Sie sind auf Seite 1von 43

Subscriber access provided by University of Massachusetts Amherst Libraries

Review
Pharmaceutical Co-crystals: Molecules, Crystals, Formulations, Medicines
Malaz A. E. Yousef, and Venu R Vangala
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01898 • Publication Date (Web): 31 Oct 2019
Downloaded from pubs.acs.org on November 2, 2019

Just Accepted

“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W.,


Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.
Page 1 of 42 Crystal Growth & Design

1
2
3
4
5
6
7
8
Pharmaceutical Co-crystals: Molecules, Crystals,
9
10
11
12
Formulations, Medicines
13
14
15 Malaz A. E. Yousef and Venu R. Vangala*
16
17
18 Centre for Pharmaceutical Engineering Science, School of Pharmacy and Medical Sciences,
19
20 University of Bradford, Bradford BD7 1DP, United Kingdom
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 1 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 2 of 42

1
2
3 ABSTRACT:
4
5
6
7 Co-crystals are long known yet recently applied molecular entities. In the last decade,
8
9
significant potential has been demonstrated by these novel solids in terms of modifying
10
11
12 physicochemical and pharmacokinetic properties of drugs. Thus far, publications outlined
13
14 various aspects of co-crystals at molecular level concentrating on their design, growing
15
16 techniques and physicochemical characterizations. However, to take co-crystals from bench to
17
18
19 bed-side, they have to be incorporated into suitable formulations notwithstanding that the
20
21 attention paid to the co-crystal formulations is so diminutive. It is the first systematic review
22
23 based exclusively on co-crystals formulation. In this contribution, impact of co-crystals on
24
25
26
essential pharmaceutical properties is glanced at before getting the spot lighted on the co-crystals
27
28 formulation. The findings suggest that pre-formulation characteristics play a significant role,
29
30 however, after which a number of approaches are desired in order to develop successful co-
31
32
crystal formulations. It further highlights the main hurdles encountered with co-crystals
33
34
35 formulation and other challenges posing the transformation of co-crystals into viable medicines
36
37 to have the full picture. There are marketed co-crystal products now and it can be said it is only a
38
39 matter of time before co-crystals are added to the main selection toolbox alongside salts for
40
41
42 developing medicinal products.
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 2 Environment
60 ACS Paragon Plus
Page 3 of 42 Crystal Growth & Design

1
2
3
4
5
6
7
8
1. Introduction
9
10
1.1 Overview of Co-crystals
11
Most of the literature refers to an addition compound, quinhydrone (benzoquinone and
12
13 hydroquinone), as the first co-crystal discovery in 1844.1, 2 Yet, co-crystals could be traced date
14
15 back to 1783 when a habit change was observed upon crystallization of sodium chloride (NaCl)
16
17 from aqueous urea. The change was described in 1933 by Bunn as “There is one complication; in
18 the aqueous system there is a compound NaCl.CO(NH2)2.2H2O, the structure of which is
19
20 unknown’’.3-5 The 1: 1: 1 co-crystal of NaCl, urea and water wasn’t isolated and analyzed till the
21
22 mid of the last century. Since then, there have been several signposts in the co-crystal research
23
arena including the proposal of hydrogen bonding rules by Etter in 1990 that aid in predicting
24
25 hydrogen-bonding pattern in organic crystals.6 An important milestone by Desiraju in 1995
26
27 introduced the concept of supramolecular synthons that contributed significantly in crystal
28
29 engineering road map in general and co-crystal design in specific.7 Only in 2004 the “Crystal
30 engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals
31
32 represent a new path to improved medicines?’’ was announced,8 that article by Almarsson and
33
34 Zaworotko as its name implies the pharmaceutical ingress to this field.
35
36
With the opportunities that the pharmaceutical co-crystals opened for engineering the solid-
37 state APIs, regulations were set for these coming products. In 2011 the United States Food and
38
39 Drug Administration (FDA) paid attention to co-crystals importance and released a draft
40
41 guidance on regulatory classification of co-crystals.9 It defined co-crystals as “dissociable API-
42
excipient molecular complexes wherein both API and excipients are present in the same crystal
43
44 lattice”. This definition has been a debate subject in academic and industrial sectors as it was
45
46 considered to present a simplistic view and doesn’t distinguish co-crystals clearly. In 2016 draft
47
48 guidance, FDA adopted a definition that had the limitations of the former.10
49 It is the case till now, in February 2018 draft, co-crystals were defined as “crystalline
50
51 materials composed of two or more different molecules, typically active pharmaceutical
52
53 ingredient (API) and co-crystal formers (“coformers”), in the same crystal lattice’’.11
54
55
56
57
58
59 3 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 4 of 42

1
2
3 On the other hand, the European Medicines Agency (EMA) adopted in their reflection paper
4
5 a definition similar to the most accepted one which was proposed by 46 scientists, it includes one
6
7 of the authors of this review. The latter defines co-crystals as “solids that are crystalline single-
8
9
phase materials composed of two or more different molecular and/or ionic compounds generally
10 in a stoichiometric ratio, which are neither solvates nor simple salts’’.12
11
12 FDA and EMA regulations do differ in some other vital points. EMA considers the
13
14 pharmaceutical co-crystals similar to salts of same API and classifies them as new active
15
substances if they demonstrate the required efficacy and safety profiles.13 However, an FDA
16
17 accepted pharmaceutical co-crystal would be classified similarly to a new polymorph of the API.
18
19 Moreover, a crucial document for accepting a new drug applications (NDAs) containing a co-
20
21 crystal to the FDA, is the evidence for the dissociation of the API from its co-crystal prior to
22 reaching the site of the biochemical activity.11 In a recent study, Nangia et al., demonstrated the
23
24 complete dissociation of the cocrystal, temozolomide-succinic acid, prior to reaching the site of
25
26 action.1
27
28
29 1.2 Co-crystals for Tailoring Physicochemical and Biopharmaceutical Attributes
30
31 It is known that solids acquire their crucial physical properties from the molecular
32
33 arrangement within their lattice. Any alteration of the position and/or interaction between these
34
35 molecules would have a direct influence on the properties of the specific material.14 Among the
36
various strategies adopted for tailoring solids properties, co-crystals represent a promising one.15
37
38 They were reported to improve solubility, dissolution rate, bioavailability, mechanical properties
39
40 and others. Recently, they have also been found to fine-tune permeability of drugs, explosivity of
41
42 energetic materials and non-linear optical properties of energetic materials.16 In this section, we
43 present selected examples illustrating the opportunities made by the co-crystals in addressing
44
45 limitations related to various pharmaceutically relevant properties.
46
47 About 40% of marketed drugs and 70-90% of drugs in the development pipelines have poor
48
49
aqueous solubility. Therefore, co-crystals were introduced as an approach of crystal engineering
50 that allows supramolecular structure modulation to enhance the solubility of APIs.16, 17, 18 2003
51
52 witnessed a report of improved solubility of the antifungal drug itraconazole via L-malic acid and
53
54 L-tartaric acid co-crystals.19 In 2004, fluoxetine hydrochloride co-crystal with succinic acid
55 achieved a similar effect.20 The work continued in this area resulting in many successful
56
57
58
59 4 Environment
60 ACS Paragon Plus
Page 5 of 42 Crystal Growth & Design

1
2
3 candidates. Interest in co-crystals development and research increased and a number of reports
4
5 and reviews contain representative examples of such co-crystals along years till now.1,3,21,22,23
6
7 It has been noted that co-crystallization effect on solubility is complex. It can increase
8
9
solubility as stated earlier and sometimes to an extent surpassing that of the amorphous
10 counterpart.24 It may also have no effect on solubility or it might even decrease it. Decreasing
11
12 solubility by co-crystals has been utilized in addressing poor residence time and fast elimination
13
14 of the topical antibiotic sulfacetamide (SACT).25 Sulfacetamide: caffeine (SACT: CAF)
15
heteroatomic interactions afforded better co-crystal packing efficiency and stronger lattice that
16
17 resulted in lower solubility and dissolution rate in a way similar to extended release formulations
18
19 (Figure 1).
20
21 In-vitro dissolution enhancement doesn’t always assure similar in-vivo performance. Yet,
22 analysis of pharmacokinetics (PK) upon co-crystallization hasn’t been much reported in the
23
24 literature. In 2014, a review was published about this aspect and only 64 co-crystals representing
25
26 21 APIs were stated to afford 76 PK studies.26 The effect of co-crystals on the area under the
27
28
curve (AUC) was described to range from 10.2-fold decrease to 28.4-fold increase. Reported
29 Cmax changes ranged from 4-fold decrease to 44-fold increase.3
30
31 Faster Tmax is a feature that can be advantageous in certain drug classes as in the case of the
32
33 non-steroidal anti-inflammatory drug (NSAID) meloxicam. Meloxicam is indicated for
34
rheumatoid arthritis and postoperative pain. It is a biopharmaceutical classification system (BCS)
35
36 class II drug having a Tmax of 4-5 hours, however, notably, its co-crystals PK studies in rats had a
37
38 less than half an hour onset of action (Tmax < 30 min) (Figure 2).27
39
40 (a) (b)
41
42
43
44
45
46
47
48
49
50
51 Figure 1. (a) Sulfacetamide crystal packing. (b) Sulfacetamide: caffeine (SACT: CAF) co-crystal packing that
52 resulted in stronger lattice, lower solubility and dissolution. Reproduced with permission from Ref. 25.
53 Copyright © 2014. The Royal Society of Chemistry.
54
55
56
57
58
59 5 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 6 of 42

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24 Figure 2. Dissolution profiles for meloxicam with different coformers (1-12) at pH 6.5 and 37 °C demonstrating
25 that co-crystals resulted in higher concentration of the drug in the dissolution media. 1-12 are the co-crystals
26
of meloxicam with 1-hydroxy-2-naphthoic acid (1), salicylic acid form III (2), succinic acid (3), 4-hydroxybenzoic
27
acid (4), glutaric acid (5), maleic acid (6), L-malic acid (7), benzoic acid (8), DL-malic acid (9), hydrocinnamic
28
29 acid (10), glycolic acid (11), and fumaric acid (12). Reproduced with permission from Ref. 27. Copyright ©
30 2012. The American Chemical Society.
31
32
33
Apart from solubility, co-crystals have also been used to tailor other critical properties of
34 drugs such as membrane permeability. Diffusion or membrane permeability is crucial for
35
36 absorption, bioavailability and imparting the desired therapeutic effect. Co-crystals proved to
37
38 provide an opportunity to enhance drugs permeability by circumventing limitations of previously
39
utilized approaches.3 Of the reported examples illustrating such an effect orally are the co-
40
41 crystals of the diuretic, furosemide (BCS class IV drug). They were proposed to cause transient
42
43 high concentration gradient at the membrane site due to their higher dissolution compared to that
44
45 of its parent entity (Figure 3).28
46
Acyclovir is found in six polymorphic forms and the form V (ACV2/3H2O) is the
47
48 commercial one. Because of the poor solubility and permeability, the bioavailability of acyclovir
49
50 reaches only 15–30%. Topical permeation enhancement was accomplished via acyclovir:
51
52 fumaric acid and acyclovir: glutaric acid co-crystals in PEG-400 ointment. Here permeability
53 optimization of this was attributed to the hydrophobic nature of the coformer (Figure 4).29
54
55
56
57
58
59 6 Environment
60 ACS Paragon Plus
Page 7 of 42 Crystal Growth & Design

