Abstract
An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three nonsolvated polymorphs, 56 crystalline solvates, and an amorphous phase. XPac analysis of the 35 experimental crystal structures (30 from this work and 5 from the CSD) containing olanzapine show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements and accommodate diverse solvents to produce structures with a similar moderate packing efficiency to form I. The crystal energy landscape confirms the inability of olanzapine to pack with an efficiency of more than 70%, explains the role of solvent in stabilizing the solvate structures, and identifies a hypothetical structural type that offers an explanation for the inability to obtain the metastable forms II and III separately. The calculations find that structures that do not contain the observed dimer are thermodynamically feasible, suggesting that kinetic effects are responsible for all the observed structures being based on the dimer. Thus, this extensive screen probably has not found all possible physical forms of olanzapine, and further form diversity could be targeted with a better understanding of the role of kinetics in its crystallization.
| Language | English |
|---|---|
| Pages | 1602-1617 |
| Number of pages | 16 |
| Journal | Crystal Growth and Design |
| Volume | 13 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2013 |
Fingerprint
Keywords
- crystallization
- crystal energy
- Olanzapine
Cite this
}
Exploring the experimental and computed crystal energy landscape of olanzapine. / Bhardwaj, Rajni M; Price, Louise S.; Price, Sarah L.; Reutzel-Edens, Susan M.; Miller, Gary J.; Oswald, Iain D. H.; Johnston, Blair F.; Florence, Alastair J.
In: Crystal Growth and Design, Vol. 13, No. 4, 04.2013, p. 1602-1617.Research output: Contribution to journal › Article
TY - JOUR
T1 - Exploring the experimental and computed crystal energy landscape of olanzapine
AU - Bhardwaj, Rajni M
AU - Price, Louise S.
AU - Price, Sarah L.
AU - Reutzel-Edens, Susan M.
AU - Miller, Gary J.
AU - Oswald, Iain D. H.
AU - Johnston, Blair F.
AU - Florence, Alastair J.
PY - 2013/4
Y1 - 2013/4
N2 - An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three nonsolvated polymorphs, 56 crystalline solvates, and an amorphous phase. XPac analysis of the 35 experimental crystal structures (30 from this work and 5 from the CSD) containing olanzapine show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements and accommodate diverse solvents to produce structures with a similar moderate packing efficiency to form I. The crystal energy landscape confirms the inability of olanzapine to pack with an efficiency of more than 70%, explains the role of solvent in stabilizing the solvate structures, and identifies a hypothetical structural type that offers an explanation for the inability to obtain the metastable forms II and III separately. The calculations find that structures that do not contain the observed dimer are thermodynamically feasible, suggesting that kinetic effects are responsible for all the observed structures being based on the dimer. Thus, this extensive screen probably has not found all possible physical forms of olanzapine, and further form diversity could be targeted with a better understanding of the role of kinetics in its crystallization.
AB - An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three nonsolvated polymorphs, 56 crystalline solvates, and an amorphous phase. XPac analysis of the 35 experimental crystal structures (30 from this work and 5 from the CSD) containing olanzapine show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements and accommodate diverse solvents to produce structures with a similar moderate packing efficiency to form I. The crystal energy landscape confirms the inability of olanzapine to pack with an efficiency of more than 70%, explains the role of solvent in stabilizing the solvate structures, and identifies a hypothetical structural type that offers an explanation for the inability to obtain the metastable forms II and III separately. The calculations find that structures that do not contain the observed dimer are thermodynamically feasible, suggesting that kinetic effects are responsible for all the observed structures being based on the dimer. Thus, this extensive screen probably has not found all possible physical forms of olanzapine, and further form diversity could be targeted with a better understanding of the role of kinetics in its crystallization.
KW - crystallization
KW - crystal energy
KW - Olanzapine
UR - http://www.scopus.com/inward/record.url?scp=84875771409&partnerID=8YFLogxK
U2 - 10.1021/cg301826s
DO - 10.1021/cg301826s
M3 - Article
VL - 13
SP - 1602
EP - 1617
JO - Crystal Growth and Design
T2 - Crystal Growth and Design
JF - Crystal Growth and Design
SN - 1528-7483
IS - 4
ER -