Drug Discovery Today
Volume 00, Number 00
April 2018 REVIEWS

Reviews
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Cyclodextrins as excipients in tablet
formulations
Q1
Jaime Conceição1, Oluwatomide Adeoye2,3, Helena Maria Cabral-Marques2 and
José Manuel Sousa Lobo1
1
UCIBIO – ReQuimTe, Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Oporto, Portugal
2
Research Institute for Medicines (iMed.ULisboa), Department of Galenic Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Universidade de
Lisboa, Lisbon, Portugal
3
Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria

This paper aims to provide a critical review of cyclodextrins as excipients in tablet formulations,
highlighting: (i) the principal pharmaceutical applications of cyclodextrins; (ii) the most relevant
technological aspects in pharmaceutical formulation development; and (iii) the actual regulatory status
of cyclodextrins. Moreover, several illustrative examples are presented. Cyclodextrins can be used as
complexing excipients in tablet formulations for low-dose drugs. By contrast, for medium-dose drugs
and/or when the complexation efficiency is low, the methods to enhance the complexation efficiency
play a key part in reducing the cyclodextrin quantity. In addition, these compounds are used as fillers,
disintegrants, binders and multifunctional direct compression excipients of the tablets.

Introduction
Cyclodextrins (CDs) are cyclic oligosaccharides that are produced
from starch or starch derivatives using CD glycosyltransferase.
These compounds were first isolated by Antoine Villiers in 1891
and they have been recognized as pharmaceutical excipients
because they can form noncovalently bonded inclusion com-
plexes (host–guest complexes) with several drugs either in solution
or
Q2 in the solid state (Fig. 1a) [1]. Regarding the chemical structure,
CDs comprise (a-1-4)-linked a-D-glucopyranose units, have a
lipophilic central cavity and a hydrophilic outer surface, and
are shaped like a truncated cone, bucket-like or doughnut-shaped
Q3 (Fig. 1b) [2].
The three natural CDs are alpha-cyclodextrin (a-CD; alfadex),
beta-cyclodextrin (b-CD; betadex) and gamma-cyclodextrin
(g-CD; gammadex), containing 6, 7 and 8 glucose units, respec-
tively. CD derivatives are divided into three groups, specifically
hydrophilic [for instance, 2-hydroxypropyl-b-CD (HP-b-CD)], hy-
drophobic (for instance, 2,6-di-O-ethyl-b-CD) and ionizable [for
instance, sulfobutyl ether-b-CD (SBE-b-CD)]. CDs are used in the
Corresponding author: Conceição, J. (jmgmconceicao@ff.up.pt)
pharmaceutical industry for different purposes [3,4] such as: (i) to
enhance the aqueous solubility, dissolution and bioavailability of
drugs; (ii) to increase drug physicochemical stability and improve
shelf-lives of medicinal products; (iii) to modify drug release site
and/or time profile; (iv) to minimize adverse drug reactions such as
gastrointestinal and ocular irritation; (v) to reduce or eliminate
unpleasant taste and smell; (vi) to prevent drug–drug or drug–
excipient interactions; and (vii) to convert liquid drugs into mi-
crocrystalline or amorphous powders. Additionally, CDs can be
used as drug substances such as sugammadex (Bridion1; Merck
Sharp & Dohme), which is a modified g-CD available in 100 mg/ml
solution for injection. According to the summary of product
characteristics [5], there are two therapeutic indications: (i) for
the reversal of neuromuscular blockade induced by rocuronium or
vecuronium in adults; and (ii) for the pediatric population, sugam-
madex is only recommended for routine reversal of rocuronium-
induced blockade in children and adolescents aged 2–17 years.
All these applications are based on the inclusion-complex-form-
ing ability of CDs. The binding or stability/equilibrium constant
(KC) of an inclusion complex (D-CD) of 1:1 stoichiometry can be
calculated from Eq. (1), where [D-CD], [D] and [CD] are the