1
2
3
4 (a) (b)
5
6
7
8
9
10
11
12
13
14
15
16
17
18 Figure 3. (a) Cumulative amount of furosemide (FSM), its co-crystals with different co-formers diffused with
19 regard to time (PPZ: piperazine (PPZ), TMPZ: 2,3,5,6-tetramethylpyrazine, ANT: anthranilamide and CAF:
20 caffeine). Measurements of its salts with cysteine (CYT) and adenine (ADE) were also carried out for
21 comparison. (b) Permeability of co-crystals and salts versus time. Reproduced with permission from Ref. 28.
22
Copyright © 2016. The American Chemical Society.
23
24
25 (a) (b)
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41 Figure 4. (a) Powder dissolution, and (b) permeation profiles of acyclovir: fumaric acid (2, blue) and acyclovir:
42 glutaric acid (3, green) in comparison with acyclovir (black) and its salt with maleic acid (red). Reproduced with
43 permission from Ref. 29. Copyright © 2013. The Royal Society of Chemistry.
44
45 Mechanical properties are critical for bulk powder compaction and tableting. Elasticity,
46
47 plasticity, viscoelasticity, and fragmentation are the traditional mechanical deformation
48
49
mechanisms of solid materials.1 Improved plasticity and hence tabletability was reported with the
50 co-crystals of 6-chloro-2,4-dinitroaniline (cda) and four of vanillin isomers; vanillin (van),
51
52 ethylvanillin (evan), iso-vanillin (ivan) and the Schiff base of ortho-vanillin (ovan) with ethylene
53
54 diamine (sb-ovan). The enhanced mechanical properties of the co-crystals were accredited to
55
their anisotropic 2D-layer structure which is unlike the isotropic structure of the initial isomers-
56
57
58
59 7 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 8 of 42

1
2
3 has active slip planes that facilitate the plastic deformation and hence tabletability (Figure 5).
4
5 The highest tabletability was encountered with sb-ovan:cda (Figure 6) as it exhibited the highest
6
7 plasticity (Figure 7) whereas those of the three other co-crystals were comparable.30 Other
8
9
examples have also been reported.31-33
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24 Figure 5. Improving the brittleness of the vanillin isomers via co-crystallization with 6-chloro-2,4-dinitroaniline.
25 Reproduced with permission from Ref. 30 Copyright © 2015. The American Chemical Society.
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42 Figure 6. Tabletability curves of vanillin isomers with 6-chloro-2,4-dinitroaniline (cda). The highest
43 tabletability was that of the Schiff base of ortho-vanillin (ovan) with ethylene diamine (sb-ovan) while the
44 others with vanillin (van), ethylvanillin (evan), iso-vanillin(ivan); van: cda, evan:cda and ivan: cda,
45
respectively- were all comparable. Reproduced with permission from Ref. 30 Copyright © 2015. The
46
47 American Chemical Society.
48
49
50
51
52
53
54
55
56 Figure 7. a) Side view of the crystal packing of the co-crystal of 6-chloro-2,4-dinitroaniline (cda) and the Schiff
57 base of ortho-vanillin (ovan) with ethylene diamine(sb-ovan) showing the slip planes that improved
58 tabletability of this compound. b) Crystal packing of sb-ovan: cda showing the weak (sp3)C‒H···O interactions
59 (2.81 Å, 111.86°) that forms the slip planes. . Reproduced with permission from Ref. 30 Copyright © 2015. The
8 Environment
60 ACS Paragon Plus
American Chemical Society.
Page 9 of 42 Crystal Growth & Design

1
2
3 Physical, chemical, photo and microbiological stability of drugs have also been tailored
4
5 by co-crystals. The first report highlighting the potential of co-crystals to attain photostability
6
7 was for the antibiotic agent, nitrofurantoin (NF).34 It exists in both anhydrous (α- and β-) and
8
9
hydrate polymorphic forms (Forms I and II). The β-form is the commercially available one for
10 this photosensitive drug. The 1: 1 co-crystal of NF (β-form) with 4-hydroxybenzoic acid (4HBA)
11
12 showed an enhanced photostability in comparison to the API (Figure 8). Moreover, that co-
13
14 crystalline system exhibited substantial stability to temperature and humidity as shown by
15
differential thermal analysis (DTA) and differential scanning calorimetry (DSC) results (Figure
16
17 9) for a descent time interval of over a period of 13 weeks (Table 1). After this study, a number
18
19 of co-crystals were designed to tackle photodegradation of the APIs and nutraceutical
20
21 materials.35-39 100

22 95
23
24
% of NF remained

90

25
85
26
27
80
28 NF
29 75
NF-4HBA (1:1)

30
31 70
0 20 40 60 80 100 120 140 160 180
32
33 Time (hours)
34
35 Figure 8. Photodegradation curves with error bars showing the improved photostability of nitrofurantoin (NF) after
36 its incorporation into 1: 1 co-crystal with 4-hydroxybenzoic acid (NF-4HBA). Samples were irradiated with UV light
37 up to a week. Reproduced with permission from Ref. 34. Copyright © 2011. The Royal Society of Chemistry.
38
104
39 o
24 C, 97% RH
NF-4HBA, 13 weeks
40
Weight (%, arbitrary units)

41
100
42 NF (-form) to
NF-H2O (Form II),
43 7 weeks
44 96
45 NF (-form)

46 NF-H2O (Form II)


47 92
48
49
50 88
50 100 150 200 250
51 o
52 Temperature ( C)
53 Figure 9. DTA/ DSC profiles showing that the co-crystal of nitrofurantoin with 4-hydroxybenzoic acid (NF-4 HBA)
54
remained stable for 13 weeks at 24°C, 97% RH [green] unlike nitrofurantoin NF (β-form) that transformed to NF-
55
H2O (Form II) by 7 weeks at 24 °C, 97% RH [red]. For comparison, DTA curves of NF (β-form) [black] and NF-H2O
56
57 (Form II) [blue] before storage are also provided. Reproduced with permission from Ref. 34. Copyright © 2011.
58 The Royal Society of Chemistry.
59 9 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 10 of 42

1
Table 1. Relative humidity stability studies at ambient and 40 C temperatures.34
2
3
Conditions (T, RH) Results
4
5 No phase change in 13 weeks
24C, <10, 33, 57, 75%RH; 40C, 75%RH
6
7
8
9 1a 24C, 97% RH In 7 weeks, NF (-form)  NF·H2O (Form II)
10
11
12
13 40C, 96% RH In 1 week, NF  NF·H2O
14
15 24C, <10, 33, 57, 75, 97%RH;
No dissociation or phase changes during 13
2a
16 weeks of storage in all the specified storages.
40C, 75, 96% RH
17
18
19 a1 and 2 represents NF and NF-4HBA (1: 1) co-crystal respectively.
20
21
22 Acemetacin is an NSAID that has the propensity to form a hydrate in an aqueous medium.
23
24 Co-crystallization with nicotinamide brought stability to hydration and 5 times faster dissolution
25 rate than stable hydrate form.40 Other examples of co-crystals that showed hydration resistance
26
27 include those of nitrofurantoin, niclosamide, and etoricoxib.1
28
29 Chemical degradation of temozolomide into an inactive by-product amino-imidazole
30
31
carboxamide is accelerated by high humidity. This compound is a first-line prodrug for
32 glioblastoma multiforme treatment and the only approved drug for treating malignant brain
33
34 tumours. Its degradation reaction is accompanied by discoloration that makes patients suspicious
35
36 about drug efficacy. These physical and chemical stability issues were modulated by the
37
formation of temozolomide: succinic acid co-crystal (Figure 10).1, 25, 41
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53 Figure 10. Color comparison of temozolomide (top) and temozolomide: succinic acid co-crystal (bottom)
54 showing the physical stability of the latter. Reproduced with permission from Ref. 41. Copyright © 2012. Wiley-
55 VCH Verlag GmbH & Co.
56
57
58
59 10 Environment
60 ACS Paragon Plus
Page 11 of 42 Crystal Growth & Design

1
2
3 Co-crystallization advantages extend to achieve solid-state formulations for APIs with low
4
5 melting points, conveying better physicochemical properties. Such a case is the conversion of the
6
7 liquid anaesthetic propofol (m.p. 18 °C) into a solid (m.p. 55 °C) via co-crystallization with
8
9
isonicotinamide (m.p. 150 °C).1
10
11
12 2. Co-crystal Formulations
13
14 Co-crystals ability to improve physicochemical properties has derived the surge of interest
15
16 in these entities as potential alternatives for salts and polymorphs with additional advantages.1, 3,
17 16, 17, 42 However, the translational development of co-crystal products requires their
18
19 incorporation into a successful formulation.17 Co-crystals and their formulation are discussed in
20
21 the following sections.
22
23
24
25
2.1 Un-intentional Co-crystal Formation in Formulations
26 Pharmaceutical formulations usually contain substances alongside the active ingredient to
27
28 serve different functions.43 These are the excipients and they are incorporated to add bulk to the
29
30 formulation, assist in the handling of the API during the manufacturing or to facilitate the drug
31
32
absorption, bioavailability, and other pharmacokinetic considerations. They might also play a
33 vital role in stabilizing the pharmaceutical product or they may bring organoleptic attributes to
34
35 the formulation. Accordingly, there are various categories of excipients, each has multiple
36
37 options from which the most suitable to a specific formulation is selected.44, 45
38
39
40 Excipients and co-crystals have a complex relationship. Some reports have shown that
41
42 certain excipients can mediate un-intentional co-crystal formation in the dosage forms. Marked
43
44 bioavailability enhancement was witnessed in a compound that was under development for acute
45 and chronic pain treatment, AMG 517. Upon investigation, it was discovered that AMG 517
46
47 formed co-crystals with ascorbic acid, a formulation preservative used that led to its aqueous
48
49 solubility improvement.46
50
51
52 Dibasic calcium phosphate dihydrate (DCPD: CaHPO4.2H2O) is a commonly used excipient
53
54 in tablet formulations to function as a filler and as a source of calcium and phosphorus in
55
56 nutritional supplements.47 Its wide application in pharmaceutical products is attributed to its
57
58
59 11 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 12 of 42

