Organic Process Research & Development 2009, 13, 1122–1124
Scalable Process for the Premix of Esomeprazole†
Lekkala Amarnath Reddy,‡ Golla China Malakondaiah,‡ Alieti Sanjay Reddy,‡ Boluguddu Vijaya Bhaskar,‡
Vurimidi Himabindu,§ Apurba Bhattacharya,‡ and Rakeshwar Bandichhor*,‡
Center of Excellence, Integrated Product DeVelopment, InnoVation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupalli,
Qutubullapur, R. R. District 500 072 Andhra Pradesh, India, and Center for EnVironment, Institute of Science and Technology,
Jawaharlal Nehru Technological UniVersity, Kukatpally, Hyderabad 500 072, India
Abstract:
An efficient, scalable process for the premix of unstable esome-
prazole base is described that allows accessibility to the stable
amorphous form of esomeprazole 1.
Figure 1. Structure of esomeprazole 1.
form of esomeprazole base to achieve a pharmaceutically
acceptable formulation.
Introduction
Prazoles are known as proton pump inhibitors that mecha-
Certain pharmaceutically active ingredients are acid labile,
and thus, they create a myriad of problems during in ViVo
absorption. Therefore, formulating such an acid-labile com-
pound in the oral pharmaceutical dosage form to allow
compatibility to the acidic environment of the stomach imposes
a great challenge. For example, a few substituted benzimidazole
derivatives have poor stability. In particular, these compounds
tend to decompose rapidly and acquire color under moist or
acidic to neutral conditions. When these compounds are
formulated for oral administration, they require specific coating
to avoid exposure to the gastric acid of the stomach. In order
to achieve effective enteric coating, granulation or pellet
formation techniques are practiced that prohibit the active
pharmaceutical ingredient (API) from being soluble in water
under acidic or neutral conditions and allow the API to be
soluble in alkaline conditions. However, the material used in
enteric coatings is often acidic, which can cause the decomposi-
tion of the acid-labile compounds. Such decomposition occurs
even during the enteric coating process, which results in the
coloration of the surface of the core. In order to avoid such
problem, an inert sub coating, which is not acidic, is often
required between the core and enteric coating, which brings
the intricacy and adds the cost of the formulation in the
manufacturing process of acid-labile compounds.
For substances that are labile in acidic media, but have better
stability in neutral to alkaline media, it is often advantageous
to add alkaline as the inactive constituents in order to increase
the stability of the active compound during manufacturing and
storage. In particular, substituted benzimidazole derivatives such
as omeprazole and esomeprazole are not only unstable in acidic
condition but also in neutral solid state. Thus, in order to
enhance the storage stability, an alkaline base such as sodium
bicarbonate is added to the formulation, and/or the substituted
benzimidazole derivatives are converted to their alkaline salts,
which are usually more stable than the free species. It is also
known that such alkaline base has adverse effects on patients
who suffer from hypertension, heart failure, etc.
nistically inhibit gastric acid secretion and are thus used as anti-
ulcer agents.1,2 The new proton pump inhibitor (PPI), esome-
prazole Mg (Nexium), developed by AstraZeneca is the
S-isomer of omeprazole, the first PPI developed as a single
optical isomer and used for the treatment of acid-related
diseases.3
Esomeprazole 1 as shown in Figure 1 is found to be a more
effective PPI than omeprazole4 due to the fact that it has superior
pharmacokinetic properties and less variability in effectiveness
as compared to omeprazole. Esomeprazole shares a similar
mechanism of action, side-effect profile, and precautions with
currently available proton-pump inhibitors. The better efficacy
of esomeprazole may be attributed to the active moiety that is
the enantiomerically pure (S)-isomer of omeprazole.
Earlier we have reported a resolution process for the
synthesis of the magnesium salt of S-omeprazole through a
transition metal complex using a combination of D-(-)-diethyl
tartrate, Ti(OiPr)4, and L-(+)-mandelic acid as resolving agents.5
In continuation of our work, we opted to stabilize an unstable
† Communication number: IPDO IPM - 00183.
* Corresponding author. Telephone: +91 40 44346430. Fax: +91 40
44346164. E-mail: rakeshwarb@drreddys.com.
‡ Dr. Reddy’s Laboratories Ltd.
§ Jawaharlal Nehru Technological University.
(1) For reviews, see: (a) Pellissier, H. Tetrahedron 2006, 62, 5559. (b)
Bentley, R. Chem. Soc. ReV. 2005, 34, 609. (c) Fernandez, I.; Khiar,
N. Chem. ReV. 2003, 103, 3651. (d) Legros, J.; Dehli, J. R.; Bolm, C.
AdV. Synth. Catal. 2005, 347, 19.
(2) For reviews, see: (a) Sachs, G.; Shin, J. M.; Howden, C. W. Aliment.
Pharmacol. Ther. 2006, 23, 2. (b) Tonini, M.; Giorgio, R. D.; Ponti,
F. D. Expert Opin. Ther. Patents 2003, 13, 639.
(3) Baker, D. E. ReV. Gastroenterol. Disord. 2001, 1, 32. (b) Cotton, H.;
Elebring, T.; Larsson, E. M.; Li, L.; So¨rensen, H.; Unge, S. V.
Tetrahedron: Asymmetry 2000, 11, 3819. (c) Larsson, E. M.; Stenhede,
U. J.; So¨rensen, H.; Unge, S. V.; Cotton, H. EP 0773940 B1, 1997. (d)
Federsel, H. J.; Larsson, E. M. In Asymmetric Catalysis on Industrial
Scale: Challenges, Approaches and Solutions; Blaser, H. U., Schmidt,
E., Eds.; Wiley-VCH: Weinheim, 2004; p 413.
(4) (a) Rabasseda, X.; Cole, P. Drugs Today 2001, 37, 767. (b) Graul, A.;
Castaner, R.; Castaner, J. Drugs Future 1999, 24, 1178.
(5) (a) Raju, S. V. N.; Purandhar, K.; Reddy, P. P.; Reddy, G. M.; Reddy,
L. A.; Reddy, K. S.; Sreenath, K.; Mukkanti, K.; Reddy, G. S. Org.
Process Res. DeV. 2006, 10, 33. (b) Reddy, L. A.; Kondaiah, G. C. M.;
Srihari, K. B.; Bhattacharya, A.; Bandichhor, R.; Himabindu, V.; Reddy,
P. P.; Anand, R. V. Org. Process Res. DeV. 2008, 12, 66.
1122
•
Vol. 13, No. 6, 2009 / Organic Process Research & Development
10.1021/op9001406 CCC: $40.75 2009 American Chemical Society
Published on Web 09/25/2009