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6 Cocrystals in Pharmaceutical Sciences
(Cmax) and area under the curve (AUC) for the baicalein-nicotinamide
cocrystals were 2.49 and 2.80 times higher, respectively, than the pure drug
[36]. e hydrotropic solubilization of nicotinamide improves the bioavail-
ability of cocrystals as a result of the concurrent improvement in solubility
and dissolution of baicalein. In a pharmacokinetic investigation carried
out on beagle dogs, apixaban-oxalic acid cocrystals demonstrated better
oral bioavailability than pure drugs [30]. Meloxicam-aspirin cocrystals
exhibited a 12-fold increase in onset of action compared to the pure drugs
in rats, as well as higher oral bioavailability [37]. Furthermore, cocrystals
of 6-mercaptopurine, categorized as a BCS class II medicine, with ison-
icotinamide, exhibited faster dissolution and greater oral bioavailability
(168.7%) than the pure drug in rats [29].
1.3.3 Stability Enhancement
Cocrystallization can increase an API’s physical stability, eliminating poly-
morphism concerns such as unwanted phase shis during storage and pro-
cessing. Cocrystals can improve the chemical stability of APIs, shielding
them from deterioration caused by environmental variables such as mois-
ture, heat, and light.
Stability studies are usually conducted throughout the development
of cocrystals, including solution, chemical, and thermal stability, relative
humidity (RH) stress, and photostability. Indomethacin-saccharin cocrys-
tals demonstrated negligible water sorption in RH investigations, and the-
ophylline cocrystals also showed RH stability at varied RH with distinct
coformers (maleic, glutaric, malonic, and oxalic acid) for diverse periods.
e study conrmed an increase in the physical quality and stability of the
drugs, particularly by avoiding hydrate formation [38].
e chemical stability of the cocrystal is usually done using accelerated
stability conditions to investigate whether there are any changes or chem-
ical deteriorations in the formulation. ere were very few publications
on cocrystals’ chemical stability. Cocrystals of glutaric with API exhibited
no degradation and high physical and chemical stability under thermal
stress and RH for 2 months [39]. Indomethacin-saccharin cocrystals also
demonstrated negligible moisture sorption during stability studies, and no
separation or conversion arose under trial circumstances [40].
Solution stability is a crucial parameter for cocrystal growth and it pro-
vides a better knowledge of cocrystal behavior in the release medium [41].
A study of the stability of carbamazepine cocrystals in water showed that
cocrystals made with poorly water-soluble coformers stayed as such in the
solution for 20 to 48 hours, whereas cocrystals with highly water-soluble
Pharmaceutical Cocrystals 7
coformers transformed to dihydrates [42]. Caeine/oxalic acid cocrystals
demonstrated superior stability at all RH up to 98% for 7 days with no
noticeable change occurring in the physical structure compared to when
the materials were suspended in aqueous medium for two days at ambient
temperature [43]. Carbamazepine and saccharine cocrystals suspended in
equal parts in water for 24 hours showed good stability as indicated by
the presence of only the cocrystals in the solution, and no other form was
discovered [44]. Nitrofurantoin cocrystals prepared with various coform-
ers showed greater photostability than pure drug and physical mixtures.
Cocrystallization can minimize the photodegradation of light-sensitive
drugs since all cocrystals demonstrated little deterioration (<3%) aer 168
hours [45].
1.3.4 Taste Masking and Palatability
Taste-masking methods are utilized to mask or overcome the bitter or
unpleasant taste of active medicinal constituents/drugs, resulting in
patient acceptance and compliance, particularly for pediatric and geriatric
patients [46]. Sweetener-based coformers have been used to mask the taste
of bitter drugs. e coformer interacts with medicinal molecules to pro-
duce single-phase crystalline assemblies via intermolecular interactions
[47]. An innovative cocrystal of paracetamol and trimethylglycine with
a sweeter taste enhanced compressibility, and dissolution rate than pure
paracetamol has been reported [48]. Likewise, the sweetness of theophyl-
line was boosted by saccharin by producing a cocrystal, thereby enhancing
stability and assuring continuous drug release [49]. However, increased
sweetness does not always indicate excellent masking of bitter taste; rather,
the avor is a mix of bitter and sweet, which could be of inferior quality.
Ogata et al. discovered that certain acids that are not sweeteners can have
benecial eects on the taste masking of bitter drugs like propiverine [50].
Hence, cocrystals can mask the taste of bitter drugs due to the inability
of human taste receptors to register the taste of cocrystals formed from
the molecular aggregation of drug and coformer [51]. As a result, some
coformers, despite their lack of sweetness, may successfully conceal the
bitter taste of medications due to their propensity to form tiny transitory
clusters with drug particles when dissolved in the mouth.
e strongly unpalatable and bitter taste of nevirapine, an antiretroviral
drug, used in newborns and children, particularly in sub-Saharan Africa,
has been masked with the cocrystals using maleic acid, benzoic acid, and
glutaric acid as coformers [51]. e data showed that the taste of the pure
coformer and solution aggregation play essential roles in taste masking.