1
2
3 compaction properties and good flow characteristics. The 20.9% w/w water of crystallization
4
5 released during dehydration of this material was reported to facilitate carbamazepine: salicylic
6
7 acid co-crystals in carbamazepine and aspirin tablets (Figure 11). That was proposed to be
8
9
caused by decomposition of aspirin by the released DCPD lattice water followed by reaction of
10 salicylic acid (decomposition product) with carbamazepine to form carbamazepine: salicylic
11
12 acid co-crystal. The same excipient was reported to arbitrate co-crystal formation between
13
14 carbamazepine and nicotinamide in intact tablets. The reaction rate, in this case, was believed to
15
be slow and of no practical interest, while in the first case, carbamazepine: salicylic acid co-
16
17 crystal formation was reported after 58 days at 40° C which is a relevant pharmaceutical storage
18
19 temperature (Figure 12). Aside, this report highlighted an important challenge which is the need
20
21 for an analytical tool to detect co-crystal formation in a complex multicomponent dosage form as
22 the utilized ones in testing quality attributes e.g. liquid chromatography require dissolution of the
23
24 dosage form. In solution, co-crystals may no longer be detected due to their disintegration into
25
26 drug and coformer.48
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57 Figure 11. X-ray diffraction patterns of carbamazepine and acetylsalicylic acid tablets (right, control; left, test) at
58 50 °C (a) and 40 °C (b) (right, control; left, test). Reproduced with permission from Ref. 48. Copyright © 2011. The
59 American Chemical Society. 12 Environment
60 ACS Paragon Plus
Page 13 of 42 Crystal Growth & Design

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36 Figure 12. Intensities of characteristic PXRD peaks of (a) carbamazepine (b) nicotinamide, and (c)
37 carbamazepine: nicotinamide co-crystal in test (green) and control (red) tablets stored at 40 °C with respect to
38 time (error bars represent standard deviation; n = 3). Reproduced with permission from Ref. 48. Copyright ©
39 2011. The American Chemical Society.
40
41
42 Water released by API dehydration can also result in co-crystal formation with excipients. It
43
44 was reported that dehydration of carbamazepine hydrate caused co-crystallization between
45
46 anhydrous carbamazepine and nicotinamide in intact tablets (Figure 13).
47
48
49 Similarly, tablets of a model system containing theophylline monohydrate (TPM) and citric
50
51 acid (CA) were reported to form co-crystals as a result of dehydration to anhydrous theophylline
52
53 (TPA), evident deliquescence of citric acid that mediated TPM: CA co-crystal formation upon
54 storage at similar conditions to carbamazepine tablets (Figure 14). This phase transformation had
55
56 an implication on the disintegration time and the dissolution profiles of the tested tablets. The co-
57
58
59 13 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 14 of 42

1
2
3 crystals formed were assumed to crystallize around the incorporated disintegrant (sodium starch
4
5 glycolate), therefore compromising its functionality which was imparted on the dissolution as
6
7 well. 49
8
9
10 (a)
11
12 (b)
13
14
15
16
17
18
19
20
21
22
23
24
25 Figure 13. (a) PXRD patterns of tablets comprising equimolar amounts of carbamazepine dihydrate (CBZD) and
26 nicotinamide (NMA) stored at 40°C in sealed Mylar® pouches for 74 days. Number of characteristic peaks of the
27 carbamazepine anhydrous (CBZA): nicotinamide was detected (red box) from the first day and nicotinamide
28 characteristic peak (green box) was there till day 6. (b) Intensities of characteristic peak of CBZA: NMA co-crystal
29 in test (green) and control (red) tablets stored at 40°C in sealed Mylar® pouches for 60 days (error bars
30 represent standard deviation; n = 3). Reproduced with permission from Ref. 49. Copyright © 2013. Springer.
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50 Figure 14. PXRD patterns of tablets comprising equimolar amounts of theophylline monohydrate (TPM) and citric
51
acid (CA) stored at 50°C in containers sealed with Kapton® tape. Number of characteristic peaks of the
52
53 theophylline anhydrous (TPA): citric acid was detected (green box). Reproduced with permission from Ref. 49.
54 Copyright © 2013. Springer.
55
56
57
58
59 14 Environment
60 ACS Paragon Plus
Page 15 of 42 Crystal Growth & Design

1
2
3 When considering deliberately formed co-crystals in relation to the different excipients, the
4
5 first to find was that co-crystals might need certain formulation additives (excipients) to achieve
6
7 their intended purpose. Yet, research in co-crystal formulations is not as much as in novel co-
8
9
crystals discovery for various physical properties modifications. The following cases are the ones
10 reported for co-crystal formulation studies.
11
12
13
14 2.2 Reported Co-crystal Formulations
15
16 Preformulation studies are integral part of co-crystal formulations; co-crystals with desired
17
physicochemical properties cannot be directly loaded into capsule form or neat co-crystal
18
19 suspension itself is inadequate to have the complete advantage of solubility but suitable
20
21 formulation is essential.50-54
22
23
24
25 2.2.1 Danazol: Vanillin Co-crystal
26
27 Danazol is a synthetic androgen which has been used to treat women with endometriosis
28 since the 1970s.55 It is a BCS class II drug that has low aqueous solubility (approximately 0.6
29
30 µg/mL) and high permeability (lopP 4.53).56 It is characterized by being a non-ionizable
31
32 compound that cannot produce salts but can form a co-crystalline system. The bioavailability
33
34
studies of danazol designated that by increasing the administered dose of this drug will not be
35 reflected in a proportional increase in its blood levels.57 The marketed product Danocrine®
36
37 capsule contains 50 mg, 100 mg or 200 mg danazol. In 2013, danazol was chosen as a model
38
39 system to evaluate the use of supersaturating formulation to a highly soluble co-crystal. An in
40
vivo performance of neat aqueous suspension of cocrystal was reported as 1.7 times higher
41
42 compared to poorly soluble danazol polymorph. Danazol: vanillin co-crystal was formulated
43
44 into an aqueous suspension containing 1% D-α-tocopherol polyethylene glycol succinate (TPGS)
45
46 as solubilizer and 2% hydroxypropyl cellulose (HPC) as precipitation inhibitor. That formulation
47 with the mentioned combination and percentages improved the bioavailability of the co-crystal
48
49 by over 10 times compared to the poorly soluble danazol form (Figure 15). It was based on
50
51 maintaining the supersaturation effect produced by co-crystals (spring effect), which was
52
53
accomplished by adding a formulation component (precipitation inhibitor) which was HPC in
54 this case. The additive hindered nucleation and crystal growth and stabilized the metastable
55
56 supersaturated system for a time sufficient for drug absorption to occur (parachute effect).
57
58
59 15 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 16 of 42

1
2
3 Combining solubilizer with the precipitation inhibitor was found to be advantageous in other
4
5 supersaturating systems and the results obtained in this work further supported that strategy.50
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Figure 15. In-vitro dissolution data and in-vivo plasma concentration for the danazol: vanillin co-crystal and
26
27 danazol polymorphs suspensions (a) unformulated, containing 0.5% polyvinylpyrrolidone (PVP) K-25 as a
28 suspending agent and (b) formulated with containing 1% D-α-tocopherol polyethylene glycol succinate (TPGS)
29 as solubilizer and 2% hydroxypropyl cellulose (HPC) as precipitation inhibitor. Reproduced with permission from
30 Ref. 50. Copyright © 2013. The American Chemical Society.
31
32
33
34 2.2.2 Carbamazepine: Succinic Acid Co-crystal
35
36 Carbamazepine is a drug that is used largely in the treatment of epilepsy and neuropathic
37
38
pain. A marketed product Tegretol® is available as conventional tablet (100 mg, 200 mg, 400
39 mg), chewable tablet (100 mg), suspension (100 mg/5 mL), and extended-release tablet (100mg,
40
41 200mg, 400 mg). Carbamazepine’s belonginess to BSC class II drugs was the drive to investigate
42
43 the various reported co-crystal systems.58 Here again, nucleation was inhibited, crystal growth
44 was stalled and the metastable supersaturated system of the co-crystal of carbamazepine:
45
46 succinic acid in solution was controlled using a crystallization inhibitor [hydroxypropyl
47
48 methylcellulose acetyl succinate (HPMC-AS)] and a solubilizer (polyvinyl caprolactam-
49
50
polyvinyl acetate-polyethylene glycol graft copolymer). Pharmacokinetics studies in rabbits
51 demonstrated that the formulation which contained 1% co-crystal, 1% HPMC-AS and 2%
52
53 polyvinyl caprolactam-polyvinyl acetate polyethylene glycol graft copolymer caused an almost
54
55
56
57
58
59 16 Environment
60 ACS Paragon Plus
Page 17 of 42 Crystal Growth & Design

1
2
3 6-fold increase in AUC and higher Cmax of 4.73 µg/mL to that of 1.07µg/mL of unformulated co-
4
5 crystal given orally (Figure 16).59
6
7
8 (a) (b)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24 Figure 16. Area under the curve (AUC) for different carbamazepine: succinic acid co-crystal suspension
25 formulations [F(1-7)-X] represented in (a) plasma concentration versus time plot and (b) histogram F7-X
26
contained 1% co-crystal, 1% HPMC-AS and 2% polyvinyl caprolactam-polyvinyl acetate polyethylene glycol
27
graft copolymer and caused an almost 6-fold increase in AUC compared to the unformulated co-crystal.
28
29 Reproduced with permission from Ref. 59. Copyright © 2017. University of Karachi.
30
31
32 Ullah et al worked on the tablet formulation for the same system. Intrinsic dissolution rate
33
34 (IDR)60 was used as a “material-sparing” tool -only tens of milligrams of the drug is required for
35
36
a single experiment- to facilitate the selection of polymeric crystallization inhibitors for
37 developing a tablet formulation for a co-crystal including carbamazepine and succinic acid. The
38
39 formulations exhibited high IDR were expected to lead to more rapid drug release from the
40
41 formulation and thus eventually potential high bioavailability. Optimum co-crystal to polymer
42
ratio was determined to be 6.25: 1 for Soluplus® (F1), 5: 1 for Kollidon® VA/64 (F2) and 6.25: 1
43
44 for HPMC-AS (F3 In a modified simulated intestinal fluid (mSIF), more than 95% of
45
46 carbamazepine was found to be released from F2 and F3 after 60 minutes, 82% was released from
47
48 F1 and only 79% of the drug was released from the commercial tablets (Epitol®) (Figure 17).
49 The formulation remained stable and the dissolution profiles showed no practical change over a
50
51 storage period for a month under 40 °C and 75% RH.18, 61
52
53
54
55
56
57
58
59 17 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 18 of 42

