Organic Process Research & Development
Article
Sullivan, K. M.; Hornby, G. A.; Scheckter, L. E.; Andree, T. H.;
Mewshaw, R. E. Bioorg. Med. Chem. Lett. 2005, 15, 911.
n-propanolate level in the drug substance is carried out as a routine
test for the drug substance release. The discontinuation of this
test is recommended only when a suitable set of data based on the
development batches is available and when more biopharma-
ceutical and clinical data are available on the effect of the
n-propanolate in the drug product performance.
(3) (a) Bergauer, M.; Bertani, B.; Biagetti, M.; Bromidge, S. M.; Falchi,
A.; Leslie, C. P.; Merlo, G.; Pizzi, D. A.; Rinaldi, M.; Stasi, L. P.; Tibasco,
J.; Vong, A. K.; Ward, S. E. Quinoline and quinazoline derivatives having
affinity for 5HT1-type receptors. WO/2005/014552, 200517022005;
(b) Bentley, J.; Bergauer, M.; Bertani, B.; Biagetti, M.; Borriello, M.;
Bromidge, S. M.; Gianotti, M.; Granci, E.; Leslie, C. P.; Pasquarello, A.;
Zucchelli, V. Fused tricyclic derivatives for the treatment of psycotic
disorders. WO/2006/024517, 2006; 09032006. (c) Serafinowska, H. T.;
Blaney, F. E.; Lovell, P. J.; Merlo, G. G.; Scott, C. M.; Smith, P. W.; Starr,
K. R.; Watson, J. M. Bioorg. Med. Chem. Lett. 2008, 5581.
(4) It is worth noting that this work is related to a process developed to
support the initial toxicology and clinical requirements, and therefore, it
might not be seen as ready for technical transfer or regulatory
submission. What is stressed here is the help that the application of the
QbD principles has given to achieve process understanding and control
and to define a robust control strategy for the solvate.
(5) (a) ICH Q8 Pharmaceutical Development, (R2); U.S. Department
of Health and Human Services, Food and Drug Administration, Center
for Drug Evaluation and Research (CDER): Rockville, MD, Aug 2009.
(b) ICH Q9 Quality Risk Management; U.S. Department of Health and
Human Services, Food and Drug Administration, Center for Drug
Evaluation and Research (CDER): Rockville, MD, June 2006. (c) ICH
Q10 Pharmaceutical Quality System; U.S. Department of Health and
Human Services, Food and Drug Administration, Center for Drug
Evaluation and Research (CDER): Rockville, MD, April 2009.
(6) See for example U.S. Food and Drug Administration Pharmaceutical
cGMPs for the 21st Century − A Risk Based Approach (initiative launched
in 2002); U.S. Food and Drug Administration, Silver Spring, MD, 2003;
12. EXPERIMENTAL PROCEDURES
Drug Substance 1 (Form 1) Preparation. IG-1 (1 wt) is
dissolved in 1-propanol (15 vol) by heating to 85 °C; then it is
passed through a clarification line-filter (5 μm). The line-filter is
washed with hot 1-propanol (2 vol). The collected filtrates are
concentrated to 9 vol by distillation at atmospheric pressure. The
resulting solution is then cooled to 70 °C (internal temperature)
and seeded with 1 (0.0025 wt). The suspension is cooled down
to 20 °C ( 2 °C) (internal temperature) over approximately 1 h
(1 °C/min ramp). The slurry is stirred for 2 h at 20 °C ( 2 °C)
(internal temperature), and then the solid is collected by filtra-
tion. The cake is washed successively with 1-propanol (2 vol),
1-propanol/isooctane 1:1 (2 vol), and isooctane (2 vol). All the
washes are carried out at 20 °C ( 2 °C). The damp cake is dried
in a vacuum oven at 50−55 °C overnight (yield about 85% w/w).
