Pharmaceutical Co-Crystals: A New Paradigm of Crystal Engineering

Altaf Ahmad Najar, Yasser Azim


A review on pharmaceutical co-crystals, nutraceutical co-crystals and pharmaceutical co-crystal polymorphs depicting their relevance both in academia and pharmaceutical industry because of their potential as new solid forms of the active pharmaceutical ingredient. The overview of crystal engineering to design co-crystals for altered and improved physicochemical properties such as solubility, dissolution rate, bioavailability, hygroscopicity etc., with some examples present in the literature till 2013.


Pharmaceutical Co-crystals; Nutraceuticals; Polymorphs; Crystal Engineering; Physicochemical Properties; Active Pharmaceutical Ingredients


R. Pepinsky, “Crystal Engineering: New Concepts in Crystallography”,

Phys. Rev. 1955, 100, pp. 971–971.

G.M. Schmidt, “Photodimerization in the Solid State”,

J. Pure Appl. Chem. 1971, 27, pp. 647–678.

J.M. Thomas, “Diffusionless reactions and crystal engineering”,

Nature 1981, 289, pp. 633–634.

L. Addadi, M. Lahav, “Towards the planning and execution

of an “absolute” asymmetric synthesis of chiral dimers

and polymers with quantitative enantiomeric yield”,

J. Pure Appl. Chem. 1979, 51, pp. 1269–1284.

G. Wegner, “Topochemische Reaktionen von Monomeren

mit konjugierten Dreifachbindungen I. Mitt.: Polymerisation

von Derivaten des 2.4-Hexadiin-1.6diols im kristallinen

Zustand”, Z. Naturforsch. B 1969, 24, pp. 824–832.

G.R. Desiraju, “Crystal Engineering. The Design of Organic

Solids”, Elsevier, Amsterdam, 1989.

(a) P. Brunet, M. Simard, J.D. Wuest, “Molecular Tectonics.

Porous Hydrogen-Bonded Networks with Unprecedented

Structural Integrity”, J. Am. Chem. Soc. 1997,

, pp. 2737–2738.

(b) M.T. McBride, T.J.M. Luo, G.T.R. Palmore, “Hydrogen-

Bonding Interactions in Crystalline Solids of Cyclic

Thioureas”, Cryst. Growth Des. 2001, 1, pp. 39–46.

(c) K.T. Holman, A.M. Pivovar, M.D. Ward, “Engineering

Crystal Symmetry and Polar Order in Molecular Host

Frameworks”, Science, 2001, 294, pp. 1907–1911.

(d) B.Q. Ma, P. Coppens, “Symmetry Mismatching as a

Tool in the Synthesis of Complex Supramolecular

Solids with Multiple Cavities”, Cryst. Growth Des.

, 4, pp. 211–213.

(e) S. George, S. Lipstman, I. Goldberg, “Porphyrin

Supramolecular Solids Assembled with the Aid of

Lanthanide Ions”, Cryst. Growth Des. 2006, 6, pp.


(f) M. Ruben, D. Payer, A. Landa, C. Comicso, N. Lin,

J.P. Collin, J.P. Sauvage, A. De Vitto, K. Kern, “2D

Supramolecular Assemblies of Benzene-1,3,5-triyltribenzoic

Acid: Temperature-Induced Phase Transformations

and Hierarchical Organization with

Macrocyclic Molecules”, J. Am. Chem. Soc. 2006, 128,

pp. 15644–15651.

(g) M.G. Siskos, A. Michaelides, A.K. Zarkadis, N.I. Tzerpos,

S. Skoulika, “Structural Diversity in a Family of

Quasi-Tetrahedral Organic Molecules: From Van Der

Waals Solids to Helices and Molecular Complexes”,

Cryst. Growth Des. 2008, 8, pp. 1966–1971.

(h) S. Mahapatra, K.N. Venugopala, T.N. Guru Row, “A

Device to Crystallize Organic Solids: Structure of

Ciprofloxacin, Midazolam, and Ofloxacin as Targets”,

Cryst. Growth Des. 2010, 10, pp. 1866–1870.

(i) W. Jones, C.N.R. Rao, “Supramolecular Organization

and Materials Design”, Eds.; University Press: Cambridge,

(j) W. Jones, “Organic Molecular Solids: Properties and

Applications”, Ed.; CRC Press: Boca Raton, FL, 1997.

(a) Y.P. He, Y. Tan, J. Zhang, “Stable Mg Metal–Organic

Framework (MOF) and Unstable Zn-MOF Based on

Nanosized Tris ((4-carboxyl) phenylduryl) amine Ligand”,

Cryst. Growth Des. 2013, 13, pp. 6–9.

(b) L. Li, S. Zhang, L. Han, Z. Sun, J. Luo, M. Hong, “A

Non-Centrosymmetric Dual-Emissive Metal–Organic

Framework with Distinct Nonlinear Optical and Tunable

Photoluminescence Properties”, Cryst. Growth

Des. 2013, 13, pp. 106–110.

(c) P. Mahata, C.M. Draznieks, P. Roy, S. Natarajan,

“Solid State and Solution Mediated Multistep

Sequential Transformations in Metal–Organic Coordination

Networks”, Cryst. Growth Des. 2013, 13, pp.


(d) M.P. Suh, H.J. Park, T.K. Prasad, D.W. Lim, “Hydrogen

storage in metal–organic frameworks”, Chem. Rev.

, 112, pp. 782–835.

(e) J. Liu, P.K. Thallapally, B.P. McGrail, D.R. Brown, J. Liu,

“Progress in adsorption based CO2 capture by metal–

organic frameworks”, J. Chem. Soc. Rev. 2012, 41, pp.


(f) H.L. Jiang, D.W. Feng, T.F. Liu, J.R Li, H.C. Zhou,

“Pore Surface Engineering with Controlled Loadings

of Functional Groups via Click Chemistry in Highly

Stable Metal–Organic Frameworks”, J. Am. Chem. Soc.

, 134, pp. 14690–14693.

(g) M. Yoon, R. Srirambalaji, K. Kim, “Homochiral Metal–

Organic Frameworks for Asymmetric Heterogeneous

Catalysis”, Chem. Rev. 2012, 112, pp. 1196–1231.

(h) Y.Q. Lan, S.L. Li, H.L. Jiang, Q. Xu, “Tailor-made

metal–organic frameworks from functionalized

molecular building blocks and length-adjustable

organic linkers by stepwise synthesis”, Chem. Eur. J.

, 18, pp. 8076–8083.

(i) Y. Cui, Y. Yue, G. Qian, B. Chen, “Luminescent functional

metal–organic frameworks”, Chem. Rev. 2012,

, pp. 1126–1162.

(j) J. ejka, (ed.) “Metal–Organic Frameworks Applications

from Catalysis to Gas Storage”, Wiley-VCH, Weinheim,

, pp. 392.