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Please cite this article in press as: Conceição, J. et al. Cyclodextrins as excipients in tablet formulations, Drug Discov Today (2018), https://doi.org/10.1016/j.drudis.2018.04.009
 DRUDIS 2221 1–10
REVIEWS
(a)
KC
D + CD CD
Reviews
POST SCREEN
FIGURE 1
(a) The interaction of drug (D) with a cyclodextrin (CD) to form an inclusion complex (D-CD) of 1:1 stoichiometry with a stability/equilibrium constant of KC. (b)
Q14 Chemical structure of the hydroxypropyl-b-cyclodextrin. Adapted, with permission, from Ref. [1].
concentrations of inclusion complex, free drug substance and free
CD, respectively [6]. Slope is the slope of the phase–solubility
profile and S0 is the concentration of drug without CD. For com-
plexes with low-to-mid KC value, binding of drug to plasma
proteins will primarily determine the pharmacokinetics [7]. By
contrast, for complexes with high KC value and low protein
binding significant decrease in distribution volume and enhanced
Q4 excretion of unmetabolized drug are observed [7].
½D  CD Slope
KC ¼ ¼ ð1Þ
½D½CD S0 ð1  SlopeÞ
For 1:1 drug–CD complexes, the complexation efficiency (CE)
can be calculated from Eq. (2) [8].
½D  CD Slope
CE ¼ S0 KC ¼ ¼ ð2Þ
½CD ð1  SlopeÞ
Oral delivery is the most common route for drug administra-
tion. Tablets are solid dosage forms that were discovered in 1843 by
William Brockedon through the publication of British Patent
Number 9977 about ‘‘shaping pills, lozenges and black lead by
Q5 pressure in dies” [9]. This pharmaceutical dosage form is the most
used in the market because it presents high-precision dosing,
chemical, physical and microbiological stability, manufacturing
efficiency and good patient compliance [9,10].
According to the European Pharmacopoeia 9 [11], in force since
January 2017, there are ten types of tablets for oral administration:
(i) uncoated tablets; (ii) coated tablets; (iii) effervescent tablets; (iv)
soluble tablets; (v) dispersible tablets; (vi) orodispersible tablets;
(vii) gastro-resistant tablets; (viii) modified release tablets; (ix)
tablets for use in the mouth; and (x) oral lyophilisates. In addition,
there are other types of tablets described in the literature such as
bilayer/multilayer tablets and mini-tablets.
A medicinal product is a physical system whose properties
depend, among others, on the individual contributions of drug
(s) and excipients. Regarding the tablet formulation process, the
pharmaceutical technologist can use several types of excipients
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Drug Discovery Today
Volume 00, Number 00
April 2018
RO
O RO
(b) OR
O
RO O O OR
O
RO OR
OR
O RO O
D OR OR
OR
O
RO
RO
OR O
O RO O
RO
O OR
RO
O
O
OR
OR
R = -[CH2-CH(CH3)-O]n-H
Drug Discovery Today
such as fillers, lubricants (glidants and antiadherents), binders,
disintegrants, wettings, colorings, absorbents, buffers, sweeteners
and flavorings. Furthermore, in the pharmaceutical industry, there
are co-processed and high-functionality excipients that result
from the combination of two or more excipients. For instance,
PROSOLV1 EASYtab SP from JRS Pharma is a unique four-in-one
system combining the strengths of frequently used excipients:
microcrystalline cellulose (96%, w/w) as a binder-filler, colloidal
silicon dioxide (2%, w/w) as a glidant, sodium starch glycolate
(1.2%, w/w) as a superdisintegrant and sodium stearyl fumarate
(0.8, w/w) as a lubricant. The manufacturer states that these
components maintain their chemical identities while synergisti-
cally providing increased functional performance.
The phenomena that occur during the preparation of tablets are
collectively called compaction and this is divided into two phases:
compression (i.e., volume reduction and particle rearrangement)
and consolidation (i.e., interparticulate bond formation) [9]. The
major manufacturing processes of tablets are: (i) direct compres-
sion; (ii) wet granulation; (iii) dry granulation; and (iv) other
processes (e.g., lyophilization and moulding technologies). The
aim of this article is to perform a critical review of CDs as excipients
in tablet formulations. It should be noted that the last review
article concerning CDs in solid-dosage forms was published in
2007 [12]. In this way, it was our objective to summarize the
current state of knowledge and to emphasize the prospects for
future research.
Functional applications of CDs in tablet formulations
As can be seen in Fig. 2, CDs have enormous potential as
excipients in tablet formulations, because they can be used with
different pharmaceutical applications. It should be emphasized
that the CD principal application is to enhance the dissolution
and bioavailability of poorly soluble drugs belonging to classes II
(low solubility and high permeability) and IV (low solubility
and low permeability) of the Biopharmaceutical Classification
System (BCS).
 DRUDIS 2221 1–10
Drug Discovery Today
Volume 00, Number 00
April 2018
To increase drug
stability
To modify/control
the release of drugs
To enhance drug
dissolution and
bioavailability
FIGURE 2
Q15 Principal CD applications in tablet formulations.
Examples of studies with CDs as excipients in tablet formula-
tions are illustrated in Table 1. Analyzing the literature it is possible
to affirm that: (i) these compounds are studied in various types of
tablets such as uncoated tablets, coated tablets, orally disintegrat-
ing tablets (ODTs), effervescent tablets, modified-release tablets,
bilayer/multilayer tablets, osmotic pump tablets, mucoadhesive
buccal tablets and mini-tablets; and (ii) the principal used CDs are
a-CD, b-CD, g-CD, HP-b-CD, randomly methylated b-CD, SBE-
b-CD, b-CD-epichlorohydrin polymer, diethyl-b-CD, triethyl-
b-CD, hydroxyethyl-b-CD, dimethyl-b-CD, triacetyl-b-CD and
O-carboxymethyl-O-ethyl-b-CD. Concrete examples will be given
in more detail below.
Temporally, it can be stated that the foundations of dissolution
research started in 1897 with the studies performed by Arthur
Amos Noyes and Willis Rodney Whitney. The development of a
relationship between dissolution and bioavailability occurred be-
tween 1950 and 1980, the emphasis on dissolution as a prognostic
tool of oral drug absorption occurred between 1980 and 2000, and
from 2000 to the present day dissolution in the framework of the
BCS was verified [13]. The drug dissolution process of solid dosages
is theoretically defined by the Noyes–Whitney equation as dem-
onstrated in Eq. (3):
dC DS
¼ ðCs  Ct Þ
dt h
where dC/dt is the dissolution rate, D is the diffusion coefficient, S
is the surface area, h is the diffusion layer thickness, Cs is the
solubility of the substance and Ct is the concentration of the
dissolved substance at time t.
To enhance the dissolution and bioavailability of carbamaze-
pine, an anticonvulsant drug with poor aqueous solubility, tablets
containing 50 mg of drug complexed with HP-b-CD in the pres-
ence of hydroxypropyl methylcellulose were prepared by direct
compression [14]. The results demonstrated an increased dissolu-
tion rate and a greater and faster absorption of the carbamazepine
from complex tablets compared with commercial tablets [14]. As
Please cite this article in press as: Conceição, J. et al. Cyclodextrins as excipients in tablet formulations, Drug Discov Today (2018), https://doi.org/10.1016/j.drudis.2018.04.009
REVIEWS
To mask the bitter
taste of drugs
To minimize
adverse drug
reactions
To act as a filler,
binder or
disintegrant
Reviews
POST SCREEN
Principal CDs
applications in To act as an
osmotic pump
tablet
agent
formulations
Drug Discovery Today
previously reported by Miller et al. [12], it is described in the
literature that often even the physical mixture of drug and CD
increases the solubility of the drug owing to the instant complex
formation upon contact with water. Thus, in these cases, the use of
CD as a filler should be considered and a wetting agent (e.g.,
sodium lauryl sulfate and polysorbate 80) and a superdisintegrant
(e.g., croscarmellose sodium, sodium starch glycolate or crospo-
vidone) can be added as dissolution enhancers. However, it is
necessary to study whether there is an interaction between the
added excipient and the CD.
As for the release of the drug(s), the pharmaceutical dosage
forms are divided into immediate release or conventional release
dosage forms and modified release dosage forms. In turn, the
modified-release dosage forms include the sustained-release dos-
age forms, the delayed-release dosage forms and the sequential-
release dosage forms [11]. Hydrophobic (e.g., diethyl-b-CD and
triacetyl-b-CD) and ionizable (e.g., O-carboxymethyl-O-ethyl-
b-CD) derivatives of b-CD are used in the formulation of sus-
tained-release or delayed-release tablets, respectively. O-carboxy-
methyl-O-ethyl-b-CD seems to cause delayed dissolution not
because of the presence of the ionizable carboxymethyl groups
but rather because of the presence of the hydrophobic ethyl groups
[15]. Besides that, CDs are noninvasive platforms for targeted drug
ð3Þ delivery [16]. Rehman et al. [17] investigated the ability of b-CD
and chitosan as components in tablet matrix formulations to
maximize the release of ibuprofen under conditions simulating
the colon by employing a wet granulation method. Formulations
with equal amounts of b-CD and ethylcellulose were the most
stable carrier systems and displayed better ibuprofen-release pro-
files than the formulations containing chitosan.
Recently, the effect of CD complexes on the chemical stability
of drugs was reviewed by Popielec and Loftsson [18]. It was
established that CD complexation can hamper hydrolysis, oxida-
tion, photodegradation, isomerization and enzyme-catalyzed deg-
radation of dissolved drugs in aqueous solution [18]. For instance,
the addition of b-CD as an excipient to tablets improved the
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DRUDIS 2221 1–10