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22 Figure 17. Dissolution profiles of carbamazepine: succinic acid co-crystal tablets in modified simulated intestinal
23 fluid (mSIF) contain different polymers; 6.25: 1 for Soluplus (F1), 5: 1 for Kollidon VA/64 (F2) and hydroxypropyl
24 methyl cellulose acetate succinate HPMCAS (F3). More than 95% of the carbamazepine is released from F2 and
25 F3 after 60 minutes, 82% is released from F1 and only 79% of drug is released from the commercial tablets
26 (Epitol®) (F0). Reproduced with permission from Ref. 61. Copyright © 2016. Taylor & Francis.
27
28
29 2.2.3 Celecoxib: Nicotinamide Co-crystal
30
31 Celecoxib (CELEBREX®) is BSC class II anti-inflammatory drug that inhibits
32 cyclooxygenase-2 enzyme (COX-2).62 It is reported to exist in four polymorphic forms.63 The
33
34 most stable of which is form III (Cel-III) the least soluble one and happens to be the form of the
35
36 marketed drug.64 Celebrex® oral capsules contain 100 mg and 200 mg of celecoxib. The first
37
38
attempt to improve the bioavailability of this drug product using another form than form III was
39 performed in 2005 via the recently described polymorph back then (Cel-IV). That form when
40
41 was isolated from the produced suspension showed to dissolve twice as fast, have 4-fold higher
42
43 bioavailability than Cel-III powder. It was also stable toward form conversion for intervals
44 longer than 16 months at 25 °C.65
45
46
47
48 The possibility of a co-crystal to enhance dissolution and bioavailability comparative to the
49
50 stable free crystalline form of a molecular entity can depend on the formulation and type and
51
52 amount of the excipients used. That was illustrated through celecoxib: nicotinamide co-crystal
53 (Cel-Nic). In presence of low concentrations of surfactants (1% sodium dodecyl sulfate, SDS),
54
55 Cel-Nic was found to convert into large aggregates of celecoxib form III. In contrast, Cel-Nic
56
57
58
59 18 Environment
60 ACS Paragon Plus
Page 19 of 42 Crystal Growth & Design

1
2
3 formulations containing (1-10%) SDS and polyvinylpyrrolidone (PVP) showed more rapid
4
5 dissolution due to its conversion to amorphous celecoxib and micronized form IV celecoxib, that
6
7 was about 4 times greater bioavailability than the commercial celecoxib form (Cel-III) (Figure
8
9
18).66
10 This example emphasised the importance of studying the form conversion of co-crystals in
11
12 aqueous media before exploring the pharmacokinetic studies and demonstrated that formulations
13
14 can be developed to overcome the fast dissociation of co-crystals and their recrystallization to the
15
poorly soluble forms of the APIs in aqueous media.
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36 Figure 18. Dissolution studies performed using 1% SDS in pH 6.5 phosphate buffer at 37 °C with a target
37 concentration of 0.4 mg/mL following a 15 min “presuspension”, at a target concentration of 2 mg/mL in 0.01
38 N HCl at 37 °C. The ratio of celecoxib/ polyvinylpyrrolidone (PVP) was identical for both Cel-III and celecoxib:
39
nicotinamide (Cel: Nic), with 1/1 ratio referring to wt/wt of Cel: Nic/PVP. Reproduced with permission from
40
Ref. 66. Copyright © 2007. The American Chemical Society.
41
42
43 2.2.4 Indomethacin: Saccharin Co-crystal
44
45 Indomethacin is an NSAID with an anti-inflammatory, analgesic and antipyretic activity.67
46
47 The commercial dosages of indomethacin include Indocin® capsule (25 mg, 50 mg), extended
48
49
release capsule (75 mg), suppository (50 mg, 100 mg) and suspension (25 mg/5 mL). It is listed
50 as Class II drug according to the BCS.68 An in-vivo study reported that co-crystals of
51
52 indomethacin: saccharin increased the bioavailability of indomethacin to a level comparative to
53
54 that of the commercial drug formulation (Indomee).69 The solubility advantage of co-crystal over
55 indomethacin is threatened by its rapid conversion to the drug crystals as a result of the high
56
57
58
59 19 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 20 of 42

1
2
3 supersaturation. With a better understanding of co-crystal behaviour in solutions and a rational
4
5 approach based on the eutectic constant (Keu),70 indomethacin: saccharin co-crystal formulation
6
7 was optimized (Figure 19).71
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23 Figure 19. Plot of eutectic constant (Keu) versus excipient concentration. The effect of Keu value on attaining co-
24 crystal dissolution advantage. Reproduced with permission from Ref. 71. Copyright © 2013. The American
25 Chemical Society.
26
27
28
29 Using 2% PVP and 100 mM sodium lauryl sulfate (SLS) enabled attainment of the solubility
30
31 advantage of indomethacin: saccharin co-crystals through differential solubilization effect
32
33 (increase the solubility of indomethacin but not saccharin) which resulted in low supersaturation
34 level of co-crystal with respect to the drug (Figures 20 and 21). The effect of that was manifested
35
36 in the prevention of fast transformation of co-crystals to their crystallized drug component for an
37
38 appropriate time for absorption to occur. Figure 22 shows the Keu values of the formulations as a
39
40
function of PVP and SLS concentrations; 2% PVP and 100 mM SLS were the ones that gave Keu
41 values with which the dissolution advantage can be attained.71
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 20 Environment
60 ACS Paragon Plus
Page 21 of 42 Crystal Growth & Design

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31 Figure 20. The concentrations of indomethacin (A) Figure 21. The concentrations of indomethacin (A)
32 and saccharin (B) in μg/ml, following the and saccharin (B) in μg/ml, following the
33 dissociation of indomethacin: saccharin co-crystal dissociation of indomethacin: saccharin co-crystal
34 at various times (in min) in at pH 3. (Δ) in buffer at various times (in min) in at pH 3. (Δ) in buffer
35 only, (○) in predissolved 250 μg/ml PVP, and (□) in only, (○) in predissolved 25 mM SLS, and (□) in
36
predissolved 2% w/v PVP. Reproduced with predissolved 100 mM SLS. Reproduced with
37
permission from Ref. 71. Copyright © 2013. The permission from Ref. 71. Copyright © 2013. The
38
39 American Chemical Society. American Chemical Society.
40
41 (a) (b)
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56 Figure 22. Keu values (○) as a function of (a) PVP concentration. Keu values, and (b) SLS concentration. The dotted
57 line represents in (b) is the theoretical presentation of Keu = 1 at various concentrations of SLS. Reproduced with
58 permission from Ref. 71. Copyright © 2013. The American Chemical Society.
59 21 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 22 of 42

1
2
3
4
2.2.5 Ivabradine Hydrochloride: (S)-Mandelic Acid Co-crystal
5 As mentioned earlier, salt co-crystals can be formed as of the reported examples fluoxetine
6
7 hydrochloride with different carboxylic acids and that of ivabradine hydrochloride is indicated
8
9 for the symptomatic treatment of chronic stable angina pectoris and chronic heart failure.72 Upon
10
11
the screening of various co-crystals, the one with (S)-mandelic acid was found to show
12 comparable stability with the polymorph used in the original drug product of that salt. Thus, it
13
14 was chosen to be formulated into a drug product. The marketed product Corlanor® is available
15
16 in tablet (film coated, 2.5 mg, 5 mg, 7.5 mg) and in suspension (5 mg/ 5 mL) forms.
17
In the pre-formulation studies, the API and the coformer were mixed with the lactose
18
19 monohydrate and granulated in an attempt to evaluate the potential of the in-situ formation of the
20
21 co-crystal during the granulation process.73 Lactose monohydrate was chosen because it was
22
23 suggested to simulate all excipients in a dosage form. When methanol was used, the potential
24 tested was found to be valid as 13C solid-state NMR results indicated (Figure 23) and the co-
25
26 crystals were produced on a small scale of 5g load in a beaker and 12g load in a special devised
27
28 high-shear granulator.
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
Figure 23. The 13C solid-state NMR spectra of lactose monohydrate (top), co-crystal of ivabradine
54
hydrochloride: (S)-mandelic acid (middle), and EtOH-granulated mixture (bottom). Reproduced with from Ref.
55
56 73. Copyright © 2017. MDPI. It is licensed under a Creative Commons Attribution 4.0 International License:
57 https://creativecommons.org/
58
59 22 Environment
60 ACS Paragon Plus
Page 23 of 42 Crystal Growth & Design

1
2
3 In the formulation development stage, the co-crystal was either pre-prepared and the
4
5 excipients were then added, or it was produced during the wet granulation in the presence of the
6
7 excipients. In the former group, the formulations were identical to some in the latter group
8
9
(mixtures A-C in Table 2 and mixtures D-H in Table 3, respectively).
10
11
Table 2. The composition of the mixtures A-C with pre-prepared co-crystal.73
12
13
14 Ingredient (mg) A B C
15
16 ICISM 10.5 10.5 10.5
17
18 Klucel EF 2.7 2.7 2.7
19
20
Lactose monohydrate 115.0 - 111.9
21
22
23 Mannitol - 115 -
24
25 Primojel type A 5.4 5.4 5.4
26
27 Meglumine - - -
28
29
Magnesium stearate 1.35 1.35 1.35
30
31
32 Tablet weight (mg) 135 135 135
33
34
35
36 The mixtures were packed into aluminium blister under ambient and nitrogen atmosphere
37
38 and preserved for 72 h at 80 C. That was done to investigate the physical and chemical stability
39
40 of the co-crystal within these combinations. Mixtures contained the pre-prepared co-crystals
41
42 were unstable; those of A and B showed co-crystal dissociation (physical instability) while that
43 of C exhibited chemical impurities formed by oxidative reactions (chemical instability). On the
44
45 other hand, the ones contained the in-situ prepared co-crystals showed variable results; mixtures
46
47 D and F were physically unstable, mixture J was chemically unstable whereas mixtures G and H
48
49
were both chemically and physically unstable. Mixtures E and I showed no physical or chemical
50 instability. The antioxidant (butylhydroxytoluene) used aided in maintaining chemical stability.
51
52 The final composition selected for further development had the co-crystal with lactose
53
54 monohydrate, klucel, primojel, magnesium stearate, and butylhydroxytoluene.73
55
56
57
58
59 23 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 24 of 42

1
2 Table 3. The composition of the mixtures D-J with co-crystal formed in-situ.73
3
4 Ingredient (mg) D E F G H I J
5
6 Ivabradine HCl 8.085 8.085 8.085 8.085 8.085 8.085 8.085
7
8
9 (S)-mandelic acid 2.436 2.436 2.436 2.436 2.436 2.436 2.436
10
11 Klucel EF 2.7 2.7 2.7 2.7 2.7 2.7 2.7
12
13 Lactose monohydrate 115.0 - 112.3 114.25 111.9 114.8 111.5
14
15
Mannitol - 115 - - - - -
16
17
18 Primojel type A 5.4 5.4 5.4 5.4 5.4 5.4 5.4
19
20 Butylhydroxytoluene - - - - - 0.27 -
21
22 Citric acid - - - - - - 3.5
23
24
Meglumine - - - 0.781 3.125 - -
25
26
27 Magnesium stearate 1.35 1.35 1.35 1.35 1.35 1.35 1.35
28
29 Tablet weight (mg) 135 135 135 135 135 135 135
30
31
32
33
34
3. Challenges Associated with Co-crystal Formulations
35
36
3.1 Excipient Mediated Co-crystal Dissociation
37 The various excipients within formulations might impart deleterious effects on the co-crystals
38
39 stability. Water-mediated co-crystal dissociation in solid-state formulations was found to be true.
40
74,75 The robust caffeine: oxalic acid co-crystal (CAFOXA) was formulated in a tablet containing
41
42
43
magnesium stearate (MgSt) as a lubricant and stored at (RT/ 75% RH) for 35 days. Caffeine
44 hydrate was detected indicating co-crystal dissociation (Figure 24). The proposed mechanism
45
46 was that the sorbed water acted as a plasticizer, increased molecular mobility and thereby eased
47
48 reactions (Figure 25).74
49
50
51
52
53
54
55
56
57
58
59 24 Environment
60 ACS Paragon Plus
Page 25 of 42 Crystal Growth & Design