(k) Z. Guo, H. Xu, S. Su, J. Cai, S. Dang, S. Xiang, G. Qian,

H. Zhang, M. O’Keeffe, B. Chen, “A robust near infrared

luminescent ytterbium metal–organic framework

for sensing of small molecules”, Chem. Commun. 2011,

, pp. 5551–5553.

(l) D. Han, F.L. Jiang, M.Y. Wu, L. Chen, Q.H. Chen, M.C.

Hong, “A non-interpenetrated porous metal–organic

framework with high gas-uptake capacity”, Chem.

Commun. 2011, 47, pp. 9861–9863.

(m) A.U. Czaja, N. Trukhan, U. Müller, “Industrial applications

of metal–organic frameworks”, Chem. Soc.

Rev. 2009, 38, pp. 1284–1293.

(n) P. Mahata, S. Natarajan, “Metal–organic framework

structures—how closely are they related to classical

inorganic structures?”, Chem. Soc. Rev. 2009, 38,

pp. 2304–2318.

(o) D.J. Tranchemontagne, J.L. Mendoza-Cortés, M.

O’Keefe, O.M. Yaghi, “Secondary building units, nets

and bonding in the chemistry of metal–organic frameworks”,

Chem. Soc. Rev. 2009, 38, pp. 1257–1283.

(p) L.Q. Ma, C. Abney, W.B. Lin, “Enantioselective catalysis

with homochiral metal–organic frameworks”,

Chem. Soc. Rev. 2009, 38, pp. 1248–1256.

(q) L.R. MacGillivray, G.S. Papaefstathiou, T. Friscic,

“Supramolecular control of reactivity in the solid

state: from templates to ladderanes to metal–organic

frameworks”, Acc. Chem. Res. 2008, 41, pp. 280–291.

(r) M. Dinc , J.R. Long, “Hydrogen storage in micro

porous metal–organic frameworks with exposed metal

sites”, Angewandte Chemie International Edition 2008,

, pp. 6766–6779.

(s) R. Banerjee, A. Phan, B. Wang, C. Knobler, H. Furukawa,

M. O’Keeffe, O.M. Yaghi, “High-Throughput

Synthesis of Zeolitic Imidazolate Frameworks and

Application to CO2 Capture”, Science 2008, 319, pp.


(t) D.K. Bu ar, G.S. Papaefstathiou, T.D. Hamilton, Q.L.

Chu, I.G. Georgiev, L.R. MacGillivray, “Template-controlled

reactivity in the organic solid state by principles

of coordination-driven self-assembly”, Eur. J. Inorg.

Chem. 2007, 29, pp. 4559–4568.

(u) E.R. Parnham, R.E. Morris, “Ionothermal Synthesis

of Zeolites, Metal–Organic Frameworks, and Inorganic-

Organic Hybrids”, Acc. Chem. Res. 2007, 40,

pp. 1005–1013.

(v) C.A. Bauer, T.V. Timofeeva, T.B. Settersten, B.D. Patterson,

V.H. Liu, B.A. Simmons, M.D. Allendorf, “Influence

of connectivity and porosity on ligand-based

luminescence in zinc metal–organic frameworks”,

J. Am. Chem. Soc. 2007, 129, pp. 7136–7144.

(w) S.M. Hawxwell, G.M. Espallargas, D. Bradshaw,

M.J. Rosseinky, T.J. Prior, A.J. Florence, J.V.S. Streek,

L. Brammer, “Ligand flexibility and framework

rearrangement in a new family of porous metal–

organic frameworks”, Chem. Commun. 2007, pp.


(x) D.F. Sun, Y.X. Ke, T.M. Mattox, S. Parkin, H.C. Zhou,

“Stability and Porosity Enhancement through Concurrent

Ligand Extension and Secondary Building

Unit Stabilization”, Inorg. Chem. 2006, 45, pp.


(y) A.K. Cheetham, C.N.R. Rao, R.K. Feller, “Structural

diversity and chemical trends in hybrid inorganicorganic

framework materials”, Chem. Comm. 2006,

pp. 4780–4795.

(z) B.L. Chen, M. Eddaoudi, S.T. Hyde, M. O’Keeffe, O.M.

Yaghi, “Interwoven Metal–Organic Framework on a

Periodic Minimal Surface with Extra-Large Pores”,

Science. 2001, 29, pp. 1021–1023.

(a) G.R. Desiraju, “The Crystal as a Supramolecular Entity.

Perspectives in Supramolecular Chemistry”, Vol. 2;

John Wiley & Sons: New York, 1996.

(b) J.L. Atwood, J.E.D. Davies, D.D. MacNicol, F. Vögtle,

J.M. Lehn, Eds., “Crystal Engineering in Comprehensive

Supramolecular Chemistry”, Vol.6; Pergamon: Oxford,

(c) D. Braga, A.G. Orpen, Eds., “Crystal Engineering: From

Molecules and Crystals to Materials”, NATO ASI Series

Kluwer: Dordecht, Netherlands, 1999.

(d) J.A.R.P. Sarma, G.R. Desiraju, “The novel 1:1

donor–acceptor complex, 3,4-dimethoxycinnamic

acid–2,4-dinitrocinnamic acid. Crystal engineering,

structure, and anomalous lack of solid-state

topochemical reactivity”, J. Chem. Soc., Perkin Trans.

II, 1985, pp. 1905–1912.

(e) C.V.K. Sharma, K. Panneerselvam, L. Shimoni, H. Katz,

H.L. Carrell, G.R. Desiraju, “3-(3′,5′-Dinitrophenyl)-


Acid: Engineered Topochemical Synthesis and

Molecular and Supramolecular Properties”, Chem.

Mater. 1994, 6, pp. 1282–1292.

(f) B.M. Foxman, M.J. Vela, “Reactive Crystals: Design and

Discovery”, Transactions ACA 1998, 33, pp. 75–84.

(g) J. Xiao, M. Yang, J.W. Lauher, F.W. Fowler, “A


Solution to a Long-Standing Problem:

The 1,6-Polymerization of a Triacetylene”, Angew.

Chem., Int. Ed. Engl. 2000, 39, pp. 2132–2135.

(h) J. Hulliger, H. Bebie, S. Kluge, A. Quintel, “Growth-

Induced Evolution of Polarity in Organic Crystals”,

Chem. Mater. 2002, 14, pp. 1523–1529.

F. Wohler, “Untersuchungen über des chinons.” Annalen

Chem. Pharm. 1844, 51, pp. 145–163.

(a) P. Pfeiffer, “Organische Molekül Verbindungen”, 2nd

ed.; Ferdinand Enke: Stuttgart, 1927.

(b) R. Foster, “Organic Charge-Transfer Complexes”, Academic:

London, 1969.

(c) F.H. Herbstein, “Crystalline Molecular Complexes and

Compounds”, Oxford University Press: Oxford, 2005;

Vols. 1 and 2.

(d) J. Bernstein, H. Regev, F.H. Herbstein, “Molecular

compounds and complexes. The ternary chargetransfer

salt pyridinium-1-naphthylamine-picrate

(Kofler’s ternary complex)”, Acta. Crystallogr.