TABLE 1
Please cite this article in press as: Conceição, J. et al. Cyclodextrins as excipients in tablet formulations, Drug Discov Today (2018), https://doi.org/10.1016/j.drudis.2018.04.009
www.drugdiscoverytoday.com

Q16 Examples of studies about tablets containing CDs as excipients

Drug and quantity per CD | Application aim Inclusion Tablet type | Tablet Tableting machine Tablet weight Observations Refs
tablet (mg) | complex method manufacturing process (mg) | Tablet
Therapeutic class of preparation diameter (mm)
Amlodipine besylate (10) b-CD | " dissolution and Kneading Bilayer buccoadhesive | Hydraulic pellet press, 166 | 10
The b-CD presence did not change [26]
| Calcium channel " permeation Direct compression Technosearch bioadhesion force and swelling behavior
blocker Instruments Thane significantly
Amoxicillin trihydrate (n. b-CD | Release rate- Sustained release Single-punch 130 | 7.45
The different weight ratios of chitosan:b-CD [32]
s.) | Antibiotic controlling polymer mucoadhesive | Direct did not appear to significantly influence the
compression drug-release profile
Benznidazole (100) | HP-b-CD | " dissolution Kneading Effervescent | Direct Eccentric press, FABBE 1250| 16
A high CD concentration seemed to hamper [33]
Antiparasitic compression the effervescence raising the disintegration
time of tablets and also making the
formulations more vulnerable to variations in
atmospheric relative humidity
Carbamazepine (50) | HP-b-CD | " dissolution Co-evaporation Immediate release | Single-punch, Korsch EK- n.s. | 15
Drug solubility was increased up to 95 times [14]
Anticonvulsant and " bioavailability Direct compression 0 by complexation with HP-b-CD in the presence
of 0.1% hydroxypropyl methylcellulose. The
dissolution and bioavailability of complex
tablets were increased compared with
commercial tablets
Cefpodoxime proxetil HP-b-CD | " dissolution Kneading Immediate release | Single stroke punching 220 | 12
The complex tablets, in the presence of [34]
(n.s.) | Antibiotic Direct compression sodium carboxymethyl cellulose, increased
drug dissolution rate, and were shown to have
more effective antimicrobial activity than
commercial tablets.
Cilostazol (50) | b-CD | "dissolution Spray-drying Orally disintegrating | Rotary press, Rimek 450 | 10
Complexation with b-CD resulted in marked [35]
Antiplatelet and Direct compression increase in the solubility and dissolution of the
vasodilator drug
Clonazepam (0.5 and 1.0) Randomly-methylated- Co-grinding, Mucoadhesive buccal | Hydraulic pump n.s. | 13
Complexation revealed to be an optimal [36]
| Benzodiazepine b-CD | " dissolution and kneading and co- Direct compression strategy to improve the performance of drug
" permeation