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Figure 24. PXRD patterns depicting (a) “as is” co-crystal, (b) ground co-crystal−magnesium stearate physical
24
25 mixture without an addition of water and (c) with an addition of water. The simulated powder patterns for
26 (d) caffeine hydrate, (e) magnesium oxalate dihydrate, and (f) stearic acid are presented for comparison.
27 Note the formation of caffeine hydrate, magnesium oxalate dihydrate, and stearic acid in the “wet ground”
28 mixture. Reproduced with permission from Ref. 74. Copyright © 2017. The American Chemical Society.
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
Figure 25. Proposed mechanism of water mediated dissociation of caffeine: oxalic acid co-crystal in the
53
54 presence of magnesium stearate. Reproduced with permission from Ref. 74. Copyright © 2017. The American
55 Chemical Society.
56
57
58
59 25 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 26 of 42

1
2
3 Other excipients were also investigated for the same purpose. Co-crystal and excipients
4
5 mixtures were studied after adding 30% w/w water to facilitate rapid assessment of dissociation
6
7 liability. That was done in pharmaceutically relevant conditions (RT/75 %RH stored for 1 week)
8
9
and the presence of caffeine hydrate peak was considered as an evidence for the co-crystal
10 dissociation. The named peak was detected with all tested excipients except polyethylene oxide
11
12 (Figure 26).74
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39 Figure 26. Overlay of PXRD patterns of binary mixtures of caffeine: oxalic acid (CAFOXA) with each depicted
40 excipient upon (a) the addition of 30.0% w/w water and (b) storage at RT/75% RH for 1 week. Note the
41 characteristic peak of caffeine hydrate (10.6° 2θ) is highlighted. Reproduced with permission from Ref. 74.
42
Copyright © 2017. The American Chemical Society.
43
44
45
46 Reaction kinetics was suspected to be dependent on many factors such as surface area of
47
48 contact between co-crystal and excipient particles and the reactivity of the components. Water
49
50
sorption potential was excluded from affecting the reaction kinetics as some excipients despite of
51 their hydrophobicity (e.g. magnesium stearate) and non-hygroscopicity (e.g. dicalcium phosphate
52
53 anhydrous)– they imparted rapid dissociation. Intact tablets of binary mixtures of the excipients
54
55 with the co-crystal were stored at RT/75% RH for 35 days and subjected to two-dimensional X-
56
57
58
59 26 Environment
60 ACS Paragon Plus
Page 27 of 42 Crystal Growth & Design

1
2
3 Ray diffraction (2D-XRD). It was performed to study the effect of the preferred orientation that
4
5 might be induced by compression. Characteristic caffeine hydrate peak was noticed after 5 days
6
7 indicating the co-crystal dissociation. It continued to increase in intensity along with the one
8
9
distinguishing stearic acid up to 35 days (Figure 27).74
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29 Figure 27. (I) 2D-XRD patterns of (A) tablet containing co-crystal and MgSt (95 and 5% w/w) at time zero and (B)
30 after 5 days at RT/75% RH. PXRD patterns of A’ and B’ represents the corresponding 1D-XRD patterns. The
31 presence of the peak at 10.6° 2θ (*), attributed to caffeine hydrate, is due to co-crystal dissociation. The peak at
32 21.6° 2θ (▲) is ascribed to the formation of stearic acid. This peak is also shown in inset for clarity. (II) PXRD
33 patterns shows the formation and gradual increase in the concentrations of caffeine hydrate and stearic acid in
34 tablets. The two highlighted regions refer to a characteristic peak of caffeine hydrate (peak at 10.6° 2θ) and
35 stearic acid (21.6° 2θ), respectively. Reproduced with permission from Ref. 74. Copyright © 2017. The American
36 Chemical Society.
37
38
It has been suggested that when the API or the coformer is ionizable, co-crystal formulations
39
40 containing ‘metal salt’ excipients should be thoroughly investigated because these excipients
41
42 have the capability of creating acidic or basic microenvironment which potentially affects co-
43
44 crystal stability. Some excipients include calcium stearate (lubricant), sodium stearyl fumarate
45 (lubricant), sodium citrate (alkalizing and emulsifying agent) and dicalcium phosphate anhydrate
46
47 (diluent) whose anions can derive a proton transfer from an acidic coformer as they did with
48
49 oxalic acid to form a metal salt and thus mediate co-crystal dissociation.74 Additional similar
50
51
examples include the highly acidic hydroxypropyl methylcellulose acetate succinate and
52 hydroxypropyl methylcellulose phthalate and the weakly basic croscarmellose sodium.45,76
53
54 Co-crystal dissociation in the reported cases was water-mediated. If that is expanded, it will
55
56 be realized that water can be sorbed from the atmosphere, be a part of the formulation or a unit
57
58
59 27 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 28 of 42

1
2
3 process (e.g. wet granulation or film coating) or it can be a part of either the API or the excipient.
4
5 In fact, it has been stated that 30% of APIs exist in hydrate form such as caffeine,
6
7 carbamazepine, and theophylline.49 Dibasic calcium phosphate dihydrate is a diluent that
8
9
contains 20.9% w/w crystalline lattice water which has been shown earlier to facilitate water-
10 mediated co-crystal formation. However, as it contains an ionic content, it may also facilitate co-
11
12 crystal dissociation in susceptible formulations.74 Colloidal silica and silica gel are examples of
13
14 excipients which can sorb water and hence they might have the capability of preventing water
15
mediated co-crystal dissociation if the formulation contains other salt excipients. On the
16
17 contrary, excipients that can sorb water yet with low adsorption power can do the opposite under
18
19 the same conditions.45 Reaction kinetics and the effect of the nature of these excipients are to be
20
21 considered as it has been reported that their character (crystallinity) can affect their water
22 sorption capability, induced-phase transition and eventually formulation instability.77
23
24 To address the hazard of the co-crystal dissociation caused by excipients, it was proposed
25
26 that absence of anions to accept protons from acidic coformers and absence of metal cations to
27
28
react with acidic coformer anion would be a potential measure. However, the number of acidic
29 coformers, especially among the most frequently used ones is considerable and the small pka
30
31 difference between co-crystal components which aids in such behaviour isn’t amenable to
32
33 change. Thus, considering the use of neutral excipients in such formulations would be a measure
34
to take.43,74
35
36
37
38 3.2 Coformer Replacement and Stoichiometric Conversion
39
40 This represents another challenge that negates co-crystal physical stability in formulations.
41
42 The role of hydrogen bonding in preferential co-crystal formation represents the driving force
43 and the best explanation for such behaviour. Alsirawan and co-workers have considered caffeine
44
45 (CA) with different structurally related dicarboxylic acids (SRD) including [(oxalic acid (OX),
46
47 malonic acid (MO), glutaric acid (GL), and maleic acid (ML)] was incorporated into co-
48
49
crystalline systems of CA: OX 2: 1 (A), CA: MO 2: 1 (B), CA: GL 1: 1 FII (C), CA: GL 1: 1 FI
50 (D), CA: ML 1: 1 (E), and CA: ML 2: 1 (F). Co-crystals were subjected to aqueous (slurry) or
51
52 mechanical (grinding) processing to mimic to various formulation processes. Replacement of the
53
54 acid coformer and change in stoichiometry was detected (Table 4). Lattice energy and Gibb’s
55 free energy were the ascribes to which the stability of the formed co-crystals correlated well
56
57
58
59 28 Environment
60 ACS Paragon Plus
Page 29 of 42 Crystal Growth & Design

1
2
3 (Figure 28).78 Thus, the presence of structurally related components in the formulation might
4
5 lead to co-crystal integrity loss.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21 Figure 28. Illustration of the co-former replacement and stoichiometry conversion of caffeine with different
22 structurally related dicarboxylic acid co-crystals upon dry grinding or aqueous processing. Lattice energy and
23 Gibbs free energy are the main determinants of such behavior. Reproduced with permission from Ref. 78.
24 Copyright © 2016. The American Chemical Society.
25
26 Benzoic acid (preservative) and vanillin (flavoring agent) are examples of excipients that be
27
28 involved in such reactions; they are reported coformers and thus can replace others if they had
29 stronger hydrogen bond propensity with the API. The reported co-crystal between the antifungal
30
31 griseofulvin and the widely used polymer excipient, polyethylene glycol,79 supports this claim.
32
33
34 Table 4. Results of mixing various structurally related dicarboxylic acids (SRD) with caffeine: dicarboxylic acid
35 (CA: DA) co-crystals using slurry and dry grinding (DG).78
36
37 SRD CA: DA Slurry DG CA: DA slurry DG CA: DA slurry DG
38
OX A A A B A A C A A
39
40 MO A A B B B B
41
42 GL A A B B C C
43
44 ML A A B B C C
45
46 NAa A A B B C C
47
OX D A A E A A F A A
48
49 MO B B B B B B
50
51 GL C C C E C C
52
53 ML C C E E E E
54
55 NAa C C E E CA + MLb F
56
57
58
59 29 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 30 of 42

1
2
3 a Co-crystals treated without structurally related dicarboxylic acids (SRDs). b Co-crystal dissociated into its native
4 components. For reference, co-crystals A = CA: OX 2: 1, B = CA: MO 2: 1, C = CA: GL 1: 1 FII, D = CA: GL 1: 1 FI, E = CA: ML 1: 1,
5 and F = CA: ML 2: 1.
6
7
8
9 3.3 Tendency of Highly Soluble Co-crystals to Less Soluble Parent Drug Crystals
10
11 during Dissolution
12
13 It was the challenge which brought attention to co-crystal formulations in the first place.50
14
15 The formulation challenge lies in having a suitable one that hinders such phase change to
16 preserve the solubility advantage of co-crystals. Such stabilization can be either thermodynamic
17
18 through depressing supersaturation level or kinetic through hindering nucleation and crystal
19
20 growth rate. Polymers have been used for such purpose, they impart kinetic stabilization through
21
specific interactions with the API co-crystal. Hydroxypropyl cellulose, polyvinylpyrrolidone,
22
23 polyethylene glycol and methylcellulose acetate succinate have been studied for that and showed
24
25 promising results as mentioned in the reported co-crystal formulations. Surfactants play a vital
26
27 role in the thermodynamic stabilization and solubilization of the co-crystals in the aqueous media
28 through the formation of micelles and prevention of the phase transformation.17 Sometimes, a
29
30 combination of surfactant and polymer may be used to achieve the desired supersaturation level
31
32 and the solubility advantage of co-crystals. Thus, the actual challenge remains in selecting the
33
34
appropriate excipient(s) and their ratio, which has also been explored through a better
35 understanding of the physicochemical properties of co-crystals and their behaviour in solution.
36
37 Rational approaches for excipients behaviour were based on all these factors and applied
38
39 successfully as discussed.
40
41
42
43 4. Beyond Co-crystals Formulation Challenges
44
45 4.1 Screening
46
Before getting into the formulation stage suitable coformer should be selected. Where only
47
48 12 acidic or basic counterions are typically screened for API salt formation,18 about 3000
49
50 compounds represent potential co-crystal formers. 2000 compounds constitute the generally
51
52 recognized as safe (GRAS)80 list with additional 1000 compounds that are considered safe food
53 additives from the 3000 compounds database of Everything Added to Food in the United States
54
55 (EAFUS).3,81 This is a double-edged sword; the increased co-crystal scope is a benefit, yet it
56
57
58
59 30 Environment
60 ACS Paragon Plus
Page 31 of 42 Crystal Growth & Design