Sect. B: Struct. Crystallogr. Cryst. Chem. 1980, 36,

pp. 1170–1175.

(e) D.E. Lynch, G. Smith, K.A. Byriel, C.H.L. Kennard, “The

unique occurrence of tri-heteromolecular adduct:

the crystal structure of the (3:1:1) 4-Aminobenzoic

acid–2,4,6-trinitrobenzoic acid-1,3,5-trinitrobenzene

cocrystal”, Chem. Commun. 1992, pp. 300–301.

(f) T. Smolka, R. Boese, R. Sustmann, “Design of a three

Component Crystal based on the Cocrystal of Phenazine

and 2, 2´-Dihydroxybiphenyl”,

Struct. Chem.

, 10, pp. 429–431.

(g) C.B. Aakeröy, A.M. Beatty, B.A. Helfrich, “Total synthesis’

supramolecular style: Design and hydrogenbond

directed assembly of ternary cocrystals”, Angew.

Chem., Int. Ed. 2001, 40, pp. 3240–3242.

(h) B.R. Bhogala, S. Basavoju, A. Nangia, “Tape and layer

structures in cocrystals of some di- and tricarboxylic

acids with 4,4′-bipyridines and isonicotinamide. From

binary to ternary cocrystals”, CrystEngComm. 2005, 7,

pp. 551–562.

(i) B.R. Bhogala, S. Basavoju, A. Nangia, “Three-Component

Carboxylic Acid–Bipyridine Lattice Inclusion

Host. Supramolecular Synthesis of Ternary Cocrystals”,

Cryst. Growth Des. 2005, 5, pp. 1683–1686.

(j) C.B. Aakeröy, J. Desper, E. Elisabeth, B.A. Helfrich,

B. Levin, J.F. Urbina, “Making reversible synthesis

stick: Competition and cooperation between intermolecular

interactions”, Z. Kristallogr. 2005, 220, pp.


(k) C.B. Aakeröy, J. Desper, J.F. Urbina, “Supramolecular

Reagents: Versatile Tools for Non-covalent Synthesis”,

Chem. Commun. 2005, pp. 2820–2822.

(l) C.B. Aakeröy, D.J. Salmon, “Building co-crystals with

molecular sense and supramolecular sensibility”, CrystEngComm

, 7, pp. 439–448.

(m) T. Fricic, A.V. Trask, W. Jones, W.D.S. Motherwell,

“Screening for inclusion compounds and systematic

construction of three-component solids by liquidassisted

grinding”, Angew. Chem. Int. Ed. 2006, 45,

pp. 7546–7550.

(a) J.A. Zerkowski, C.T. Seto, G.M. Whitesides, “Solidstate

structures of ‘Rosette’ and ‘Crinkled Tape’ motifs

derived from the cyanuric acid melamine lattice”,

J. Am. Chem. Soc. 1992, 114, pp. 5473–5475.

(b) Ö. Almarsson, M.J. Zaworotko, “Crystal engineering

of the composition of pharmaceutical phases.

Do pharmaceutical co-crystals represent a new path

to improved medicines?” Chem. Commun. 2004, 17,

pp. 1889–1896.

(c) B. Rodriguez-Spong, C.P. Price, A. Jayasankar, A.J.

Matzger, N. Rodrı’guez-Hornedo, “General principles

of pharmaceutical solid polymorphism: a supramolecular

perspective”, Adv. Drug Delivery Rev. 2004,

, pp. 241–274.

(d) N. Blagden, Matas, P.T. Gavan, P. York, “Crystal

engineering of active pharmaceutical ingredients to

improve solubility and dissolution rates”, Adv. Drug.

Delivery Rev. 2007, 59, pp. 617–630.

S. Aitipamula, R. Banerjee, A.K. Bansal, K. Biradha, M.L.

Cheney, A.R. Choudhury, G.R. Desiraju, A.G. Dikundwar,

R. Dubey, N. Duggirala, P.P. Ghogale, S. Ghosh, K.

Goswami, N.R. Goud, R.R.K.R. Jetti, P. Karpinski, P.

Kaushik, D. Kumar, V. Kumar, B. Moulton, A. Mukherjee,

G. Mukherjee, A.S. Myerson, V. Puri, A. Ramanan, T.

Rajamannar, C.M. Reddy, N. Rodriguez-Hornedo, R.D.

Rogers, T.N. Guru Row, P. Sanphui, N. Shan, G. Shete, A.

Singh, C.C. Sun, J.A. Swift, R. Thaimattam, T.S. Thakur,

R.K. Thaper, S.P. Thomas, S. Tothadi, V.R. Vangala, N.

Variankaval, P. Vishweshwar, D.R. Weyna, M.J. Zaworotko,

“Polymorphs, Salts, and Cocrystals: What’s in a Name?”,

Cryst. Growth Des. 2012, 12, pp. 2147–2152. (References


(a) J.D. Dunitz, “Crystal and co-crystal: a second opinion”,

CrystEngComm 2003, 5, pp. 506–506.

(b) G.R. Desiraju, “Crystal and co-crystal”, CrystEngComm

, 5, pp. 466–467.

(c) P. Vishweshwar, J.A. McMahom, J.A. Bis, M.J.

Zaworotko, “Pharmaceutical co-crystals”, J. Pharm.

Sci. 2006, 9, pp. 499–516.

(d) C.B. Aakeröy, M.E. Fasulo, J. Desper, “Cocrystal or

salt: does it really matter?” Mol. Pharm. 2007, 4,

pp. 317–322.

(e) S.L. Childs, G.P. Stahly, A. Park, “The salt-cocrystal

continuum: the influence of crystal structure on ionization

state”, Mol. Pharm. 2007, 4, pp. 323–338.

(f) F. Lara-Ochoa, G. Espinosa-Pérez, “Crystals and Patents”,

Cryst. Growth Des. 2007, 7, pp. 1213–1215.

(g) J.Z. Schpector, E.R.T. Tiekink, “What is a Co-crystal?”,

Z. Kristallogr. 2008, 223, pp. 233–234.

FDA Challenges and Opportunity on the Critical Path to

New Medical Products.


J.A. DiMasi, R.W. Hansen, H.G. Grabowski, “The price

of innovation: new estimates of drug development costs”,

Journal of Health Economics, 2003, 22, pp. 151–185.

(a) J. Bernstein, “Polymorphism in Molecular Crystals”,

Clarendon, Oxford, 2002.

(b) R.J. Davey, “Pizzas, Polymorphs and pills”, Chem.

Commun. 2003, 13, pp. 1463–1467.

(c) A. Llinás, J.M. Goodman, “Polymorph control: past,

present and future”, Drug Discovery Today, 2008 13,

pp. 5–6.

(d) M. Kitamura, “Strategy for control of crystallization

of polymorphs” CrystEngComm, 2009, 11, pp.