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evaporation from tablets aimed for local or systemic action
in terms, respectively, of increased release rate
and permeation properties
Clozapine (12.5) | HP-b-CD | " dissolution Co-evaporation Orally disintegrating | Rotary press, GLZP-10A 140 | 8.5
Tablets showed a higher dissolution rate and [29]
Atypical antipsychotic and " bioavailability Direct compression bioavailability compared with the commercial
tablets
Eslicarbazepine acetate b-CD | " dissolution and Co-evaporation Orally disintegrating | Rotary press, Jaguar, 1200 | 16
Tablets showed low disintegration time, [37]
(800) | Anticonvulsant " bioavailability Direct compression General Machinery higher in vitro drug release and higher
Corporation bioavailability compared with the marketed
tablets
Famotidine (n.s.) | SBE-b-CD | Slow-release Slow release | Direct Hydraulic press 190 | 10
A simple blending of chitosan and SBE-b-CD [38]
Histamine H2 receptor agent compression retarded the release of famotidine from tablets.
antagonist The slow release of the drug was reflected in in
vivo absorption after oral administration to rats
Felodipine (5) | Calcium HP-b-CD | " dissolution Lyophilization Buccoadhesive Single-punch, Cadmach 115 | 8
The release of drug from buccal tablets [39]
channel blocker and " permeation (sustained release) | comprising inclusion complex and
Direct compression hydroxypropyl methylcellulose demonstrated
a complete and sustained release of the drug
associated with an enhanced buccal
permeation
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DRUDIS 2221 1–10

TABLE 1 (Continued )
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Drug and quantity per CD | Application aim Inclusion Tablet type | Tablet Tableting machine Tablet weight Observations Refs
tablet (mg) | complex method manufacturing process (mg) | Tablet
Therapeutic class of preparation diameter (mm)
Fenoprofen calcium b-CD | " dissolution and Lyophilization Three-layered gum | Single-punch, Royal 1800 | 17
The highest significant release was achieved [40]
(200) | Nonsteroidal anti- " bioavailability Direct compression Artist from the lyophilized ternary complex
inflammatory containing 100 mg of drug in presence of
polyvinylpyrrolidone. The relative
bioavailability of the gum tablet was found to
be 166.06% compared to NalfonJ 200 mg
capsules
Furosemide (20) | CD polymer | Immediate release | Shimadzu hydraulic 254 | 13
The CD polymer improved the disintegration [41]
Diuretic Disintegrant Direct compression press and the dissolution rate, and increased the
hardness of the tablets and provided good
stability of dissolution profile
Furosemide (20) | CD polymer | Binder and Immediate release | Shimadzu hydraulic 250 | 13
CD polymer was used advantageously in [42]
Diuretic disintegrant Direct compression press direct compression systems as a binder-
disintegrant
Glipizide (5) | b-CD | " dissolution and Trituration Compression-coated | Single-punch, Shanghai 418 | 11
The compression-coated tablets with [43]
Sulfonylurea " bioavailability Wet granulation (core Pharmaceutical glipizide-b-CD and hydroxypropyl cellulose in
tablet) Machinery Factory the outer layer displayed a zero-order
controlled release function
Glyburide (5) | HP-b-CD | " dissolution Co-evaporation, Immediate release | Mini tablet press, 122 to 371.3
Tablets produced by spray granulation, fluid- [44]
Sulfonylurea spray granulation Granulation, spray Kambart, Cadmach | 6 and 9 bed processing and co-evaporation-
and fluid bed granulation and fluid Machinary granulation had almost identical dissolution
processing bed processing profile in water and 0.1% sodium lauryl sulfate
Ibuprofen (1.54) | b-CD | " dissolution Kneading and Mini-tablet | Direct Universal mechanical 10 | 2.5
The drug release from the mini-tablets [45]
Nonsteroidal anti- suspension/ compression (manually) press, Lloyd Instruments showed no dependency on the amount of
inflammatory solution with LR 50 K water used in the formation of the complexes
different
processes of
drying (air
stream, spray-
drying and
lyophilization)
Ibuprofen sodium (100) | b-CD | Filler Orally disintegrating | Single-punch, Erweka 400 | 12
b-CD improved the hardness of tablets [46]
Nonsteroidal anti- Direct compression EKO without increasing the disintegration time
inflammatory
Itraconazole (100 mg of SBE-b-CD | " dissolution Lyophilization Vaginal bioadhesive Single-punch, Korsch EK- 200 | 8
The inclusion complexes enhanced the [47]
complex) | Antifungal and # side effects sustained release | Direct 0 solubility of drug and improved its antifungal
compression activity. Tablet-containing inclusion complexes
prolonged the residence time and the drug
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release on the vaginal mucosa

