
Polymer properties
21
1. Which molecular descriptors are more relevant in terms of providing adequate ASD stability? Our work indicates: drug-polymer interactions Interactions will lead to physical stability (prevent crystallization)
22
2.
What types of functional groups on excipients are desired?
Q. Hu et. Al, Amorphous Solid Dispersions, Theory and Practice pag 171
23
4.
How does the excipient grade impact ASD stability?
We have to see this question from 2 different perspectives: functional groups and molecular weight. Functional groups – Polymers with substitution groups capable to interact with the API (i.e. of similar nature) will produce more stable solutions
Molecular weight – As a consequence of the molecular weight increase, viscosity of the solid solution also increases, reducing molecular mobility.
24
What’s the ratio of the functional groups on HPMC-AS? How does this ratio contribute to the ASD stabilizing property of the polymer? If the functional groups are responsible for the drug-polymer interaction, then the ratio can potentially contribute to stabilization. Bend & Dow have demonstrated the impact of functional groups substitution ratio on the performance (see next slide) of HPMCAS solid dispersions.
25
What’s the ratio of the functional groups on HPMC-AS? How does this ratio contribute to the ASD stabilizing property of the polymer?
D. T. Vodak and M. Morgen, Amorphous Solid Dispersions, Theory and Practice pag 310
26
Accelerated stability studies
27
Michelle Fung; Poster #: T3270
Effect of plasticizer on physical stability of amorphous solid dispersions Correlation between molecular mobility and crystallization PVP-COX PVP-COX + 1% glycerol PVP-COX + 2% glycerol
100
Log 1/k = M Log tau + C
Molecular mobility strongly couples with crystallization
•
Addition of plasticizer increases molecular mobility and accelerates crystallization
•
Coupling between molecular mobility and crystallization can be determined in shorter timescales
•
Physical stability prediction
1/k (s)
10
•
1
M0% gly= 0.79 M1% gly= 0.81 M2% gly = 0.89
0.1 10-6
10-5
10-4
10-3
10-2
Tau (s)
Similar coupling coefficients
Effect of sorbed water on structural relaxation and physical stability in the supercooled state log(𝑡𝑐 ) = 𝑀𝑙𝑜𝑔(𝜏𝛼 ) + c 4.2 4.0
Dry Felodipine - PVP ASD 1.5% w/w sorbed water
log tc (s)
3.8 3.6 3.4 3.2
Mdry = 0.6 M1.5% = 0.6
3.0 2.8 2.6 -5.0
-4.5
-4.0
log
-3.5
-3.0
(s)
Mehak Mehta, PhD dissertation work CONFIDENTIAL – UNPUBLISHED DATA
29
Crystallization in the glassy state
30
Correlation between molecular mobility and crystallization behavior Above Tg 6 4
Below Tg
12
Structural relaxation time above Tg
-relaxation below Tg relaxation
-relaxation
JG
Characteristic crystallization time, tc
above Tg
10
Structural relaxation time below Tg
2
βJG-relaxation 0
6 4
-2
2
-4
0
Above Tg
Note the parallel relationship between crystallization time and -relaxation time
0.0028
0.0030
0.0032 -1
0.0034 -1
T (K ) CONFIDENTIAL – UNPUBLISHED DATA
0.0036
log tc (s)
log (s)
8
Below Tg
Note the parallel relationship between crystallization time and βJG-relaxation time 31
Effect of drug-polymer interaction on structural relaxation and physical stability in the glassy state Strength of H-bonding
3.5
log (s)
Relaxation time
Physical stability (at 45 oC)
PVP > HPMCAS > NIF
PVP > HPMCAS > NIF PVP, 21 d
Nifedipine alone Nif-PVP (10% w/w) Nif-HPMCAS (10% w/w)
3.0
PVP > HPMCAS
HPMCAS, 21 d
2.5 2.0
NIF, 21 d
1.5 1.0
0.00
314
0.00
45 °C
31 6
3 0.00
18
0.00
320 -1
0.00 -1
322
T (K )
0.00
324
0.00
326
33 °C Mehak Mehta, PhD dissertation work CONFIDENTIAL – UNPUBLISHED DATA
32
General questions
33
Does particle size matter? Particles size will influence the dissolution rate?
Y. Huang, W.-G. Dai, Acta Pharmaceutica Sinica B 2014;4(1):18–25
34
Theoretical vs. empirical approach?
35
How does high drug loading impact ASD stability? Kothari et al, 2014
36
ASD stability in regards to surface chemistry vs. bulk property.
Same ASD evaporated from solvent mixtures with different composition
- Adjusting solvent composition resulted in structural changes on the API/polymer ratios and consequently with impact on the stability poster T2212 & M1259
Collaboration with prof Feng Zhang (Univ. Texas Austin)
What API properties influence the superstation potential? Most important for the amorphous solubility ratio was molecular weight, number of hydrogen bond acceptors, melting point, number of torsional bonds and polar surface área - Eur J Pharm Sci. 2013 Feb 14;48(3):554-62 - Martin Kuentza & Georgios Imanidi
What API properties can be used to predict good an poor glass formers?