(e) C.B. Aakeröy, N.R. Champness, C. Janiak, “Recent

advances in crystal engineering”, CrystEngComm,

, 12, pp. 22–43.

(a) K.R. Seddon, “Pseudopolymorph: A polemic”, Cryst.

Growth Des. 2004, 4, pp. 1087.

(b) G.R. Desiraju, “Counterpoint: What’s in a Name?”

Cryst. Growth Des. 2004, 4, pp. 1089–1090.

(c) J. Bernstein, “And another comment on pseudopolymorphism”,

Cryst. Growth Des. 2005, 5, pp.


(d) A. Nangia, “Pseudopolymorph: retain this widely

accepted term”, Cryst. Growth Des. 2005, 6, pp. 2–4.

(a) H.G. Brittain, E.F. Fiese, “Effect of pharmaceutical

processing on drug polymorphs and solvates. In Polymorphism

in Pharmaceutical Solids”, H.G. Brittain, Ed.,

Marcel Dekker, Inc. 1999, pp. 331–362.

(b) S.L. Morissette, Ö. Almarsson, M.L. Peterson,

J.F. Remenar, M.J. Read , A.V. Lemmo, S. Ellis , M.J.

Cima, C.R. Gardner, “High-throughput crystallization:

polymorphs, salts, co-crystals and solvates of pharmaceutical solids”, Adv. Drug. Deliv. Rev. 2004,

, pp. 275–300.

R. Thakuria, A. Nangia, “Highly soluble olanzapinium

maleate crystalline salts”, CrystEngComm, 2011, 13,

pp. 1759–1764.

(a) W. Jones, W.D.S. Motherwell, A.V. Trask, “Pharmaceutical

Cocrystals: An Emerging Approach to Physical

Property Enhancement”, MRS Bull. 2006, 31, pp.


(b) M.K. Stanton, A. Bak, “Physicochemical Properties

of Pharmaceutical Co-Crystals: A Case Study of Ten

AMG 517 Co-Crystals”, Cryst. Growth Des. 2008, 8, pp.


(c) N. Shan, M.J. Zaworotko, “The Role of Cocrystals in

Pharmaceutical science”, Drug Discovery Today 2008,

, pp. 440–446.

(a) D.P. McNamara, S.L. Childs , J. Giordano, A. Iarriccio,

J. Cassidy, M.S. Shet, R. Mannion, E. O’Donnell,

A. Park, “Use of a glutaric acid cocrystal to improve

oral bioavailability of a low solubility API”, Pharm. Res.

, 23, pp. 1888–1897.

(b) S. Karki, T. Friš ic, L. Fábián, P.R. Laity, G.M. Day, V.

Jones, “Improving mechanical properties of crystalline

solids by cocrystal formation: New compressible

forms of paracetamol”, Adv Mater. 2009, 21,

pp. 3905–3909.

(c) C.B. Aakeröy, S. Forbes, J. Desper, “Using Cocrystals to

Systematically Modulate Aqueous Solubility and Melting

Behavior of an Anticancer Drug”, J. Am. Chem.

Soc. 2009, 137, pp. 17048–17049.

(d) N. Schultheiss, A. Newman, “Pharmaceutical Cocrystals

and Their Physicochemical Properties”, Cryst.

Growth Des. 2009, 9, pp. 2950–2967.

(e) S.L. Childs, M.J. Zaworotko, “The Reemergence of

Cocrystals: The Crystal Clear Writing is on the Wall,

in Introduction to Virtual Special Issue on Pharmaceutical

Cocrystals”, Cryst. Growth Des. 2009, 9,

pp. 4208–4211.

(f) C.B. Aakeröy, P.D, “Chopade, Cocrystals: Synthesis, Structure,

and Applications in Supramolecular Chemistry: from

Molecules to Nanomaterials”, J.W. Steed and P.A. Gale

(Eds). John Wiley & Sons Ltd., 2012, pp. 2975–2992.

(g) A. Nangia, N.J. Babu, “Solubility advantages of amorphous

drugs and pharmaceutical cocrystals”, Cryst.

Growth Des. 2011, 11, pp. 2662–2679.

A.V. Trask, “An overview of pharmaceutical cocrystals as intellectual

property”, Mol. Pharmaceutics. 2007, 4, pp. 301–309.

(a) G.R. Desiraju, “Chemistry beyond the molecule”,

Nature, 2001, 412, pp. 397–400.

(b) J.M. Lehn, “Toward complex matter: Supramolecular

chemistry and self-organization”, PNAS, 2002, 99, pp.


(a) K.R. Seddon, C.B. Aakeröy, “The Hydrogen Bond

and Crystal Engineering”, Chem. Soc. Rev. 1993, 22,

pp. 397–407.

(b) J.W. Steed, J.L. Atwood, “Supramolecular Chemistry”,

nd ed. John Wiley & Sons, Ltd., 2009.

J.W. Steed, J.L. Atwood, “Supramolecular Chemistry”,

nd ed. John Wiley & Sons, Ltd., 2009, pp. 30.

A.I. Kitaigorodskii, “Molecular Crystals and Molecules”,

Academic Press, New York, 1973.

(a) G.R. Desiraju, “Reflections on the Hydrogen Bond

in Crystal Engineering”, Cryst. Growth Des. 2011, 11,

pp. 896–898.

(b) G.R. Desiraju, V. Vittal, A. Ramanan, “Crystal Engineering:

A textbook”, 1st ed., World Scientific, Ltd.,

(c) T.S. Thakur, Y. Azim, T. Srinu, G.R. Desiraju,

“N–H⋅⋅⋅O and C–H⋅⋅⋅O interaction mimicry in the

:1 molecular complexes of 5,5-diethylbarbituric

acid with urea and acetamide”, Curr. Sci., 2010, 98

(6), pp. 793–802.

G.R. Desiraju, “Crystal engineering: A brief overview”,

J. Chem. Sci., 2010, 122 (5), pp. 667–675.

G.R. Desiraju, “Supramolecular synthons in crystal engineering-

a new organic synthesis”, Angew. Chem. Int. Ed.

Engl. 1995, 34, pp. 2311–2327.

M.C. Etter, “Hydrogen bonds as design elements in organic

chemistry”, J. Phys. Chem. 1991, 95, pp. 4610–4618.

M.C. Etter, “Encoding and Decoding Hydrogen-Bond

Patterns of Organic Compounds”, Acc. Chem. Res. 1990,

, pp. 120–126.

F.H. Allen, “The Cambridge Structural Database: a quarter

of a million crystal structures and rising”, Acta Crystallogr.

, B58, pp. 380–388.

J. Devane, “Oral drug delivery technology: Addressing the

solubility/permeability paradigm”, Pharm. Technol. 1998,

, pp. 68–74.

A.M. Thayer, “Finding solutions”, Chem. Eng. News 2010,

, pp. 13–18.

(a) H.S. Gwak, J.S. Choi, H.K. Choi, “Enhanced bioavailability

of piroxicam via salt formation with ethanolamines”,

Int. J. Pharm. 2005, 297, pp. 156–161.