Ketoconazole (10) | HP-b-CD | " dissolution Kneading Immediate release | Hydraulic press 76 | 4
Tablets containing the CD complex showed a [48]
Antifungal and " bioavailability Direct compression higher in vitro dissolution rate and
bioavailability compared with the tablets
containing drug alone
Levocetirizine HP-b-CD | " palatability Co-evaporation Effervescent | Direct Single-punch, Erweka 350 | 13
The use of HP-b-CD at a molar ratio of 1:10 [49]
hydrochloride (5) | compression GmbH showed a considerable positive effect on the
Antihistamine taste masking of the drug

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REVIEWS

DRUDIS 2221 1–10

TABLE 1 (Continued )
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Drug and quantity per CD | Application aim Inclusion Tablet type | Tablet Tableting machine Tablet weight Observations Refs
tablet (mg) | complex method manufacturing process (mg) | Tablet
Therapeutic class of preparation diameter (mm)
Limaprost alfadex (50) | b-CD | " stability Lyophilization Immediate release | VELA, Kikusui Seisakusho n.s. | 6.5
b-CD as a tableting excipient improved the [19]
Prostaglandin E1 analog Direct compression stability of drug in tablets of the lyophilized
composites (with b-CD).
Lorazepam (4) | HP-b-CD | " dissolution Lyophilization Immediate release | Eight-station single n.s. | 7
Tablets containing complexes prepared with [50]
Benzodiazepine Direct compression rotary, Cadmach CD had significant improvement in the release
Machinery profile of lorazepam as compared to tablets
containing lorazepam without CD
Lornoxicam (16: 8 + 8) | HP-b-CD | " dissolution Lyophilization Bilayer | Direct Single-punch 400 (200 + 200)
Lornoxicam–HP-b-CD freeze-dried product [51]
Nonsteroidal anti- compression | n.s. in 1:2 (drug–CD) showed the highest
inflammatory dissolution and was used in the drug rapid
release layer
Meclizine hydrochloride HP-b-CD | " dissolution Kneading Orally disintegrating | 16 station rotary, 200 | 9.5
The solubility and dissolution rate of drug [52]
(25) | Antihistamine Direct compression Cadmach, Manesty were significantly improved by complexation
with HP-b-CD. The prepared formulation
showed better release than a marketed tablet
Melatonin (2) | Hormone a-CD, b-CD, g-CD, HP- Co-evaporation Hydrophilic matrix | n.s. Hydraulic press, Maassen 200 | 10
Melatonin was released faster from the drug– [53]
b-CD, sulfated b-CD, HP- type MP 150 CD complexes than from the rest matrix
a-CD and HP-g-CD | " systems
dissolution
Meloxicam (7.5) | HP-b-CD | # unpleasant n.s. Orally disintegrating | Hand hydraulic press 200 | 9.5
Tablets containing the mixture of resinate [54]
Nonsteroidal anti- taste and " dissolution Direct compression machine, Specac P/N and drug–HP-b-CD complexes provided
inflammatory 15011/25011 complete drug dissolution and masked the
bitter taste
Metformin hydrochloride Triacetyl-b-CD | Spray-drying and Sustained release | Direct Perkin-Elmer hydraulic 825 | 10
Different sustained-release effects were [55]
(50) | Biguanide Sustained-release agent grinding compression press obtained by varying the relative amounts of
drug–CD as co-ground or spray-dried product
Naproxen (n.s.) | HP-b-CD | " dissolution Kneading Colonic-release | Direct Rotary tablet press, 330 | 9
The tablet with enteric coatings which [23]
Nonsteroidal anti- and # side effects compression Korea Machine contained inclusion complex and disintegrants
inflammatory could be useful to deliver naproxen to the