1H NMR (600 MHz, DMSO-d6) δ 2.64 (m, 2 H), 2.63 (s,
3 H), 2.74 (br, s, 4 H), 2.78 (m, 2 H), 3.04 (br s, 4 H), 3.39 (m,
2 H), 3.84 (dd, J = 8.94, 7.01 Hz, 2 H), 6.89 (d, J = 7.70 Hz, 1 H),
6.91 (m, 1 H), 7.11 (dd, J = 6.60, 1.92 Hz, 1 H), 7.21 (t, J =
7.97 Hz, 1 H), 7.39 (m, 2 H), 7.46 (t, J = 1.65 Hz, 1 H), 7.59 (m,
2 H), 8.34 (d, J = 8.80 Hz, 1 H). m/z; 416
Drug Substance 1 (n-Propanolate) Preparation. Proce-
dure 1. A sealed and saturated solution of drug substance 1 in
n-propanol is aged at −20 °C for about 10 days. The solution of
drug substance 1 crystallizes as n-propanol solvate.
(7) Cimarosti, Z.; Bravo, F.; Stonestreet, P.; Tinazzi, F.; Vecchi, O.;
Camurri, G. Org. Process Res. Dev 2010, 14 (4), 993−998.
(8) Each of the elements of control can be categorised into three
control modes, as follows: (i) attribute controls, which include in-process
controls (IPCs), and specifications for starting materials, intermediates,
solvents, and drug substance (ii) parametric controls, which involve
operation within proven acceptable ranges (PARs) for critical process
parameters (CPPs) which are linked to CQAs, it is worth noting that, in
this case the PARs were not defined due to the early phase of the project
(iii) procedural controls, which describe operations linked to CQAs
such as facilities setup, equipment configuration, order of addition,
reagent, and solvent choice, sequence of events, etc.
(9) Cimarosti, Z.; Giubellina, N.; Stabile, P.; Laval, G.; Tinazzi, F.;
Maton, W.; Pachera, R.; Russo, P; Moretti, R.; Rossi, S; Cooke, J.;
Westerduin, P. Org. Process Res. Dev. 2011, 15, 1287−1296.
(10) International Conference on Harmonisation ICHQ3C(R5) -
(11) The HPLC method used in the solubility screening is a generic
HPLC gradient method with Phenomenex Luna C18 column. Mobile
phases: A1 = TFA 0.05% vol/vol in water, B1 = TFA 0.05% vol/vol in
acetonitrile. Gradient from 0% B1 to 95% B1 in 8 min. UV detection at
220 nm.
(12) Ethanol was initially considered, but it was decided not to test it as
its water affinity (water activity) was considered an additional risk with
respect to the formation of a monohydrate form; this aspect is discussed
in the paper cited in reference 9.
(13) A polymorph study was carried out, after the selection of n-
propanol as a crystrallization solvent, on 48 solvents and different
experiment types; the result of this study highlighted the possible
existence of the n-propanolate, but it was decided to continue with the
use of this solvent for the initial phases of development.
Procedure 2. A microfluidized solution of drug substance 1
(Form 1) is left ageing at 4 °C for about 1 year. After the ageing
period the drug substance 1 is isolated as an n-propanol solvate.
Procedure 3. Drug substance 1 (Form 1, 1 wt) is dissolved in
n-propanol (20 vol) at 70 °C. The resulting solution is then
cooled to 40 °C (internal temperature) and seeded with drug
substance 1 (n-propanolate, 0.03 wt). The suspension is cooled
down to an internal temperature of 10 °C ( 2 °C) over
approximately 20 min. The slurry is stirred for 3 h at 10 °C
( 2 °C), and then the solid is collected by filtration. The cake is
washed twice with 2 vol of n-propanol at room temperature. The
wet solid is dried in a vacuum oven at room temperature.
ASSOCIATED CONTENT
* Supporting Information
Stability data mentioned in section 8, Development of an NIR
Method in Support of the Control Strategy. This material is
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AUTHOR INFORMATION
Corresponding Author
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Notes
The authors declare no competing financial interest.
REFERENCES
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