(b) V.M. Rao, M. Nerurkar, S. Pinnamaneni, F. Rinaldi,

K. Raghavan, “Co-solubilization of poorly soluble

drugs by micellization and complexation.” Int.

J. Pharm. 2006, 319, pp. 98–106.

(c) M. Vogt, K. Kunath, J.B. Dressman, “Dissolution

enhancement of fenofibrate by micronization, cogrinding

and spray-drying: comparison with commercial

preparations”, Eur. J. Pharm. Biopharm. 2008, 6, pp.


(d) H.X. Zhang, J.X. Wang, Z.B. Zhang, Y. Le, Z.G. Shen,

J.F. Chen, “Micronization of atorvastatin calcium by

antisolvent precipitation process”, Int. J. Pharm. 2009,

, pp. 106–111.

(e) Z.B. Zhang, , Z.G. Shen J.X. Wang, H.X. Zhang, H.

Zhao, J.F. Chen, J. Yun, “Micronization of silybin by

the emulsion solvent diffusion method”, Int. J. Pharm.

, 376, pp. 116–122.

(f) N. Seedher, M. Kanojia, “Co-solvent solubilization of

some poorly-soluble antidiabetic drugs”, Pharm. Dev.

Technol. 2009, 14, pp. 185–192.

P. Vishweshwar, J.A. McMahon, J.A. Bis, M.J. Zaworotko,

“Pharmaceutical co-crystals”, J. Pharm. Sci. 2006, 95,

pp. 499–516.

L.D. Bighley, S.M. Berge, D.C. Monkhouse, “Encyclopedia

of Pharmaceutical Technology”, J. Swarbrick, J.C. Boylan,

Eds., Marcel Dekker: New York, 1996, Vol. 13.

P.H. Stahl, C.G. Wermuth, Eds. “Monographs on Acids and

Bases, in Handbook of Pharmaceutical Salts: Properties,

Selection and Use”, Verlag Helvetica Chimica Acta: Zurich,

(a) FDA GRAS notices can be found at www.cfsan.fda.


(b) N. Schultheiss, M. Roe, S.X.M. Boerrigter, “Cocrystals

of nutraceutical p-coumaric acid with caffeine

and theophylline: polymorphism and solid-state


explored in detail using their crystal graphs”,


, 13, pp. 611–619.

(c) N. Schultheiss, S. Bethune, J.O. Henck, “Nutraceutical

cocrystals: utilizing pterostilbene as a cocrystal

former”, CrystEngComm. 2010, 12, pp. 2436–2442.

(d) M. Sowa, K. Slepokurab, E.M. Jona, “A 1:1 cocrystal

of baicalein with nicotinamide”, Acta Cryst. 2012,

C68, pp. 262–265.

(e) L. Andreas, B. Joel, “The co-crystal of two GRAS

substances: citric acid and nicotinamide. Formation

of four hydrogen bonding heterosynthons in one

co-crystal”, CrystEngComm, 2010, 12, pp. 2029–2033.

(a) S. Varughese, Y. Azim, G.R. Desiraju, “Molecular complexes

of alprazolam with carboxylic acids, boric acids,

boronic acids and phenols. Evaluation of supramolecular

heterosynthons mediated by triazole ring”,

J. Pharm. Sci., 2010, 99, pp. 3743–3753.

(b) H.G. Brittain, “Pharmaceutical cocrystals: The coming

wave of new drug substances”, J. Pharm. Sci. 2013, 102,

pp. 311–317.

(c) H.G. Brittain, “Cocrystal systems of pharmaceutical

interest: 2010”, Cryst. Growth Des. 2012, 12, pp.


(d) H.G. Brittain, “Cocrystal systems of pharmaceutical

interest: 2011”, Cryst. Growth Des. 2012, 12, pp.


(e) N. Huang, N. Rodríguez-Hornedo, “Engineering

cocrystal solubility, stability, and pHmax by micellar

solubilization”, J. Pharm. Sci. 2011, 100, pp.


(f) M. Majunder, G. Buckton, C. Rawlinson-Malone, A.C.

Williams, M.J. Spillman, N. Shankland, K. Shankland,

“A Carbamazepine- Indomethacin (1:1) Cocrystal

Produced by Milling”, CrystEngComm, 2011, 13,

pp. 6327–6328.

(g) A. Mukherjee, P. Grobelny, T.S. Thakur, G.R. Desiraju,

“Polymorphs, Pseudo-polymorphs, and Cocrystals

of Orcinol: Exploring the Structural Landscape with

High Throughput Crystallography” Cryst. Growth Des.

, 11, pp. 2637–2653.

(h) Z. Rahman, C. Agarabi, A.S. Zidan, S.R. Khan, M.A.

Khan, “Physico-mechanical and stability evaluation

of carbamazepine cocrystal with nicotinamide”, AAPS

PharmSciTech. 2011, 12, pp. 693–704.

(i) M.A. Mohammad, A. Alhalaweh, S.P. Velaga, “Hansen

Solubility Parameter as a Tool to Predict Cocrystal Formation”,

Int. J. Pharm. 2011, 407, pp. 63–71.

(j) J. Wouters, L. Quere, D.E. Thurston, A. Martinez, Eds.

“Pharmaceutical Salts and Co-crystals”, RSC, 2011.

(k) M.A. Elbagerma, H.G.M. Edwards, T. Munshi, M.D.

Hargreaves, P. Matousek, I.J. Scowen, “Characterization

of New Cocrystals by Raman Spectroscopy,

Powder X-ray Diffraction, Differential Scanning

Calorimetry, and Transmission Raman Spectroscopy”,

Cryst. Growth Des. 2010, 10, pp. 2360–2371.

(l) D. Braga, F. Grepioni, L. Maini, P.P. Mazzeo, K. Rubini,

“Solvent-Free Preparation of Cocrystals of Phenazine

and Acridine with Vanillin”, Thermochim. Acta. 2010,

, pp. 1–8.

(m) M. Khan, V. Enkelmann, G. Brunklaus, “Crystal Engineering

of Pharmaceutical Co-crystals: Application

of Methyl Paraben as Molecular Hook”, J. Am. Chem.

Soc. 2010, 132, pp. 5254–5263.

(n) E.R.T. Tiekink, J.J. Vittal, Eds., “Frontiers in Crystal

Engineering”, John Wiley & Sons, Ltd., 2006, pp.


(a) A.D. Bond, “What is a cocrystal?” Cryst. Eng. Commun.

, 9, pp. 833–834.

(b) K. Seefeldt, J. Miller, F. Alvarez-Nunez, N. Rodriguez-

Hornedo, “Crystallization

pathways and kinetics of

carbamazepine–nicotinamide cocrystals from the

amorphous state by in situ thermomicroscopy, spectroscopy

and calorimetry studies”, J. Pharm. Sci. 2007,

, pp. 1147–1158.