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lower small intestine and upper colon with
increased dissolution and reduced intestinal
tissue damage
Natamycin (25 mg of g –CD | " dissolution, " Lyophilization Vaginal bioadhesive | Single-punch, Korsch EK- 50 | 5.5
The complexation improved the aqueous [56]
complex) | Macrolide stability and # side Direct compression 0 solubility of drug without modifying its
antimycotic effects antimycotic activity
Oxaprozin (100) | Randomly-methylated- Cofusion Orally disintegrating | Hydraulic press n.s. | n.s.
The tablets containing the drug as co-fused [57]
Nonsteroidal anti- ß-CD | " dissolution Direct compression system with CD, l-arginine and sepiolite
inflammatory nanoclay were more effective than the
marketed tablet in terms of faster and more-
intense pain-relieving effect in the treatment
of adjuvant-induced arthritis
Perphenazine (2) | HP-b-CD | " dissolution Co-evaporation Orally disintegrating | Rotary press, GLZP-10A, 80 | 6
Tablets with inclusion complexes showed [58]
Antipsychotic Direct compression Beijing gylongli sci. & least disintegration time and improved drug
tech. Co. dissolution profile
DRUDIS 2221 1–10

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Refs

[59]

[60]

[61]

[62]
stability of limaprost, a prostaglandin E1 derivative [19]. Never-
theless, it should be noted that some drugs that are stabilized by

valsartan with improved dissolution rate were

methylcellulose matrix tablets. The dissolution

developed tablets and the commercial tablets

methylcellulose ternary system was completed

disintegration time and rapid dissolution rate

Multicomponent complexes were prepared

CDs in aqueous solutions are destabilized by the same CDs in solid

Pharmacokinetic results demonstrated that

were prepared using inclusion complexes.

The drug dissolution from the mannitol

Press-coated pulsatile release tablets of

rate and oral bioavailability of drug were

dosage forms [18].

tablets loaded with the drug-randomly

Many taste-masking methods such as physical barrier coatings,

Tablets with desirable taste, short

chemical modification (e.g., the complexation of drugs with CDs)

and formulated in hydroxypropyl

methylated-ß-CD-hydroxypropyl
and sensory masking have been developed [20]. By way of exam-
ple, the intensely bitter taste of aceclofenac, a nonsteroidal anti-
inflammatory drug, was masked by complexing with HP-b-CD on

Reviews
POST SCREEN

significantly improved
ODTs [21]. Taste evaluation of tablets in human volunteers
were bioequivalent

revealed considerable taste masking with the degree of bitterness

Observations

below a threshold value. This aspect is of importance because it

after 5 min
developed

promotes therapeutic compliance. The guideline on good phar-

macovigilance practices [22], published by the European Medi-
cines Agency (EMA) in 2017, defines an adverse drug reaction as a
response to a medicinal product that is noxious and unintended.
200 and 300 | 8
diameter (mm)
Tablet weight

CDs are used to minimize drug side effects such as gastric/intesti-

(mg) | Tablet

370–420 | 12

nal and ocular irritation. Naproxen is a nonsteroidal anti-inflam-

400 | 12

200 | 10

matory drug with poor water solubility and undesirable

gastrointestinal toxicity such as gastrointestinal intolerance and
ulceration when given orally. To overcome this situation, Piao
Single rotary press, ZDY-

Single-punch, Korsch EK-

punch press, Specac Ltd

et al. [23] developed tablets with enteric coatings containing

Mini Press I, Karnavati

naproxen inclusion complexes with HP-b-CD to deliver the drug

Instrumented single-
8, Shanghai Far-east
Tableting machine

into the colonic region.

Pharmaceutical
Machinery Co.

In tablet formulations, CDs have been used as a direct compres-

sion filler (e.g., b-CD), disintegrating agent (e.g., CD polymer),
binder (e.g., b-CD) and osmotic pump agent (e.g., SBE-b-CD). For
instance, Garcia-Fernandez et al. [24] developed a new multifunc-
0

tional direct compression excipient based on citric acid b-CD

manufacturing process

Sustained release matrix

polymer in its water-insoluble (PCD-I) and soluble (PCD-S) forms.

Tablet type | Tablet

| Direct compression
Press-coated | Direct

Other excipients such as binders, lubricants or disintegrants were

Immediate release |
Direct compression
Dispersible | Direct

not added during the studies. The results highlighted the multi-
functional excipient properties of PCD-I/PCD-S polymers (i.e.,
compression

compression

good flow and compression properties, no signs of toxicological

symptoms and modulable disintegration time). In the past years,
several scientific studies involving CDs in bilayer tablets and ODTs
have been described in the literature. Bilayer (and multilayer)
complex method

tablets offer several advantages over the conventional tablets like

of preparation

Lyophilization

layers with different drug-release profiles, separation of chemically

Spray-drying
Inclusion

Kneading

Kneading

incompatible ingredients, patient compliance and combination

therapy [25]. For example, amlodipine bilayer buccal tablets of a
hydroxypropyl methylcellulose matrix system containing Carbo-
pol1-b-CD as the drug layer and ethyl cellulose as the non-
ß-CD | # unpleasant taste

b-CD and SBE-b-CD | "

swellable backing layer were developed [26]. Amlodipine is a

Randomly-methylated-
CD | Application aim

Abbreviatios: ", increase; #, decrease; n.s., not specified.

b-CD | " dissolution

ß-CD | " dissolution

dihydropyridine calcium antagonist with poor water solubility

dissolution and "

and bioavailability, and high photosensitivity [26]. The presence

bioavailability

of inclusion complexes in the tablet improved permeation owing

to its enhanced dissolution at the site of biointerface of tablet and
buccal mucosa [26].
ODTs provide several advantages over conventional tablets such
as suitability for patients with swallowing difficulties, mainly in
Zaleplon (10) | Sedative-
Drug and quantity per