8 Cocrystals in Pharmaceutical Sciences
1.3.5 Controlled Release
Cocrystals can be designed to alter drug release rates, enabling con-
trolled or sustained release formulations that have improved therapeutic
outcomes. Cocrystallization has been shown as a promising strategy for
producing controlled-release formulations of olaparib, a PARP1/2 inhib-
itor with blockbuster anticancer activity, that have a shorter half-life and
limited dose-limiting toxicity than marketed immediate-release formula-
tions [52]. Sustained-release cocrystals of olaparib with kaempferol and
the cocrystal solvate of olaparib with quercetin showed 21.4% and 18.6%
reduction in the dissolution rate, respectively, in comparison to the origi-
nal drug. Furthermore, the cocrystals exhibited increased pharmacologi-
cal activity and inhibited ovarian cancer cells signicantly more eectively
than the pure drug.
Human insulin has been cocrystallized at predetermined proportions
with octanoyl-Nε-LysB29-human insulin (C8-HI), a lipophilic modi-
ed insulin derivative [53]. e cocrystal mimics the neutral protamine
Hagedorn (NPH) cocrystals generated by human insulin, generally used
as a long-acting insulin element in diabetes treatment. e release rates of
the cocrystal can be controlled, in vitro and in vivo, by altering the quanti-
ties of the two insulin contents. e cocrystal ratio-dependent release rate
provides a successful method to regulate insulin pharmacodynamics, sug-
gesting that a crystalline protein matrix is capable of supporting a chemical
alteration that changes the rate of dissolution of the crystals in an intensely
benecial manner while remaining adequate to maintain the medicinal
quality and the therapeutic eects of the parent drug.
1.3.6 Increased Tabletability
Tabletability denotes a material’s capacity to be converted to a compact.
Tabletability, compatibility, and crystal packing are critical characteristics
in preformulation. Cocrystallization with appropriate coformers can alter
these characteristics to improve the tabletability of poorly compressible
pharmaceutical powders. e tabletability of resveratrol, a poorly com-
pressible drug, has been increased by cocrystallization [54]. Resveratrol
cocrystals with coformers 4-amino benzamide and isoniazid exhibited
improved tabletability, leading to the formation of tablets with acceptable
tensile strength even at low compression pressure.
Cocrystallization can be used to alter the mechanical characteristics of
medicinal compounds. Vanillin isomers cocrystals with the coformer have
demonstrated greater tabletability than single materials [55]. Paracetamol
Pharmaceutical Cocrystals 9
is poorly compressible, and wet granulation which is a tedious process
requiring the use of binders is used to overcome this problem. Studies have
shown that paracetamol cocrystals prepared using caeine as a coformer
using techniques such as solvent evaporation, liquid-assisted grinding, dry
grinding, and the addition of anti-solvent improved the compression and
the mechanical properties of paracetamol tablets [56].
1.3.7 Combination erapy
Cocrystals allow for the formulation of multiple drugs in a unit dos-
age form, facilitating combination therapy and synergistic outcomes.
Cocrystals consisting of two or more active ingredients, generally known
as drug-drug, multi-drug, or multi-API cocrystals, are made feasible by
noncovalent connections between the active drugs, which enables the
drugs to retain their activity [57]. e two or more therapeutically useful
elements are bound in a stoichiometric equilibrium in a single crystal lat-
tice structure where they can interact primarily through nonionic interac-
tions and, on some occasions, through a hybrid interaction with or without
the inclusion of solvate molecules [58].
Furthermore, drug-drug cocrystals provide possible answers to restric-
tions like solubility, stability, and chemical instabilities between the APIs,
which are frequently encountered in standard combination therapy [57].
Table 1.1 presents some multi-drug cocrystals developed to date, as well as
their preparation techniques and uses.
Table 1.1 Drug-drug and nutraceuticals cocrystals developed to date [58].
Drug combination
Method of
preparation Indication Refs
eophylline–
phenobarbital
(2:1)
Distillation Sedative-
hypnotic and
Antiasthmatic
[58]
Sulfadimidine–
aspirin (1:1)
Solvent evaporation NSAID and
Antibacterial
[74]
Sulfadimidine–4-
ASA (1:1)
Antibacterial [74]
eophylline–5-FU
(2:1)
Antiasthmatic and
anticancer
[75]
(Continued)
10 Cocrystals in Pharmaceutical Sciences
Table 1.1 Drug-drug and nutraceuticals cocrystals developed to date [58].