Q. Hu et. Al, Amorphous Solid Dispersions, Theory and Practice pag 168
39
Can other excipients improve the stability and performance of ASDs? • Surfactants;
• Buffering agents (e.g. in the formulation that contain polymer with and acidic character); • Antioxidants (e.g. in the formulation with PVP); • Plasticization agents (e.g. from the formulations produced by HME)
40
How can we more accurately establish IVIVC for ASD formulations? • Profound differences between species: GI track volume, residence
time, pH, membrane transport, etc. • Therapy dependent
41
Polymer properties General questions 1
Phase and state diagram
How does that solubility and miscibility of API and polymer impact ASD stability?
How does intrinsic properties of API such as ‘fast crystallization” impact ASD stability? 2
8. How does that solubility and miscibility of API and polymer impact ASD stability?
Qian et al, J Pharm Sci, 2010
3
Drug-polymer interaction
4
Polymer hydrogen bonding with drug Kothari et al, Mol Pharm 12, 2015,
5
Polymer strongly interacting with drug
6
7
8
Miscibility • Observation of >1 Tg in DSC experiment – red flag! • Determination of 1H Spin-lattice relaxation times by ssNMR (Munson et al Mol Pharm 11, 2014) • Experimentally determining the interaction parameter (using melting-point depression or low molecular weight analog for polymer) and calculating Gibb’s free energy of mixing by Flory-Huggins theory. (Taylor et al. Pharm Res 26(1) 2009) • Microscopic evidence of immiscibility by AFM and TEM (Taylor et al. J. Pharm. Sci 99(1) 2010)
9
Formulation Challenges Spray Drying SD powders typically include:
HME The intermediate appears as
Co-precipitation Powders are usually free-
relatively small particles;
solid strands or films of
flowing with a certain
low bulk density;
Undefined length;
porosity and surface roughness
often show poor flowability
Pelletization, Milling Dry Granulation compression can result in amorphous–amorphous phase separation or increased
crystallinity
The final dense particles, having a high bulk density, enabling capsule filling with a powder blend or direct compression
Milling ?
What are the approaches to perform physical stability prediction? Relaxation / Molecular mobility Enthalpy recovered (J/• g)
2.0
t = 9 days at 66ºC
1.6
1.2 Tg-15ºC 0.8
Tg-25ºC Tg-35ºC
0.4
DH from the Tg
Tg-55ºC
0.0 0
5
10
Aging time (h)
15
20
t = n years at 26ºC
Crystallization time of amorphous solid dispersions by controlling the combined effect of temperature and moisture content
Greco et all. Pharm Res (2012) 29:2792–2805
11
High-throughput screening techniques Using 96-well plates to screen supersaturated state stability Page et al Eur J Pharm Biopharm 84, 2013
12
High-throughput screening techniques Hovione’s Approach
Other examples: Memphis (Evonik); BASF HTS tool 13
High-throughput screening techniques PLM to study crystallization onset time in spin-coated dispersions Taylor et al. Mol Pharm 7(4) 2010
14
Solid state versus solution experiments Early screening of the polymers can be based either on solution experiments like (precipitation inhibition/supersaturation) or on solid state experiments (miscibility, melting point depression etc.) or both. “Which approach is more suitable during early stages of ASD development and what are the advantages of using one approach over the other?” or “Do we need to carry out polymer screening in both solution and solid state simultaneously during early stages of ASDs development?” 15
What is the impact of ASD manufacture method? ASD of a given composition prepared by: • Spray-drying • Hot melt extrusion • Melt quenching Any information in the literature?
This is product dependent and influenced by properties like: melting point; solubility, Tg, candidate formulation, etc. Powder properties will be very different: particles size, porosity, density, etc They also require specific downstream processing. 16
Dissolution
17
Factors influencing ASD dissolution (in vitro)? • • • •
Hydrophobicity of polymers (and drug) pH dependence solubility of the drug and polymer wettability of the dispersion Particle size of ASD (applicable when doing powder dissolution) • drug-polymer interactions in solution • equilibrium solubility and amorphous “solubility” of the drug in dissolution media • Recrystallization kinetics of drug in dissolution media 18
Dissolution (QC) tests for ASDs • What is the best method to test dissolution of ASDs as a QC criteria? • Sticking/gel formation observed in USP apparatus 2
19
What are the effects of surfactants (in vivo) on dissolution behavior of ASD? - Improve wettability - Maintain supersaturation - Comparing the impact of polymer on stabilizing ASD, the influence of surfactant is somewhat more complicated and can go in both directions.
20
Polymer properties
21
1. Which molecular descriptors are more relevant in terms of providing adequate ASD stability? Our work indicates: drug-polymer interactions Interactions will lead to physical stability (prevent crystallization)
22
2.
What types of functional groups on excipients are desired?
Q. Hu et. Al, Amorphous Solid Dispersions, Theory and Practice pag 171
23
4.
How does the excipient grade impact ASD stability?