Pyridostigmine bromide

Angiotensin II receptor

the geriatric and pediatric population, and faster onset of action

TABLE 1 (Continued )

(60) | Cholinesterase

Cerebral vasodilator

[27]. The FDA [28] established that ODTs should present the
Therapeutic class

Vinpocetine (20) |

following attributes: (i) tablet weight 500 mg; (ii) friability per-
Valsartan (n.s.) |
tablet (mg) |

centage 1.0%; (iii) disintegration time 30 s; (iv) acceptable and

antagonist

hypnotic
inhibitor

palatable taste for the patient population; (v) content uniformity,

drug release and stability as applicable to tablet dosage form; and
(vi) pharmacokinetics similar to the conventional tablet dosage

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 DRUDIS 2221 1–10
REVIEWS
form (bioequivalent). For instance, ODTs of clozapine, a potent
antipsychotic that belongs to class II of the BCS, and complexes
with HP-b-CD, were prepared by an evaporation method [29].
Tablets (140 mg) developed by direct compression showed suitable
technological characteristics and a higher in vitro dissolution rate
and bioavailability compared with the commercial tablets [29].
Regarding future developments, 3D printed tablets can be de-
veloped containing CDs as excipients. This technology has gained
Reviews
POST SCREEN
more attention in pharmaceutical manufacturing since the FDA
approved the first 3D-printed tablet Spritam1 (levetiracetam) to
treat epilepsy in August 2015 [30]. In addition, 3D printing is a
layer-by-layer, automated process that can produce complex, per-
sonalized products on demand [30]. At this moment, there are no
studies published in the literature concerning 3D-printed tablets
with CDs. Another future possibility is the development of tablets
containing CDs with a sensor that digitally tracks whether patients
have ingested their medication. For example, the FDA approved
Otsuka Pharmaceutical and Proteus1 a digital medicine system
named Abilify MyCite1 [31] – a drug–device combination product
comprising aripiprazole tablets embedded with an ingestible event
marker sensor.
Functional requirements of CD in tablet formulations
Drug quantity (therapeutic dose) per tablet
According to Jambhekar and Breen [6], there are three require-
ments for the formulation of a solid dosage form with CDs: (i) the
dose:solubility ratio must be 250 ml; (ii) the upper limit of the
drug dose and excipients per tablet is 800 mg; and (iii) drug
dissolution from the tablet must be satisfactorily quick to avoid
dissolution rate-limited drug absorption. The major drawback of
CDs in tablet formulations is their formulation bulk [1]. This
aspect limits the use of CDs in these delivery systems to potent
drugs (low-dose drugs). The formulation bulk, resulting from CDs
elevated molecular weight (e.g., SBE-b-CD has 2163 g/mol), and
drugs exhibiting low CE (Eq. (2)) will frequently be too large for a
single-dose tablet [8]. The relative increase in formulation bulk
(RIFB) increases when the molecular weight of the CD (MWCD)
increases and the CE decreases, as can be seen from Eq. (4) where
Q6 MWD is the molecular weight of the drug [63].
 