(c) S.L. Reddy, J.N. Babu, A. Nangia, “Carboxamide- pyridine

N-oxide heterosynthon for crystal engineering

and pharmaceutical cocrystals”, Chem. Commun. 2006,

pp. 1369–1371.

(d) B.R. Bhogala, S. Basavoju, A. Nangia, “Three-Component

Carboxylic Acid-Bipyridine Lattice Inclusion

Host. Supramolecular Synthesis of Ternary Cocrystals”,

Cryst. Growth Des. 2005, 5, pp. 1683–1686.

(e) C.B. Aakeröy, D.J. Salmon, “Building Cocrystals with

Molecular Sense and Supramolecular Sensibility”

CrystEngComm 2005, 7, pp. 439–448.

(f) A.V. Trask, J. Van de Streek, S.W.D. Motherwell, W. Jones,

“Achieving Polymorphic and Stoichiometric Diversity

in Cocrystal Formation: Importance of Solid-State

Grinding, Powder X-ray Structure Determination, and

Seeding”, Cryst. Growth. Des. 2005, 6, pp. 2233–2241.

(g) P. Vishweshwar, J.A. McMahon, M.L. Peterson, M.B.

Hickey, T.R. Shattock, M.J. Zaworotko, “Crystal engineering of pharmaceutical cocrystals from polymorphic

active pharmaceutical ingredients”, Chem.

Commun. 2005, pp. 4601–4603

(h) A.V. Trask, W. Jones, “Crystal engineering of organic

cocrystals by the solidstate grinding approach”,

Organic Solid-State Reactions. 2005, 254, pp. 41–70.

(i) M.W. Hosseini, “Reflection on molecular tectonics”,

CrystEngComm 2004, 6, pp. 318–322.

(j) T.R. Shattock, P. Vishweshwar, Z. Wang, M.J.

Zaworotko, “18-Fold Interpenetration and Concomitant

Polymorphism in the 2:3 CoCrystal of

Trimesic Acid and 1,2-Bis(4-pyridyl)ethane”, Cryst.

Growth. Des. 2005, 6, pp. 2046–2049.

(k) C.B. Aakeröy, J. Desper, D.J. Salmon, M.M. Smith,

“Cyanophenyloximes: Reliable and Versatile Tools

for Hydrogen-Bond Directed Supramolecular Synthesis

of Cocrystals”, Cryst. Growth Des. 2006, 4, pp.


(l) C.B. Aakeröy, M.E. Fasulo, J. Desper, “Improving success

rate of hydrogen bond driven synthesis of co-crystals”,

CrystEngComm. 2006, 8, pp. 586–588.

(m) G.R. Desiraju, “Crystal and co-crystal”, CrystEngCommun.

, 5, pp. 466–467.

I.D.H. Oswald, D.R. Allan, P.A. McGregor, W.D.S. Motherwell,

S. Parsons, C.R. Pelham, “The formation of paracetamol

(acetaminophen) adducts with hydrogen-bond

acceptors”, Acta Crystallogr. 2002, B58, pp. 1057–1066.

R.D.B. Walsh, M.W. Bradner, S. Fleischman, L.A. Morales,

B. Moulton, N. Rodriguez- Hornedo, M.J. Zaworotko,

“Crystal engineering of the composition of pharmaceutical

phases”, Chem. Commun. 2003, pp. 186–187.

(a) M.L. Cheney, N. Shan, E.R. Healey, M. Hanna, L. Wojtas,

M.J. Zaworotko, V. Sava, S. Song, J.R. Sanchez-Ramos,

“Effects of crystal form on solubility and pharmacokinetics:

a crystal engineering case study of lamotrigine”,

Cryst. Growth Des. 2010, 10, pp. 394–405.

(b) N. Shan, M.J. Zaworotko, “Polymorphic crystal forms

and cocrystals in drug delivery (crystal engineering)”,

In Burger’s Medicinal Chemistry and Drug Discovery

and Development, 2010, pp. 187–218.

(c) A. Alhalaweh, A. Sokolowski, N. Rodríguez-Hornedo,

S.P. Velaga, “Solubility Behavior and Solution Chemistry

of Indomethacin Cocrystals in Organic Solvents”,

Cryst. Growth Des. 2011, 11, pp. 3923–3929.

(d) D.R. Weyna, M.L. Cheney, N. Shan, M. Hanna, M.J.

Zaworotko, V. Sava, S. Song, J.R. Sanchez-Ramos,

“Improving Solubility and Pharmacokinetics of Meloxicam

via Multiple-Component Crystal Formation.”

Mol. Pharmaceutics 2012, 9, pp. 2094–2102.

(e) N.J. Babu, A. Nangia, “Solubility Advantage of Amorphous

Drugs and Pharmaceutical Cocrystals”, Cryst.

Growth Des. 2011, 11, pp. 2662–2679.

(f) D.J. Good, N.R. Hornedo, “Solubility Advantage of

Pharmaceutical Cocrystals”, Cryst. Growth Des. 2009,

(5), pp. 2252–2264.

G.L. Amidon, H. Lennernas, V.P. Shah, J.R. Crison, “A

theoretical basis for a biopharmaceutic drug classification:

The correlation of in vitro drug product dissolution

and in vivo bioavailability”, Pharm. Res. 1995, 12(3), pp.


A.K. Nair, O. Anand, N. Chun, D.P. Conner, M.U. Mehta,

D.T. Nhu, J.E. Polli, L.X. Yu, B.M. Davit, “Statistics on

BCS Classification of Generic Drug Products Approved

Between 2000 and 2011 in the USA”, AAPS Journal, 2012,

,(4), pp. 664–666.

M. Lindenberg, S. Kopp, J.B. Dressman, “Classification of

orally administered drugs on the World Health Organization

Model list of Essential Medicines according to the

biopharmaceutics classification system”, Eur. J. Pharm.

Sci., 2004, pp. 58, 265–78.

(a) Committee for Medicinal Products for Human Use.

Guidelines on the investigation of Bioequivalence

(CPMP/EWP/QWP/1401/98 Rev. 1) July 2008.

(b) D.J. Birkett, “Generics-Equal or Not?”, Australian Prescriber

26, pp. 85–87.

(a) S. Zhanga, A.C. Rasmuson, “The theophylline–oxalic

acid co-crystal system: solid phases, thermodynamics

and crystallization”, CrystEngComm, 2012, 14, pp.


(b) D.K. Bu ar, F.H. Henry, X. Lou, R.W. Duerst, T.B. Borchardt,

L.R. MacGillivray, G.G.Z. Zhang, “Co-Crystals

of Caffeine and Hydroxy-2-naphthoic Acids: Unusual

Formation of the Carboxylic Acid Dimer in the

Presence of a Heterosynthon”, Mol. Pharmaceutics,

, 4, pp. 339–346.

(c) J. Kastelic, N. Lah, D. Kikelj, I. Leban, “A 1:1 Cocrystal

of Fluconazole with Salicylic Acid”, Acta Crystallogr.

, C67, pp. 370–372.