1
2
3 raises a challenge in terms of screening efforts. Fortunately, the need for rational co-crystal
4
5 design and screening protocols will be met by intensive research in this area. Several successful
6
7 approaches have been developed and discussed in many publications. 1,3,4,11,12,17,18, 82-85
8
9
10
4.2 Polymorphism
11 The propensity for polymorphism in co-crystals has been an interest and debate subject.86-88
12
13 Previously it was thought that co-crystals are less prone to polymorphism and can be used to
14
15 minimize this phenomenon.3 In 2004, in Almarsson and Zaworotko article, it was reported that
16
17
“there may be opportunity to reduce the practical extent of polymorphism of drug compounds
18 specifically by co-crystal formation although there may be exceptions.’’6 In a review article,
19
20 Aitipamula et al., was reported that 114 polymorphic co-crystals were known from the
21
22 Cambridge Structural Database, however, those data couldn’t lead to generalization of co-crystal
23
polymorphism as that was outside the scope of that study.89 These co-crystals reached 150
24
25 according to recent literature and still increasing.90
26
27
28
29 Both nonionized and zwitterionic tautomers of piroxicam can exist in its 1: 1 co-crystal with
30 4-hydroxybenzoic acid, resulting in having two polymorphic forms of this co-crystal each with
31
32 distinct properties.91 Thus, polymorphism of co-crystals can be seen from the perspective of
33
34 offering additional opportunities to alter properties, enhancing marketed formulations and
35
36
protecting patents. On the other hand, upon conducting a systemic polymorphic screening on
37 many co-crystals, no polymorphs were observed. That comes with the suggestion of using co-
38
39 crystals to “cure polymorphism’’.1, 3, 82 At the end, it is as McCrone stated in 1965, “In general,
40
41 the number of forms known for that compound is proportional to the time and money spent in
42
research on that compound”.92
43
44
45
46 4.3 Scale up
47
48 The traditional methods for processing co-crystals are faced with several limitations and
49
50 scalability is an essential one. Solution-based methods are challenged by the liability of the less
51 soluble component to supersaturate and crystallize first. While the high mechanical stress and
52
53 difficulty of achieving homogenous mix represent the main obstacles for large-scale processing
54
55 by grinding method. However, this challenge as in screening case has been faced by many
56
57
58
59 31 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 32 of 42

1
2
3 existing and innovative technologies such as resonant acoustic mixing, hot melt extrusion
4
5 (HME), supercritical fluid technology (SCF), spray drying and others. Furthermore, some
6
7 techniques have been facilitated by process analytical technologies (PAT) introducing of robust
8
9
processes for large-scale production of co-crystals.3, 17,82
10
11 4.4 Establishing an In Vitro-In Vivo Correlation (IVIVC)
12
13 Reduction of development time and formulation optimization offered by IVIVC is an
14
15 essential advantage that co-crystals have difficulty to obtain. The challenge of correlating co-
16
17
crystals in-vitro testing to their in-vivo performance was attributed to the change in their
18 solubility along the varying gastrointestinal tract conditions due to the presence of endogenous
19
20 surfactants, lipids, and pH media.17 It can be solved by studying developed co-crystals behaviour
21
22 in the different pHs. Co-crystals behaviour in solution has been investigated and that can be
23
taken as a starting point.82
24
25 Failure of co-crystal IVIVC was also reasoned by the improper selection of in-vitro
26
27 dissolution conditions due to the fact of being a supersaturating drug delivery system.93
28
29 Amorphous solid dispersions (ASDs) are another supersaturating system whose marketed based
30 products were recommended by United States Pharmacopeia (USP) and US-FDA to be tested
31
32 under non-sink dissolution conditions. Thus, for co-crystals, it was suggested that knowledge
33
34 generated for ASDs can be extrapolated to them and the non-sink dissolution conditions, along
35
36
with the use of bio-relevant media can be exploited to solve the co-crystals IVIVC challenge.
37 However, it was stated that additional scientific understanding is necessary to validate the
38
39 usefulness of this approach.3, 15
40
41
42 5. Conclusions
43
Co-crystals are long known yet recently applied molecular entities to modify various
44
45 physicochemical and pharmacokinetic properties of drug substances. Their advantageous impact
46
47 made their use in pharmaceutical products to be considered as a part of the selection toolbox
48
49 along with salts. However, to take these novel molecular entities from bench to bed-side, they
50 have to be incorporated into suitable formulations. Research in co-crystals has been focusing
51
52 mainly at molecular level on their design to tailor a predetermined property without considering
53
54 the formulation part which is crucial in the translational development of medicines. Although
55
56
what applies to pharmaceutical formulations in general is to be encountered with the co-crystals,
57
58
59 32 Environment
60 ACS Paragon Plus
Page 33 of 42 Crystal Growth & Design

1
2
3 yet there are special challenges posed with co-crystalline materials. Some are co-crystal
4
5 dissociation in formulation, coformer replacement and stoichiometric conversion and the
6
7 tendency of highly soluble co-crystals to convert to the less soluble parent drug crystal during
8
9
dissolution. These to be counted with other general challenges limiting co-crystals translation
10 into pharmaceutical products such as polymorphism, scale-up and difficulty of establishing
11
12 IVIVC.
13
14
15
Understanding different excipients, their behaviour related to gastrointestinal physiology and
16
17 their effect on the product performance needs to be first investigated through statistically sound
18
19 experiments to aid in developing a rationale formulation. Depakote® is a marketed drug of
20
21 sodium valproate-valproic acid co-crystal, for years it hasn’t been recognized as a co-crystal and
22 yet was produced as normal tablet formulation.3 Entresto® (valsartan- sacubitril)94 and Suglat®
23
24 (iprogliflozin-L-proline)95 are recently approved co-crystal drug products. These three with other
25
26 examples proves that addressing the various challenges associated with the co-crystalline
27
28
pharmaceutical product is not a tremendous obstacle to jump over, it is only a matter of rationale
29 thinking approaches to be taken.
30
31
32 Further avenues to consider include but not limited to theoretical methods for the prediction of
33
34
co-crystal formation could be equipped for investigating their behavior in the formulation blend
35 and predicting the possibility of new phases formation within the same mixture. Additionally,
36
37 the various process analytical technology (PAT) tools would serve in monitoring co-crystals
38
39 integrity throughout various production stages.
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 33 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 34 of 42

1
2
3 AUTHOR INFORMATION
4
5
6 Corresponding Author
7
8
9 Venu R. Vangala
10
11
12 *E-mail: V.G.R.Vangala@bradford.ac.uk;
13
14
15 Phone: 44 1274236116.
16
17
18
19 ORCID ID: orcid.org/0000-0002-0836-2052
20
21
22
23
24 Author Contributions
25
26
27 The manuscript was written through contributions of all authors. All authors have given approval
28
29 to the final version of the manuscript. ‡These authors contributed equally. (match statement to
30
31 author names with a symbol)
32
33
34
35
36
37
Notes
38
39
40 Any additional relevant notes should be placed here.
41
42
43
44
45
46 ACKNOWLEDGMENTS
47
48 Venu R. Vangala thanks Prof. Gautam R. Desiraju for inspiring discussions on Molecular
49
50 Crystals and Co-crystals. Malaz A. E. Yousef acknowledges Dr. Huda Osman for being the
51
52
53
source of inspiration in the Pharmaceutical Research. We thank Prof Anant Paradkar for helpful
54
55 discussion on pharmaceutical formulations.
56
57
58
59 34 Environment
60 ACS Paragon Plus
Page 35 of 42 Crystal Growth & Design

1
2
3 REFERENCES
4
5
6 1. Bolla, G.; Nangia, A., Pharmaceutical cocrystals: walking the talk. Chem. Commun.
7 2016, 52, 8342-8360.
8 2. Aitipamula, S.; Chow, P. S.; Tan, R. B. H., Structural, spectroscopic and thermal
9 analysis of cocrystals of carbamazepine and piracetam with hydroquinone. J. Chem. Crystallogr.
10 2011, 41, 1604-1611.
11
3. Duggirala, N. K.; Perry, M. L.; Almarsson, Ö.; Zaworotko, M. J., Pharmaceutical
12
13
cocrystals: along the path to improved medicines. Chem. Commun. 2016, 52, 640-655.
14 4. Bunn, C. W., Adsorption, oriented overgrowth and mixed crystal formation. Proc. Roy.
15 Soc.(London), Ser. Abt A 1933, 141, 567-593.
16 5. Wang, G.; Hu, W.-B.; Zhao, X.-L.; Liu, Y. A.; Li, J.-S.; Jiang, B.; Wen, K.,
17 Engineering a pillar [5] arene-based supramolecular organic framework by a co-crystallization
18 method. Dalton Trans. 2018, 47, 5144-5148.
19
6. Etter, M. C., Encoding and decoding hydrogen-bond patterns of organic compounds. Acc.
20
21 Chem. Res. 1990, 23, 120-126.
22 7. Desiraju, G. R., Supramolecular synthons in crystal engineering—a new organic
23 synthesis. Angew. Chem. Int. Ed. Engl. 1995, 34, 2311-2327.
24 8. Almarsson, Ö.; Zaworotko, M. J., Crystal engineering of the composition of
25 pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved
26 medicines? Chem. Commun. 2004, 1889-1896.
27
28
9. https://www.gpo.gov/fdsys/pkg/FR-2011-12-02/pdf/2011-31022.pdf.
29 10. https://www.fda.gov/downloads/Drugs/Guidances/UCM516813.pdf.
30 11. https://www.fda.gov/downloads/Drugs/Guidances/UCM281764.pdf.
31 12. Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A.
32 R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.; Ghogale, P. P.; Ghosh, S.;
33
Goswami, P. K.; Goud, N. R.; Jetti, R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.;
34
35 Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri, V.; Ramanan, A.;
36 Rajamannar, T.; Reddy, C. M.; Rodriguez-Hornedo, N.; Rogers, R.; Row, T. N. G.; Sanphui, P.;
37 Shan, N.; Shete, G.; Singh, A.; Sun, C. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Thaper,
38 R. K.; Thomas, S. P.; Tothadi, S.; Vangala, V. R.; Variankaval, N.; Vishweshwar, P.; Weyna, D.
39
40 R.; Zaworotko, M. J. Polymorphs, salts, and cocrystals: what’s in a name? Cryst. Growth Des.
41 2012, 12, 2147-2152.
42 13.
43 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/07/WC500
44
170467.pdf.
45
46 14. Seddon, K. R.; Zaworotko, M., Crystal Engineering: The Design and Application of
47 Functional Solids. Springer Science & Business Media: 1999; Vol. 539.
48 15. Berry, D. J.; Steed, J. W., Pharmaceutical cocrystals, salts and multicomponent systems;
49 intermolecular interactions and property based design. Adv. Drug Delivery Rev. 2017.
50 16. Aitipamula, S.; Vangala, V. R., X-ray crystallography and its role in understanding the
51 physicochemical properties of pharmaceutical cocrystals. J. Indian Inst. Sci. 2017, 97, 227-243.
52
17. Kale, D. P.; Zode, S. S.; Bansal, A. K., Challenges in translational development of
53
54 pharmaceutical Cocrystals. J. Pharm. Sci. 2017, 106, 457-470.
55 18. Jones, W.; Motherwell, W. D. S.; Trask, A. V., Pharmaceutical cocrystals: an emerging
56 approach to physical property enhancement. MRS Bull. 2006, 31, 875-879.
57
58
59 35 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 36 of 42