We have to see this question from 2 different perspectives: functional groups and molecular weight. Functional groups – Polymers with substitution groups capable to interact with the API (i.e. of similar nature) will produce more stable solutions
Molecular weight – As a consequence of the molecular weight increase, viscosity of the solid solution also increases, reducing molecular mobility.
24
What’s the ratio of the functional groups on HPMC-AS? How does this ratio contribute to the ASD stabilizing property of the polymer? If the functional groups are responsible for the drug-polymer interaction, then the ratio can potentially contribute to stabilization. Bend & Dow have demonstrated the impact of functional groups substitution ratio on the performance (see next slide) of HPMCAS solid dispersions.
25
What’s the ratio of the functional groups on HPMC-AS? How does this ratio contribute to the ASD stabilizing property of the polymer?
D. T. Vodak and M. Morgen, Amorphous Solid Dispersions, Theory and Practice pag 310
26
Accelerated stability studies
27
Michelle Fung; Poster #: T3270
Effect of plasticizer on physical stability of amorphous solid dispersions Correlation between molecular mobility and crystallization PVP-COX PVP-COX + 1% glycerol PVP-COX + 2% glycerol
100
Log 1/k = M Log tau + C
Molecular mobility strongly couples with crystallization
•
Addition of plasticizer increases molecular mobility and accelerates crystallization
•
Coupling between molecular mobility and crystallization can be determined in shorter timescales
•
Physical stability prediction
1/k (s)
10
•
1
M0% gly= 0.79 M1% gly= 0.81 M2% gly = 0.89
0.1 10-6
10-5
10-4
10-3
10-2
Tau (s)
Similar coupling coefficients
Effect of sorbed water on structural relaxation and physical stability in the supercooled state log(𝑡𝑐 ) = 𝑀𝑙𝑜𝑔(𝜏𝛼 ) + c 4.2 4.0
Dry Felodipine - PVP ASD 1.5% w/w sorbed water
log tc (s)
3.8 3.6 3.4 3.2
Mdry = 0.6 M1.5% = 0.6
3.0 2.8 2.6 -5.0
-4.5
-4.0
log
-3.5
-3.0
(s)
Mehak Mehta, PhD dissertation work CONFIDENTIAL – UNPUBLISHED DATA
29
Crystallization in the glassy state
30
Correlation between molecular mobility and crystallization behavior Above Tg 6 4
Below Tg
12
Structural relaxation time above Tg
-relaxation below Tg relaxation
-relaxation
JG
Characteristic crystallization time, tc
above Tg
10
Structural relaxation time below Tg
2
βJG-relaxation 0
6 4
-2
2
-4
0
Above Tg
Note the parallel relationship between crystallization time and -relaxation time
0.0028
0.0030
0.0032 -1
0.0034 -1
T (K ) CONFIDENTIAL – UNPUBLISHED DATA
0.0036
log tc (s)
log (s)
8
Below Tg
Note the parallel relationship between crystallization time and βJG-relaxation time 31
Effect of drug-polymer interaction on structural relaxation and physical stability in the glassy state Strength of H-bonding
3.5
log (s)
Relaxation time
Physical stability (at 45 oC)
PVP > HPMCAS > NIF
PVP > HPMCAS > NIF PVP, 21 d
Nifedipine alone Nif-PVP (10% w/w) Nif-HPMCAS (10% w/w)
3.0
PVP > HPMCAS
HPMCAS, 21 d
2.5 2.0
NIF, 21 d
1.5 1.0
0.00
314
0.00
45 °C
31 6
3 0.00
18
0.00
320 -1
0.00 -1
322
T (K )
0.00
324
0.00
326
33 °C Mehak Mehta, PhD dissertation work CONFIDENTIAL – UNPUBLISHED DATA
32
General questions
33
Does particle size matter? Particles size will influence the dissolution rate?
Y. Huang, W.-G. Dai, Acta Pharmaceutica Sinica B 2014;4(1):18–25
34
Theoretical vs. empirical approach?
35
How does high drug loading impact ASD stability? Kothari et al, 2014
36
ASD stability in regards to surface chemistry vs. bulk property.
Same ASD evaporated from solvent mixtures with different composition
- Adjusting solvent composition resulted in structural changes on the API/polymer ratios and consequently with impact on the stability poster T2212 & M1259
Collaboration with prof Feng Zhang (Univ. Texas Austin)
What API properties influence the superstation potential? Most important for the amorphous solubility ratio was molecular weight, number of hydrogen bond acceptors, melting point, number of torsional bonds and polar surface área - Eur J Pharm Sci. 2013 Feb 14;48(3):554-62 - Martin Kuentza & Georgios Imanidi
What API properties can be used to predict good an poor glass formers?
Q. Hu et. Al, Amorphous Solid Dispersions, Theory and Practice pag 168
39
Can other excipients improve the stability and performance of ASDs? • Surfactants;
• Buffering agents (e.g. in the formulation that contain polymer with and acidic character); • Antioxidants (e.g. in the formulation with PVP); • Plasticization agents (e.g. from the formulations produced by HME)
40
How can we more accurately establish IVIVC for ASD formulations? • Profound differences between species: GI track volume, residence
time, pH, membrane transport, etc. • Therapy dependent
41