MWCD 1
RIFB ¼ 1þ ð4Þ
MWD CE
In general, the tablet weight ranges from 60–100 mg (diameter
6 mm) to 900–1000 mg (diameter 16 mm). Tablets with high
weights and diameters cause difficulties in swallowing, which
leads to a decrease in therapeutic compliance, especially in pedi-
atrics and geriatrics and chronic treatments. In addition, some
types of tablets should present low weight such as, for instance,
buccal tablets (150 mg) [64]. In this way, for medium-dose drugs
and/or when the CE is low, the main methods that can be used to
increase the CE play a key part in reducing the CD amount in the
pharmaceutical formulation. These methods are as follows [8]: (i)
pH adjustment of the complexation medium; (ii) formation of
multicomponent complexes with hydroxy acids (e.g., tartaric,
lactic, citric and a-ketoglutaric acids), hydroxylamines (e.g.,
monoethanolamine, diethanolamine and triethanolamine) and
amino acids (e.g., lysine, cysteine, valine, glycine, isoleucine and
arginine); (iii) formation of multicomponent complexes with
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Drug Discovery Today
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April 2018
water-soluble polymers (e.g., sodium carboxymethylcellulose,
hydroxypropyl methylcellulose and polyvinylpyrrolidone); (iv)
use of co-solvents (e.g., ethanol, propylene glycol, glycerine and
polyethylene glycol) and metal complexes; and (v) combination of
two or more of these methods. By way of example, sodium carboxy-
methylcellulose was used as a water-soluble polymer to increase the
complexation of cefpodoxime proxetil by HP-b-CD [34]. The drug
dissolution rate and antimicrobial activity of complex tablets were
higher when compared with commercial tablets [34].
Flow properties of the prepared complexes
Analyzing the studies described in the literature, it can be stated
that the principal methods used to prepare the CD inclusion
complexes in tablet formulations are as follows: (i) methods in
the solid state (milling and co-grinding); (ii) methods in the semi-
solid state (kneading); and (iii) methods in solution (co-precipita-
tion, solvent evaporation, lyophilization and freeze-drying and
atomization and spray drying). The flow properties are very im-
portant in the development of solid dosage forms and are used to
predict the compression ability of a powder, granule or pellet. A
material shows an excellent flow when presenting the following
characteristics [11]: (i) angle of repose 25–30 ; (ii) flow time
10.0 s/100 g; (iii) ability to settle 20 ml; (iv) Carr index or
compressibility index 10%; and (v) Hausner ratio 1.11. The
Carr index and the Hausner ratio can be calculated from Eqs (5)
and (6), respectively, where d0 is the is the apparent density before
tapping (bulk density), d10 is the apparent density after 10 taps and
d500 is the apparent density after 500 taps [65,66].
d500  d0
Carr index ¼  100 ð5Þ
d500
d500
Hausner ratio ¼ ð6Þ
d10
Salústio et al. [45] studied the flow properties of inclusion
complexes of ibuprofen and b-CD obtained by two complexation
methods, namely suspension/solution (with water removed by air
stream, spray- and freeze-drying) and kneading. All studied mate-
rials have shown poor flow properties and a glidant had to be
added to the formulations to prepare mini-tablets. Another study
indicated good compressibility and flow properties of the loraze-
pam complexes with HP-b-CD prepared by kneading, spray-drying
and lyophilization [50]. Thus, in our opinion, the flow properties
of the prepared inclusion complex should be evaluated to predict
the compressibility and to avoid tabletting problems (e.g., varia-
tion in tablet weight and drug content).
Direct compression is the preferred manufacture method of tablets
by the pharmaceutical industry because it has fewer steps compared
with granulation processes, is the most economical and can be used
for moisture or heat-sensitive materials. However, this method
requires that materials present the following properties: (i) sufficient
density; (ii) constant flow; (iii) agglutination and cohesion capacity;
and (iv) absence of friction (i.e., no adherence to the surfaces).
Therefore, direct compression can only be used for inclusion com-
plexes with good flow properties and compressibility or in situations
by adding a direct compression filler (e.g., microcrystalline cellulose,
lactose monohydrate, calcium hydrogen phosphate and mannitol)
or a co-processed excipient (for example, MicroceLac1 100 that
 DRUDIS 2221 1–10
Drug Discovery Today
Volume 00, Number 00
April 2018
comprises 75% alpha-lactose monohydrate and 25% microcrystal-
line cellulose). It should be noted that direct compression is the
manufacturing process described most in the literature to prepare
tablets containing CDs. Nevertheless, sometimes the compression
Q7 chamber (die) filling is done by manual mode and this is not suitable
for industrial application.
If the complex does not show good flow properties and com-
pressibility, other manufacturing processes should be considered
such as wet granulation, dry granulation or another process.
Gyanani et al. [44] demonstrated that spray granulation is a simple
and cost-effective process for low-dose poorly soluble drugs,
whereas fluid-bed processing is appropriate for poorly soluble
drugs with a moderate dose. By contrast, for drugs with high doses,
if multiple dose units are suitable for administration, then fluid-
bed processing can be considered.
Regulatory status of CDs
The principal pharmacopoeias worldwide include monographs of
CDs (e.g., the European Pharmacopoeia and the United States
Pharmacopoeia National Formulary) or monographs of compounds
with CDs (e.g., Alprostadil Alfadex in the Japanese Pharmacopoeia).
In addition, these compounds exhibit favorable toxicological pro-
files for human use [67]. Concerning CDs that can be used in tablet
formulations for oral administration, b-CD (betadex), HP-b-CD
(hydroxypropyl betadex) and SBE-b-CD (betadex sulfobutyl ether
sodium) are the most commonly described in the literature.
In 2014, the EMA published a document on the ‘Background
review for CDs used as excipients’ [68]. In relation to oral products,
b-CD, g-CD, HP-b-CD and SBE-b-CD are applied. Table 2 displays
examples of commercial tablets containing CDs, including drug
and trade names, pharmaceutical dosage form, therapeutic indi-
cation, manufacturer and region. It should be noted that: (i) only
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REVIEWS
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CDs are complexing excipients in tablet formulations mainly for
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Reviews
POST SCREEN
the methods to enhance CE play a key part in reducing the CD
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Inclusion complex flow properties play a crucial part in the tablet
manufacture process. Direct compression is the most utilized
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ODTs and bilayer/multilayer tablets have been published. Regard-
ing future developments, 3D-printed tablets and tablets with
sensors could be developed containing CDs as excipients. Finally,
CDs are present in commercial tablets and there are CD mono-
graphs in several pharmacopoeias.
Acknowledgments
Jaime Conceição is grateful to the FCT PhD Programme in Q8
Medicines and Pharmaceutical Innovation (i3DU) for funding this
work through scholarship PD/BD/127813/2016. Oluwatomide
Adeoye is grateful for scholarship funding from Tertiary Education
Fund (TETFUND) Nigeria and iMed.ULisboa financed by national
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April 2018
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