1
2
3 19. Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.;
4
5
Guzmán, H. R.; Almarsson, Ö., Crystal engineering of novel cocrystals of a triazole drug with 1,
6 4-dicarboxylic acids. J. Am. Chem. Soc 2003, 125, 8456-8457.
7 20. Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.; Stahly, B. C.; Stahly, G.
8 P., Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic
9 acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric
10 acids. J. Am. Chem. Soc. 2004, 126, 13335-13342.
11
21. Mir, Niyaz A.; Dubey, Ritesh; Desiraju, Gautam R. Strategy and methodology in the
12
13
synthesis of multicomponent molecular solids: The quest for higher cocrystals, Acc. Chem. Res.,
14 2019, 52, 2210-2220.
15 22. Devogelaer, J. J.; Meekes, H.; Vlieg, E.; de Gelder, R. Cocrystals in the Cambridge
16
Structural Database: A network approach, Acta Crystallogr., Sec B. Struct. Sci. 2019, 75, 371-
17
18 383.
19 23. Kavanagh, O. N.; Croker, D. M.; Walker, G. M.; Zaworotko, M. J. Pharmaceutical
20
21 cocrystals: from serendipity to design to application, Drug Discovery Today, 2019, 24, 796-804
22 24. Aitipamula, S.; Vangala, V. R.; Chow, P. S.; Tan, R. B. H., Cocrystal hydrate of an
23 antifungal drug, griseofulvin, with promising physicochemical properties. Cryst. Growth Des.
24 2012, 12, 5858-5863.
25 25. Goud, N. R.; Khan, R. A.; Nangia, A., Modulating the solubility of sulfacetamide by means
26 of co-crystals. CrystEngComm 2014, 16 (26), 5859-5869.
27
26. Shan, N.; Perry, M. L.; Weyna, D. R.; Zaworotko, M. J., Impact of pharmaceutical
28
29 cocrystals: the effects on drug pharmacokinetics. Expert Opin. Drug Metab. Toxicol. 2014, 10,
30 1255-1271.
31 27. Weyna, D. R.; Cheney, M. L.; Shan, N.; Hanna, M.; Zaworotko, M. J.; Sava, V.;
32 Song, S.; Sanchez-Ramos, J. R., Improving solubility and pharmacokinetics of meloxicam via
33 multiple-component crystal formation. Mol. Pharmaceutics 2012, 9, 2094-2102.
34 28. Banik, M.; Gopi, S. P.; Ganguly, S.; Desiraju, G. R., Cocrystal and salt forms of
35
36
furosemide: solubility and diffusion variations. Cryst. Growth Des. 2016, 16, 5418-5428.
37 29. Yan, Y.; Chen, J.-M.; Lu, T.-B., Simultaneously enhancing the solubility and
38 permeability of acyclovir by crystal engineering approach. CrystEngComm 2013, 15, 6457-6460.
39 30. Krishna, G. R.; Shi, L.; Bag, P. P.; Sun, C. C.; Reddy, C. M., Correlation among crystal
40 structure, mechanical behavior, and tabletability in the co-crystals of vanillin isomers. Cryst.
41 Growth Des. 2015, 15, 1827-1832.
42
31. Bag, P. P.; Chen, M.; Sun, C. C.; Reddy, C. M., Direct correlation among crystal
43
44 structure, mechanical behaviour and tabletability in a trimorphic molecular compound.
45 CrystEngComm 2012, 14, 3865-3867.
46 32. Chow, S. F.; Chen, M.; Shi, L.; Chow, A. H. L.; Sun, C. C., Simultaneously improving
47 the mechanical properties, dissolution performance, and hygroscopicity of ibuprofen and
48 flurbiprofen by cocrystallization with nicotinamide. Pharm. Res. 2012, 29, 1854-1865.
49 33. Karki, S.; Friščić, T.; Fabian, L.; Laity, P. R.; Day, G. M.; Jones, W., Improving
50
mechanical properties of crystalline solids by cocrystal formation: new compressible forms of
51
52 paracetamol. Adv. Mater. 2009, 21, 3905-3909.
53 34. Vangala, V. R.; Chow, P. S.; Tan, R. B. H., Characterization, physicochemical and
54 photo-stability of a co-crystal involving an antibioticdrug, nitrofurantoin, and 4-hydroxybenzoic
55 acid. CrystEngComm 2011, 13, 759-762.
56
57
58
59 36 Environment
60 ACS Paragon Plus
Page 37 of 42 Crystal Growth & Design

1
2
3 35. Vangala, V. R.; Chow, P. S.; Tan, R. B. H., Co-crystals and co-crystal hydrates of the
4
5
antibiotic nitrofurantoin: structural studies and physicochemical properties. Crystal Growth &
6 Design 2012, 12, 5925-5938.
7 36. Geng, N.; Chen, J.-M.; Li, Z.-J.; Jiang, L.; Lu, T.-B., Approach of co-crystallization to
8 improve the solubility and photostability of tranilast. Cryst. Growth Des. 2013, 13, 3546-3553.
9 37. Zhu, B.; Wang, J.-R.; Zhang, Q.; Mei, X., Improving dissolution and photostability of
10 vitamin K3 via cocrystallization with naphthoic acids and sulfamerazine. Cryst. Growth Des.
11
2015, 16, 483-492.
12
13
38. Yu, Q.; Yan, Z.; Bao, J.; Wang, J.-R.; Mei, X., Taming photo-induced oxidation
14 degradation of dihydropyridine drugs through cocrystallization. Chem. Commun. 2017, 53,
15 12266-12269.
16 39. Teraoka, R.; Fukami, T.; Furuishi, T.; Nagase, H.; Ueda, H.; Tode, C.; Yutani, R.; Kitagawa,
17
18 S.; Sakane, T. Improving the solid-state photostability of furosemide by its cocrystal formation,
19 Chem. Pharm. Bull. 2019, 67, 940-944.
20 40. Sanphui, P.; Bolla, G.; Nangia, A.; Chernyshev, V., Acemetacin cocrystals and salts:
21
22 structure solution from powder X-ray data and form selection of the piperazine salt. IUCrJ 2014,
23 1, 136-150.
24 41. Babu, N. J.; Sanphui, P.; Nangia, A., Crystal engineering of stable temozolomide
25
cocrystals. Chem.–Asian J. 2012, 7, 2274-2285.
26
27
42. Sun, C. C., Cocrystallization for successful drug delivery. Expert Opin. Drug Delivery
28 2013, 10, 201-213.
29 43. Vandecruys, R.; Peeters, J.; Verreck, G.; Brewster, M. E., Use of a screening method to
30 determine excipients which optimize the extent and stability of supersaturated drug solutions and
31 application of this system to solid formulation design. Int. J. Pharm. 2007, 342, 168-175.
32 44. Aulton, M. E.; Taylor, K. M. G., Aulton's Pharmaceutics E-Book: The Design and
33
Manufacture of Medicines. Elsevier Health Sciences: 2017.
34
35 45. Rowe, R. C.; Sheskey, P. J.; Owen, S. C., Handbook of Pharmaceutical Excipients.
36 Pharmaceutical press London: 2006; Vol. 6.
37 46. Bak, A.; Gore, A.; Yanez, E.; Stanton, M.; Tufekcic, S.; Syed, R.; Akrami, A.; Rose,
38 M.; Surapaneni, S.; Bostick, T., The co-crystal approach to improve the exposure of a water-
39 insoluble compound: AMG 517 sorbic acid co-crystal characterization and pharmacokinetics. J.
40 Pharm. Sci. 2008, 97, 3942-3956.
41
42
47. Kaushal, A. M.; Vangala, V. R.; Suryanarayanan, R., Unusual effect of water vapor
43 pressure on dehydration of dibasic calcium phosphate dihydrate. J. Pharm. Sci. 2011, 100, 1456-
44 1466.
45 48. Arora, K. K.; Tayade, N. G.; Suryanarayanan, R., Unintended water mediated cocrystal
46 formation in carbamazepine and aspirin tablets. Mol. Pharmaceutics 2011, 8, 982-989.
47 49. Arora, K. K.; Thakral, S.; Suryanarayanan, R., Instability in theophylline and
48
carbamazepine hydrate tablets: Cocrystal formation due to release of lattice water. Pharm. Res.
49
50
2013, 30, 1779-1789.
51 50. Childs, S. L.; Kandi, P.; Lingireddy, S. R., Formulation of a danazol cocrystal with
52 controlled supersaturation plays an essential role in improving bioavailability. Mol.
53 Pharmaceutics 2013, 10, 3112-3127.
54
55
56
57
58
59 37 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 38 of 42