(Continued)
Drug combination
Method of
preparation Indication Refs
Trimethoprim–
sulfadimidine
(1:1, 1:2)
Antibacterial [76, 77]
Trimethoprim–
sulfamethoxy-
pyridazine (1:1)
Heating at boiling
point followed by
instant cooling
Antibacterial [78]
Tetroxoprim–
sulfametrole (1:1)
Cogrinding and
solvent evaporation
Antibacterial [79, 80]
Piracetam–gentisic
acid (1:1)
Co-grinding and
solvent evaporation
Nootropic agent
and NSAID
[81]
Amoxicillin
trihydrate–
potassium
clavulanate (3:7,
5:5, 7:3)
Melting at 50°C for
30 min
Antibacterial and
β-lactamase
inhibitor
[82]
Lamivudine–
zidovudine (1:1)
Solvent evaporation Antiviral [83]
eophylline–
gentisic acid (1:1)
ermal-assisted
solvent evaporation
Antiasthmatic and
NSAID
[84]
Ethenzamide–
gentisic acid (1:1)
Solvent evaporation Both drugs are
NSAIDs, the
latter also has
anti-ageing
properties
[49]
Sulfamethazine–
theophylline (2:1)
Antibacterial and
antiasthmatic
[85]
Meloxicam–aspirin
(1:1)
Solution
crystallization,
solvent and slurry
drop grinding
methods
NSAIDs [37]
(Continued)
Pharmaceutical Cocrystals 11
Table 1.1 Drug-drug and nutraceuticals cocrystals developed to date [58].
(Continued)
Drug combination
Method of
preparation Indication Refs
Isoniazid–4-ASA
(1:1)
Solvent drop grinding Antitubercular
drugs
[86]
Pyrazinamide–4-
ASA (1:1)
Carbamazepine–
salicylic acid (1:1)
Unexpected in
the presence of
moisture
Antiepileptic
and anti-
inammatory
[87]
Pyrazinamide–
diunisal (1:1)
Ball mill grinding Antitubercular
and NSAID
[88]
Curcumin–
pyrogallol (1:1)
Liquid-assisted
manual grinding
Anticancer [83]
Aceclofenac–
paracetamol (1:1)
Various methods NSAIDs [89]
Isoniazid–2-chloro-
4-nitro benzoic
acid (1:1)
Solvent evaporation Antitubercular
and antiviral
compounds
[90]
Piracetam–lithium
chloride (1:1)
Solvent evaporation
and grinding
Nootropic agent
and mood-
stabilizing
agent
[91]
Furosemide–
pentoxifylline
(1:1)
Solvent evaporation Loop diuretic; the
latter is used for
the treatment
of intermittent
claudication
[92]
Pyrimethamine–
carbamazepine
(1:1)
Antimalarial and
antiepileptic
[93]
Pyrimethamine–
theophylline (1:1)
Solvent evaporation Antimalarial and
antiasthmatic
(Continued)
12 Cocrystals in Pharmaceutical Sciences
1.4 Challenges in the Development of Cocrystals
e fundamental problem in developing therapeutic cocrystals is the choice
of appropriate coformers. Given the vast number of potential coformers, it
is necessary to design an approach to screening that can predict the most
probable coformers [59]. e prospective coformers should subsequently
be evaluated experimentally to see whether cocrystals occur [60]. Owing to
the expanded study on the subject of cocrystals over the past few decades,
enough evidence has been amassed to estimate the likely coformers.
Table 1.1 Drug-drug and nutraceuticals cocrystals developed to date [58].
(Continued)
Drug combination
Method of
preparation Indication Refs
Ciprooxacin–
noroxacin (1:1)
Antibacterial [94]
Paracetamol–
indomethacin
and mefenamic
acid (1:1)
NSAIDs [95]
Sildenal–aspirin
(1:1)
Antihypertensive
and NSAID
[96]
Diclofenac and
Diunisal–
eophylline
(1:1)
Solvent evaporation
and Solvent drop
grinding
Antiasthmatic and
NSAID
[97]
Dapsone–
sulfanilamide
avone, luteolin,
caeine and
benzothiazolone
(1:1)
Solution
crystallization
Antileprotic,
antibacterial
and
antioxidants
[98]
Carbamazepine–
ibuprofen
Solution
crystallization
Antiepileptic and
NSAID
[99]
Abbreviations: 4-ASA, 4-aminosalicyic acid; NSAID, Non-steroidal anti-inammatory
agent.
Pharmaceutical Cocrystals 13
Some of the eective methods for screening coformers include hydro-
gen bond propensity, Hansen solubility parameter, Cambridge Structural
Database, pKa rule, and supramolecular synthon approach. However,
there is a need to develop more ecient screening techniques for the fruit-
ful implementation of the use of cocrystals in drug development in the
pharmaceutical sector [61].