(d) J.F. Remenar, M.L. Peterson, P.W. Stephens, Z. Zhang,

Y. Zimenkov, M.B. Hickey, “Celecoxib : Nicotinamide

Dissociation: Using Excipients to Capture the

Cocrystals Potential”, Mol. Pharmaceutics 2007. 4, pp.


(e) S.G. Fleischman, S.S. Kuduva, J.A. McMahon,

B. Moulton, R.D.B. Walsh, N.R. Hornedo, M.J.

Zaworotko, “Crystal Engineering of the Composition

of Pharmaceutical Phases: Multiple-Component Crystalline

Solids Involving Carbamazepine”, Cryst. Growth

Des. 2003, 3, pp. 909–919.

(f) L.S. Reddy, S.J. Bethune, J.W. Kampf, N.R. Hornedo,

“Cocrystals and Salts of Gabapentin: pH Dependent

Cocrystal Stability and Solubility”, Cryst. Growth Des.

, 9, pp. 378–385.

(g) V.R. Vangala, P.S. Chow, R.B.H. Tan, “Characterization,

physicochemical and photo-stability of a co-crystal

involving an antibiotic drug, nitrofurantoin, and

-hydroxybenzoic acid”, CrystEngComm, 2011, 13, pp.


(h) S. Aitipamula, A.B.H. Wong, P.S. Chow, R.B.H. Tan,

“Pharmaceutical cocrystals of ethenzamide: structural, solubility and dissolution studies”, CrystEngComm,

, 14, pp. 8515–8524.

(i) R. Chadha, A. Saini, P. Arora, S. Chanda, D.S. Jain,

“Cocrystals of efavirenz with selected coformers: preparation

and characterization”, Int. J. Pharm. Sci. 2012,

, pp. 244–250.

(j) M. Majumder, G. Buckton, C. Rawlinson-Malone, A.C.

Williams, M.J. Spillman, N. Shankland, K. Shankland,

“A Carbamazepine-Indomethacin (1:1) Cocrystal

Produced by Milling”, CrystEngComm 2011, 13,

pp. 6327–6328.

(k) R. Chadha, A. Saini, P. Arora, D.S. Jain, A. Dasgupta,

T.N. Guru Row, “Multicomponent Solids of Lamotrigine

with some Selected Coformers and their Characterization

by Thermoanalytical, Spectroscopic, and

X-Ray Diffraction Methods”, CrystEngComm, 2011,

, pp. 6271–6284.

(l) R.A.E. Castro, J.D.B. Ribeiro, T.M.R. Maria, M.R. Silva,

C. Yeste-Vivas, J. Canotilho, M.E.S. Eusébio, “Naproxen

Cocrystals with Pyridinecarboxamide Isomers”, Cryst.

Growth Des. 2011, 11, pp. 5396–5404.

(m) S. Cherukuvada, N.J. Babu, A. Nangia, “Nitrofurantoin-

p-Aminobenzoic Acid Cocrystal: Hydration

Stability and Dissolution Rate Studies”, J. Pharm. Sci.,

, 100, pp. 3233–3244.

(n) M.A. Elbagerma, H.G.M. Edwards, T. Munshi, I.J. Scowen,

“Identification of a new cocrystal of citric acid

and paracetamol of pharmaceutical relevance”, CrystEngComm,

, 13, pp. 1877–1884.

(o) D.R. Weyna, M.L. Cheney, N. Shan, M. Hanna, L.

Wojtas, M.J. Zaworotko, “Crystal engineering of

multiple-component organic solids: Pharmaceutical

cocrystals of tadalafil with persistent hydrogen

bonding motifs”, CrystEngComm, 2012, 14,

pp. 2377–2380.

S.L. Childs, L.J. Chyall, J.T. Dunlap, V.N. Smolenskaya,

B.C. Stahly, G.P. Stahly, “Crystal Engineering Approach

to Forming Cocrystals of Amine Hydrochlorides with

Organic Acids. Molecular Complexes of Fluoxetine

Hydrochloride with Benzoic, Succinic, and Fumaric Acids”,

J. Am. Chem. Soc. 2004, 126, pp. 13335–13342.

(a) A.V. Trask, W.D.S. Motherwell, W. Jones, “Pharmaceutical

Cocrystallization: Engineering a Remedy for

Caffeine Hydration”, Cryst. Growth Des. 2005, 5, pp.


(b) S. Aitipamula, P.S. Chowa, R.B.H. Tan, “Co-crystals of

caffeine and piracetam with 4-hydroxybenzoic acid:

Unravelling the hidden hydrates of 1:1 co-crystals”,

CrystEngComm, 2012, 14, pp. 2381–2385.

(a) A.V. Trask, S.W.D. Motherwell, W. Jones, “Physical stability

enhancement of theophylline via cocrystallization”,

Int. J. of Pharm. 2006, 320, pp. 114–123.

(b) S. Zhanga, A.C. Rasmuson, “The theophylline–oxalic

acid co-crystal system: solid phases, thermodynamics

and crystallization”, CrystEngComm, 2012, 14,

pp. 4644–4655.

S.F. Chow, M. Chen, L. Shi, A.H.L. Chow, C.C. Sun, “Simultaneously

improving stability, mechanical properties,

and dissolution properties of ibuprofen and flurbiprofen

by cocrystallization with nicotinamide”, Pharm. Res. 2012,

, pp. 1854–1865.

M.K. Stanton, A. Bak, “Physicochemical Properties

of Pharmaceutical Co-Crystals: A Case Study of Ten

AMG 517 Co-Crystals”, Cryst. Growth Des. 2008, 8, pp.


(a) M.B. Hickey, M.L. Peterson, L.A. Scoppettuolo, “Performance

comparison of a cocrystal of carbamazepine

with marketed product”, Eur. J. Pharma. Biopharma. 2007,

, pp. 112–119.

(a) J.F. Remenar, S.L. Morissette, M.L. Peterson,

B. Moulton, J. MacPhee, H.R. Guzmán, Ö. Almarsson,

“Crystal engineering of novel cocrystals of a Triazole

drug with 1,4-dicarboxylic acids”, J. Am. Chem. Soc.

, 125, pp. 8456–8457.

(b) Nonappa, M. Lahtinen, E. Kolehmainen, J. Haarala,

A. Shevchenko, “Evidence of Weak Halogen Bonding:

New Insights on Itraconazole and its Succinic

Acid Cocrystal”, Cryst. Growth Des. 2013, 13, pp.


S. Aitipamula, V.R. Vangala, P.S. Chow, R.B.H. Tan,” Cocrystal

Hydrate of an Antifungal Drug, Griseofulvin, with

Promising Physicochemical Properties”, Cryst. Growth

Des. 2012, 12, pp. 5858–5863.

S. Aitipamula, A.B.H. Wong. P.S. Chow, R.B.H. Tan,

“Pharmaceutical cocrystals of ethenzamide: structural,

solubility and dissolution studies”, CrystEngComm, 2012,

, pp. 8515–8524.

