International Journal of Pharmaceutics 515 (2016) 403–415

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Review

Co amorphous systems: A product development perspective

Rahul B Chavana , Rajesh Thipparaboinaa , Dinesh Kumara,b , Nalini R Shastria,*
a
Solid State Pharmaceutical Research Group (SSPRG), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER),
Hyderabad, India
b
Solid State Pharmaceutical Cluster (SSPC), School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, The University of Dublin, Ireland

A R T I C L E I N F O A B S T R A C T

Article history:
Received 24 September 2016 Solubility is one of the major problems associated with most of the new chemical entities that can be
Received in revised form 18 October 2016 reasonably addressed by drug amorphization. However, being a high-energy form, it usually tends to re-
Accepted 19 October 2016 crystallize, necessitating new formulation strategies to stabilize amorphous drugs. Polymeric amorphous
Available online 19 October 2016 solid dispersion (PASD) is one of the widely investigated strategies to stabilize amorphous drug, with
major limitations like limited polymer solubility and hygroscopicity. Co amorphous system (CAM), a new
Keywords: entrant in amorphous arena is a promising alternative to PASD. CAMs are multi component single phase
Co amorphous system amorphous solid systems made up of two or more small molecules that may be a combination of drugs or
Amorphous solid dispersion
drug and excipients. Excipients explored for CAM preparation include amino acids, carboxylic acids,
Polymers
nicotinamide and saccharine. Advantages offered by CAM include improved aqueous solubility and
Miscibility
Phase separation physical stability of amorphous drug, with a potential to improve therapeutic efficacy. This review
Stability attempts to address different aspects in the development of CAM as drug products. Criterion for co-
former selection, various methods involved in CAM preparation, characterization tools, stability, scale up
and regulatory requirements for the CAM product development are discussed.
ã 2016 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

2. History of co amorphous system and its classification . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
2.1. Drug-drug CAM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
2.2. Drug-excipient CAM . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
3. Development of co amorphous system . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
3.1. Co-former selection . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
3.2. Preparation methods . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
3.3. Scale up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
3.4. Characterization of CAM . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
3.5. Evaluation of pharmaceutical and biopharmaceutical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
3.6. Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
3.7. Regulatory approval . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
4. Future perspectives and concluding remarks . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413

1. Introduction

Poor physicochemical properties such as low solubility and

* Corresponding author at: Department of Pharmaceutics, National Institute of
Pharmaceutical Education & Research NIPER, Balanagar, Hyderabad, 500037, India.
E-mail addresses: nalini@niperhyd.ac.in, svcphod@yahoo.co.in,
nalini.niperhyd@gov.in (N.R. Shastri).
permeability, pose challenges during the transition of promising
new chemical entities (NCE) into a successful drug. Low solubility
is accompanied by slow dissolution and poor bioavailability.

http://dx.doi.org/10.1016/j.ijpharm.2016.10.043
0378-5173/ã 2016 Elsevier B.V. All rights reserved.