A variety of cocrystallization procedures can be employed to screen
cocrystals. Solvent-based cocrystallization procedures present obstacles,
such as the selection of the proper solvent, adjustments in the solubility of
active drug and coformer in the selected solvent (compatible and incom-
patible), concentration eects, and the selection of appropriate cooling
and heating proles [62]. e solid-state grinding approach of screening
cocrystals outperforms solvent-based methods. However, occasionally
phase transitions in medicinal cocrystals occur in cocrystals prepared by
solid-state grinding [63].
e chance of cocrystal separation owing to the contact with other
excipients, the substitution of coformers by excipients, alteration of the
cocrystal stoichiometry, and its transformation to a poorly soluble form
of the parent drug during dissolution needs to be addressed during the
cocrystal preparation [64, 65].
Sometimes, the selected coformers may not generate cocrystals with
appropriate processability, and physical, chemical, and pharmacokinetic
qualities [41]. e obstacles encountered in the production and evaluation
of cocrystals include the formation of hybrids, salts, or solvates, polymor-
phism of cocrystals, and alteration to the less soluble form of the parent
drug [66–68]. In addition, pH, surface active agent concentration, solubil-
ity and dissolution rates, and inherent instability of cocrystals in the solu-
tion phase can hinder the successful formulation [69, 70].
Industrial cocrystallization processes must be scalable, exible, and
environmentally friendly, and the cocrystal quality should not be jeopar-
dized by commercial-scale manufacture. However, there are no recognized
strategies for scaling up the production of medicinal cocrystals. Methods
such as hot-melt extrusion, supercritical uid technologies spray con-
gealing, and spray drying are now being used for commercial scale-up of
cocrystal production. An additional obstacle in the large-scale production
of cocrystals is the reliable regulation of stoichiometry [71] and the lack of
correlation features in vitro and in vivo, which can drastically shorten the
development period [72, 73].
14 Cocrystals in Pharmaceutical Sciences
Table 1.2 Some commercial pharmaceutical cocrystals.
Commercial
name Approval API Coformer Improved property Indi cation Manufacturer References
Suglat
®
Japan 2014 Ipragliozin l-Prolin Stability against
hydrate formation
Diabetes Kotobuki
Pharmaceuticals,
Nishina,
Shizuoka, Japan,
and Astellas
Pharma, Tokyo,
Japan
[100]
Cafcit
®
USFDA
1999
Caeine Citric acid Improved dis solution
behavior
and lower
hygroscopicity
Infantile apnoea Hikma
Pharmaceuticals
Plc, London, UK
[100–102]
Entresto
®
USFDA
2015
Valsartan Sacubitril Improved
pharmacokinetics
and bioavailability
Heart failure Novartis, Basel,
Switzerland
[103, 104]
Lamivudine/
zidovudine
Tev a
®
EMA 2011 Lamivudine Zidovudine Improved solubility,
stability, and
bioavailabilit y
HIV infection Teva Pharma B.V.,
Tel Aviv-Yafo,
Israel
[76, 102,
105]
Steglatro
®
USFDA
2017
Ertugliozin Z-Pyroglutamic acid Improved stability Diabetes Pzer, New York,
USA
[106, 107]
Depakote
®
USFDA
1983
Valproic acid Valproate sodium Improved stabil ity Epilepsy Abbott Laboratories,
Illinois, USA
[100, 108]
(Continued)
Pharmaceutical Cocrystals 15
Table 1.2 Some commercial pharmaceutical cocrystals. (Continued)
Commercial
name Approval API Coformer Improved property Indi cation Manufacturer References
Lexapro
®
USFDA
2002
Escitalopram Oxalate Improved stabil ity
of API
Anxiety and
depression
Allergan Inc.,
Dublin, Ireland
[109]
ESIX-10
®
USFDA
2009
Escitalopram Oxalate Improved stabil ity
of API
Anxiety and
depression
Sag Health Science
Pvt Ltd., New
Delhi, India
[59, 83]
Beta-chlor
®
USFDA
1963
Chloral hydrate Betaine Improved thermal
stability
Sedation Mead Johnson,
Illinois, USA
[100, 110]
Abilify
®
USFDA
2002
Aripiprazole Fumaric acid Improved the
dissolution rate
and solubility
Schizophrenia Otsuka
Pharmaceuticals,
Tokyo, Japan
[111, 112]
Odomzo
®
USFDA
2015
Sonidegib Phosphoric acid Improve its solubility
and bioavailability
Basal cell
carcinoma
Sun Pharma Global,
Mumbai, India
[83, 113,
114]
Mayzent
®
USFDA
2019
Siponimod Fumaric acid Improved
bioavailability and
aqueous solubility
Multiple
sclerosis
Novartis, Basel,
Switzerland
[115, 116]
Seglentis
®
USFDA
2021
Celecoxib Tramadol Improved stability Acute pain Kowa
Pharmaceuticals,
Alabama, USA
[116, 117]
(Continued)