1
2
3 51. Venczel, M.; Szvoboda, I.; Podányi, B.; Valente, D.; Menegotto, J. Pintye-Hódi, K.; Ujhelyi,
4
5 G. Formulation possibilities of a weak base with a narrow solubility range, Cryst. Growth Des.
6 2012, 12, 1101-1110.
7 52. Smet, L. D.; Saerens, L.; Beer, T. D.; Carleer, R.; Adriaensens, P.; Bocxlaer, J. V.; Vervaet,
8 C; Remon, J. P. Formulation of itraconazole nanococrystals and evaluation of their
9
10
bioavailability in dogs, Eur. J. Pharm. Biopharm. 2014, 87, 107–113.
11 53. Matteo D'este, M.; Renier, D. Viscoelastic gels as novel fillers, U.S. Patent 0190644 A1,
12 2012.
13 54. Brittain, H. G.; Felice, Philip V. Intravenous formulation with water-soluble cocrystals of
14
15
acetylsalicylic acid and theanine, U.S. Patent 0190655 A1, 2012.
16 55. Greenblatt, R. B.; Dmowski, W. P.; Mahesh, V. B.; Scholer, H. F., Clinical studies with
17 an antigonadotropin--Danazol. Fertility and Sterility 1971, 22, 102-112.
18 56. Kaukonen, A. M.; Boyd, B. J.; Charman, W. N.; Porter, C. J. H., Drug solubilization
19 behavior during in vitro digestion of suspension formulations of poorly water-soluble drugs in
20 triglyceride lipids. Pharm. Res. 2004, 21, 254-260.
21
22
57. Sunesen, V. H.; Vedelsdal, R.; Kristensen, H. G.; Christrup, L.; Müllertz, A., Effect of
23 liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug.
24 Eur. J. Pharm. Sci. 2005, 24, 297-303.
25 58. Albani, F.; Riva, R.; Baruzzi, A., Carbamazepine clinical pharmacology: a review.
26 Pharmacopsychiatry 1995, 28, 235-244.
27 59. Ullah, M.; Raza Shah, M.; Asad, H. B.; Hassham, M.; Farid Hasan, S. M.; Hussain, I.,
28
Improved in vitro and in vivo performance of carbamazepine enabled by using a succinic acid
29
30
cocrystal in a stable suspension formulation. Pak. J. Pharm. Sci. 2017, 30, 2139-2145.
31 60. Zakeri-Milani, P.; Barzegar-Jalali, M.; Azimi, M.; Valizadeh, H., Biopharmaceutical
32 classification of drugs using intrinsic dissolution rate (IDR) and rat intestinal permeability. E.
33 Pharm. Biopharm 2009, 73, 102-106.
34 61. Ullah, M.; Hussain, I.; Sun, C. C., The development of carbamazepine-succinic acid
35 cocrystal tablet formulations with improved in vitro and in vivo performance. Drug Dev. Ind.
36
Pharm. 2016, 42, 969-976.
37
38 62. Habeeb, A. G.; Praveen Rao, P. N.; Knaus, E. E., Design and synthesis of celecoxib and
39 rofecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of
40 sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere. J Med. Chem. 2001,
41 44, 3039-3042.
42 63. Hageman, M. J.; He, X.; Kararli, T. T.; Mackin, L. A.; Miyake, P. J.; Rohrs, B. R.;
43 Stefanski, K. J., Solid-state form of celecoxib having enhanced bioavailability. Google Patents:
44
45
2005.
46 64. Ferro, L. J., Polymorphic crystalline forms of celecoxib. United States Patent 7476744
47 2000.
48 65. Lu, G. W.; Hawley, M.; Smith, M.; Geiger, B. M.; Pfund, W., Characterization of a
49 novel polymorphic form of celecoxib. J. Pharm. Sci. 2006, 95, 305-317.
50 66. Remenar, J. F.; Peterson, M. L.; Stephens, P. W.; Zhang, Z.; Zimenkov, Y.; Hickey,
51
M. B., Celecoxib: nicotinamide dissociation: using excipients to capture the cocrystal's potential.
52
53
Mol. Pharmaceutics 2007, 4, 386-400.
54 67. Rogers, J.; Kirby, L. C.; Hempelman, S. R.; Berry, D. L.; McGeer, P. L.; Kaszniak, A.
55 W.; Zalinski, J.; Cofield, M.; Mansukhani, L.; Willson, P., Clinical trial of indomethacin in
56 Alzheimer's disease. Neurology 1993, 43, 1609-1609.
57
58
59 38 Environment
60 ACS Paragon Plus
Page 39 of 42 Crystal Growth & Design

1
2
3 68. Matta, J. M.; Siebenrock, K. A., Does indomethacin reduce heterotopic bone formation
4
5
after operations for acetabular fractures? A prospective randomised study. J. Bone Jt. Surg. 1997,
6 79, 959-963.
7 69. Jung, M. S.; Kim, J. S.; Kim, M. S.; Alhalaweh, A.; Cho, W.; Hwang, S. J.; Velaga, S.
8 P., Bioavailability of indomethacin-saccharin cocrystals. J. Pharm. Pharmacol 2010, 62, 1560-
9 1568.
10 70. Good, D. J.; Rodríguez-Hornedo, N., Cocrystal eutectic constants and prediction of
11
solubility behavior. Cryst. Growth Des. 2010, 10, 1028-1032.
12
13
71. Alhalaweh, A.; Ali, H. R. H.; Velaga, S. P., Effects of polymer and surfactant on the
14 dissolution and transformation profiles of cocrystals in aqueous media. Cryst. Growth Des. 2013,
15 14, 643-648.
16 72. Swedberg, K.; Komajda, M.; Böhm, M.; Borer, J. S.; Ford, I.; Dubost-Brama, A.;
17 Lerebours, G.; Tavazzi, L.; investigators, S., Ivabradine and outcomes in chronic heart failure
18 (SHIFT): a randomised placebo-controlled study. Lancet 2010, 376, 875-885.
19
73. Sládková, V.; Dammer, O.; Sedmak, G.; Skořepová, E.; Kratochvíl, B., Ivabradine
20
21 hydrochloride (S)-mandelic acid co-crystal: In situ preparation during formulation. Crystals
22 2017, 7, 13-29.
23 74. Duggirala, N. K.; Vyas, A.; Krzyzaniak, J. F.; Arora, K. K.; Suryanarayanan, R.,
24 Mechanistic insight into caffeine–oxalic cocrystal dissociation in formulations: Role of
25 excipients. Mol. Pharmaceutics 2017, 14, 3879-3887.
26 75. Koranne, S.; Sahoo, A.; Krzyzaniak, J. F.; Luthra, S.; Arora, K. K.; Suryanarayanan,
27
28
R., Challenges in transitioning cocrystals from bench to bedside: Dissociation in prototype drug
29 product environment. Mol. Pharmaceutics 2018, 15, 3297-3307.
30 76. Qiu, Y.; Chen, Y.; Zhang, G. G. Z.; Yu, L.; Mantri, R. V., Developing Solid Oral
31 Dosage Forms: Pharmaceutical Theory and Practice. Academic press: 2016.
32 77. Airaksinen, S.; Karjalainen, M.; Kivikero, N.; Westermarck, S.; Shevchenko, A.;
33 Rantanen, J.; Yliruusi, J., Excipient selection can significantly affect solid-state phase
34
transformation in formulation during wet granulation. AAPS PharmSciTech 2005, 6, E311-E322.
35
36
78. Alsirawan, M. H. D. B.; Vangala, V. R.; Kendrick, J.; Leusen, F. J. J.; Paradkar, A.,
37 Coformer replacement as an indicator for thermodynamic instability of cocrystals: competitive
38 transformation of caffeine: dicarboxylic acid. Cryst. Growth Des. 2016, 16, 3072-3075.
39 79. Zhong, Z.; Guo, C.; Chen, L.; Xu, J.; Huang, Y., Co-crystal formation between poly
40 (ethylene glycol) and a small molecular drug griseofulvin. Chem. Commun. 2014, 50, 6375-
41 6378.
42
80. Burdock, G. A.; Carabin, I. G., Generally recognized as safe (GRAS): history and
43
44 description. Toxicol. Lett. 2004, 150, 3-18.
45 81. Food and Drug, A., Everything added to food in the United States (EAFUS). 2008.
46 82. Schultheiss, N.; Newman, A., Pharmaceutical cocrystals and their physicochemical
47 properties. Cryst. Growth Des. 2009, 9, 2950-2967.
48 83. Grecu, T.; Hunter, C. A.; Gardiner, E. J.; McCabe, J. F., Validation of a computational
49 cocrystal prediction tool: comparison of virtual and experimental cocrystal screening results.
50
51
Cryst. Growth Des. 2013, 14, 165-171.
52 84. Karimi-Jafari, M.; Padrela, L.; Walker, G. M.; Croker, D. M., Creating cocrystals: A
53 review of pharmaceutical cocrystal preparation routes and applications. Cryst. Growth Des.
54 2018, 18, 6370-6387.
55
56
57
58
59 39 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 40 of 42

1
2
3 85. Bag, P. P.; Patni, M.; Reddy, C. M., A kinetically controlled crystallization process for
4
5
identifying new co-crystal forms: fast evaporation of solvent from solutions to dryness.
6 CrystEngComm 2011, 13, 5650-5652.
7 86. Vangala, V. R.; Chow, P. S.; Schreyer, M.; Lau, G.; Tan, R. B. H., Thermal and in situ
8 X-ray diffraction analysis of a dimorphic co-crystal, 1: 1 caffeine–glutaric acid. Cryst. Growth
9 Des. 2016, 16, 578-586.
10 87. Chow, P. S.; Lau, G.; Ng, W. K.; Vangala, V. R., Stability of pharmaceutical cocrystal
11
during milling: A case study of 1: 1 caffeine–glutaric acid. Cryst. Growth Des. 2017, 17, 4064-
12
13
4071.
14 88. Pagire, S. K.; Jadav, N.; Vangala, V. R.; Whiteside, B.; Paradkar, A., Thermodynamic
15 investigation of carbamazepine-saccharin co-crystal polymorphs. J. Pharm. Sci. 2017, 106,
16 2009-2014.
17 79. Aitipamula, S.; Chow, P. S.; Tan, R. B. H., Polymorphism in cocrystals: a review and
18 assessment of its significance. CrystEngComm 2014, 16 (17), 3451-3465.
19
90. Mnguni, M. J.; Michael, J. P.; Lemmerer, A. Binary polymorphic cocrystals_ an update
20
21 on the available literature in the Cambridge Structural Database, including a new polymorph of
22 the pharmaceutical 1_1 cocrystal theophylline-3,4-dihydroxybenzoic acid. Acta Crystallogr.,
23 Sect. C: Struct. Chem. 2018, C74, 715–720.
24 91. Childs, S. L.; Hardcastle, K. I., Cocrystals of piroxicam with carboxylic acids. Cryst.
25 Growth Des. 2007, 7, 1291-1304.
26 92. Desiraju, G. R., Crystal engineering: a holistic view. Angew. Chem. Int. Ed. 2007, 46,
27
28
8342-8356.
29 93. Takano, R.; Takata, N.; Saito, R.; Furumoto, K.; Higo, S.; Hayashi, Y.; Machida, M.;
30 Aso, Y.; Yamashita, S., Quantitative analysis of the effect of supersaturation on in vivo drug
31 absorption. Mol. Pharmaceutics 2010, 7, 1431-1440.
32 94. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm453845.htm.
33 95. https://www.astellas.com/en/news/11351.
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 40 Environment
60 ACS Paragon Plus
Page 41 of 42 Crystal Growth & Design

1
2
3 For Table of Contents Use only
4
5
6
7
8
9
10
Pharmaceutical Co-crystals: Molecules, Crystals,
11
12
13
14 Formulations, Medicines
15
16
17 Malaz A. E. Yousef and Venu R. Vangala*
18
19
20 Centre for Pharmaceutical Engineering Science, School of Pharmacy and Medical Sciences,
21
22
23 University of Bradford, Bradford BD7 1DP, United Kingdom
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 41 Environment
60 ACS Paragon Plus
Crystal Growth & Design Page 42 of 42

1
2
3 Co-crystals emerged as promising solids in positively modifying drug properties. To take co-
4
5 crystals from bench to bed-side, they have to be incorporated into suitable formulations,
6
7 however, the attention paid in this direction is so diminutive. This review spots the light on the
8
9
co-crystal formulations. Further, it highlights the main hurdles encountered with cocrystals
10 formulation and the transformation into viable medicines.
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 42 Environment
60 ACS Paragon Plus