Y. Gao, H. Zu, J. Zhang, “Enhanced dissolution and stability

of adefovir dipivoxil by cocrystal formation”, J. Pharm.

Pharmacol. 2011, 63, pp. 483–490.

Y. Luo, B. Sun, “Pharmaceutical Co-crystals of Pyrazinecarboxamide

(PZA) with Various Carboxylic acids: Crystallography,

Hirshfeld Surfaces and Dissolution Study”,

Cryst. Growth Des. 2013, 13(5), pp. 2098–2106.

N.R. Goud, S. Gangavaram, K. Suresh, S. Pal, S.G. Manjunatha,

S. Nambiar, A. Nangia, “Novel Furosemide Cocrystals

and Selection of High Solubility Drug Forms”,

J. Pharm. Sci. 2012, 101, pp. 664–680.

S. Basavoju, D. Bostroem, S.P. Velaga, “Pharmaceutical

cocrystal and salts of norfloxacin”, Cryst. Growth Des.

, 6, pp. 2699–2708.

U.S. Food and Drug Administration, Office of Combination

Products,, 21 CFR

Part 3.2(e).

(a) A.I. Wertheimer, A. Morrison, “Combination drugs:

innovation in pharmacotherapy”, P&T. 2002, 27(1),

pp. 44–49.

(b) K.K. Bucci, C.J. Possidente, “Combination-drug products:

benefit or burden to patients?”, Am. J. Health.

Syst. Pharm., 2006, 63, pp. 1654–1655.

(c) S. Frantz, “The trouble with making combination

drugs”, Nat. Rev. Drug Discovery, 2006, 5, pp. 881–882.

M.L. Cheney, D.R. Weyna, N. Shan, M. Hanna, L. Wojtas,

M.J. Zaworotko, “Coformer Selection in Pharmaceutical

Cocrystal Development: a Case Study of a

Meloxicam Aspirin Cocrystal That Exhibits Enhanced

Solubility and Pharmacokinetics”, J. Pharm. Sci. 2011, 100,

pp. 2172–2181.

A.O.L. Évora, R.A.E. Castro, T.M.R. Maria, M.T.S. Rosado,

M.R. Silva, A.M. Beja, J. Canotilho, M.E.S. Eusébio,

“Pyrazinamide-Diflunisal: A New Dual-Drug Co-Crystal”,

Cryst. Growth Des. 2011, 11, pp. 4780–4788.

P.M. Bhatt, Y. Azim, T.S. Thakur, G.R. Desiraju, “Co-crystals

of the anti-HIV drugs lamivudine and zidovudine”,

Cryst. Growth Des. 2009, 9, pp. 951–957.

(a) B. Lockwood, “Nutraceuticals”, Pharmaceutical Press:

London, UK, 2007.

(b) M. Mannion, “Nutraceutical revolution continues at

Foundation for Innovation in Medicine Conference”,

Am. J. Nat. Med. 1998, 5, pp. 30–33.

A.J. Smith, P. Kavuru, L. Wojtas, M.J. Zaworotko, R.D.

Shytle, “Cocrystals of quercetin with improved solubility

and oral bioavailability”, Mol. Pharmaceutics 2011, 8,

pp. 1867–1876.

P. Sanphui, N.R. Goud, U.B.R. Khandavilli, A. Nangia,

“Fast Dissolving Curcumin Cocrystals”, Cryst. Growth Des.

, 11, pp. 4135–4145.

S.J. Bethune, N. Schultheiss, J.O. Henck, “Improving the

Poor Aqueous Solubility of Nutraceutical Compound

Pterostilbene through Cocrystal Formation”, Cryst.

Growth Des. 2011, 11, pp. 2817–2823.

W.C. McCrone, “Polymorphism in Physics and

Chemistry of the Solid State”, D. Fox, M.M. Labes,

A. Weissberger, Eds.; Interscience, New York: 1965; 2,

pp. 725–767.

(a) T. Siegrist, C. Kloc, J.H. Schon, B. Batlogg, R.C. Haddon,

S. Berg, G.A. Thomas, “Enhanced Physical Properties

in a Pentacene Polymorph” Angew. Chem., Int.

Ed. Engl. 2001, 40, pp. 1732–1736.

(b) D.J.W. Grant, “In Polymorphism in Pharmaceutical

Solids”, H.G. Brittain, , Ed.; Marcel Dekker, Inc.: New

York, 1999; 95, pp. 1–33.

P. Vishweshwar, J.A. McMahon, M.L. Peterson,

M.B. Hickey, T.R. Shattock, M.J. Zaworotko, “Crystal Engineering

of Pharmaceutical Co-crystals from Polymorphic

Active Pharmaceutical Ingredients”, Chem. Commun.,

, pp. 4601–4603.

(a) S. Aitipamula, P.S. Chow, R.B.H. Tan, “Dimorphs of a

:1 cocrystal of ethenzamide and saccharin: solid-state

grinding methods result in metastable polymorph”,

CrystEngComm, 2009, 11, pp. 889–895.

(b) M. Gryl, A. Krawczuk, K. Stadnicka, “Polymorphism

of urea-barbituric acid co-crystals”, Acta Crystallogr.

Sect. B, 2008, 64, pp. 623–632.

(c) W.W. Porter III, S.C. Elie, A.J. Matzger, “Polymorphism

in Carbamazepine cocrystals”, Cryst. Growth Des. 2008,

, pp. 14–16.

(d) J.H.T. Horst, P.W. Cains, “Co-crystal polymorphism

from a Solvent-Mediated Transformation”, Cryst.

Growth Des. 2008, 8, pp. 2537–2542.

T. Ueto, N. Takata, N. Muroyama, A. Nedu, A. Sasaki, S.

Tanida, K. Terada, “Polymorphs and a Hydrate of Furosemide–

Nicotinamide 1:1 Cocrystal” Cryst. Growth Des.

, 12, pp. 485–494.

D. Braga, G. Palladino, M. Polito, K. Rubini, R. Grepioni,

M.R. Chierotti, R. Gobetto, “Three polymorphic forms

of the co-crystal 4,4′-bipyridine/pimelic acid and their

structural, thermal, and spectroscopic characterization”,

Chem. Eur. J. 2008, 14, pp. 10149–10159.

S. Aitipamula, P.S. Chow, R.B.H. Tan, “Trimorphs of

a pharmaceutical cocrystal involving two active pharmaceutical

ingredients: potential relevance to combination

drugs”, CrystEngComm, 2009, 11, pp. 1823–1827.

(a) G.R. Desiraju, “Cryptic Crystallography”, Nature

Materials, 2002, 1, pp. 77–79.

(b) H.C.S. Chan, J. Kendrick, M.A. Neumann, F.J.J.

Leusen, “Towards ab initio screening of co-crystal

formation through lattice energy calculations and

crystal structure prediction of nicotinamide, isonicotinamide,

picolinamide and paracetamol multicomponent

crystals”, CrystEngComm, 2013, 15,

pp. 3799–3807.

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