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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 pharmaceutical industry for different purposes [3,4] such as: (i) to
Cyclodextrins (CDs) are cyclic oligosaccharides that are produced enhance the aqueous solubility, dissolution and bioavailability of
from starch or starch derivatives using CD glycosyltransferase. drugs; (ii) to increase drug physicochemical stability and improve
These compounds were first isolated by Antoine Villiers in 1891 shelf-lives of medicinal products; (iii) to modify drug release site
and they have been recognized as pharmaceutical excipients and/or time profile; (iv) to minimize adverse drug reactions such as
because they can form noncovalently bonded inclusion com- gastrointestinal and ocular irritation; (v) to reduce or eliminate
plexes (host–guest complexes) with several drugs either in solution unpleasant taste and smell; (vi) to prevent drug–drug or drug–
or
Q2 in the solid state (Fig. 1a) [1]. Regarding the chemical structure, excipient interactions; and (vii) to convert liquid drugs into mi-
CDs comprise (a-1-4)-linked a-D-glucopyranose units, have a crocrystalline or amorphous powders. Additionally, CDs can be
lipophilic central cavity and a hydrophilic outer surface, and used as drug substances such as sugammadex (Bridion1; Merck
are shaped like a truncated cone, bucket-like or doughnut-shaped Sharp & Dohme), which is a modified g-CD available in 100 mg/ml
Q3 (Fig. 1b) [2]. solution for injection. According to the summary of product
The three natural CDs are alpha-cyclodextrin (a-CD; alfadex), characteristics [5], there are two therapeutic indications: (i) for
beta-cyclodextrin (b-CD; betadex) and gamma-cyclodextrin the reversal of neuromuscular blockade induced by rocuronium or
(g-CD; gammadex), containing 6, 7 and 8 glucose units, respec- vecuronium in adults; and (ii) for the pediatric population, sugam-
tively. CD derivatives are divided into three groups, specifically madex is only recommended for routine reversal of rocuronium-
hydrophilic [for instance, 2-hydroxypropyl-b-CD (HP-b-CD)], hy- induced blockade in children and adolescents aged 2–17 years.
drophobic (for instance, 2,6-di-O-ethyl-b-CD) and ionizable [for All these applications are based on the inclusion-complex-form-
instance, sulfobutyl ether-b-CD (SBE-b-CD)]. CDs are used in the 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
Corresponding author: Conceição, J. (jmgmconceicao@ff.up.pt)
RO
O RO
(a) (b) OR
O
RO O O OR
O
RO OR
OR
O RO O
KC D OR OR
OR
D + CD CD O
RO
RO
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OR O
O RO O
RO
O OR
RO
O
O
OR
OR
R = -[CH2-CH(CH3)-O]n-H
Drug Discovery Today
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 such as fillers, lubricants (glidants and antiadherents), binders,
CD, respectively [6]. Slope is the slope of the phase–solubility disintegrants, wettings, colorings, absorbents, buffers, sweeteners
profile and S0 is the concentration of drug without CD. For com- and flavorings. Furthermore, in the pharmaceutical industry, there
plexes with low-to-mid KC value, binding of drug to plasma are co-processed and high-functionality excipients that result
proteins will primarily determine the pharmacokinetics [7]. By from the combination of two or more excipients. For instance,
contrast, for complexes with high KC value and low protein PROSOLV1 EASYtab SP from JRS Pharma is a unique four-in-one
binding significant decrease in distribution volume and enhanced system combining the strengths of frequently used excipients:
Q4 excretion of unmetabolized drug are observed [7]. microcrystalline cellulose (96%, w/w) as a binder-filler, colloidal
silicon dioxide (2%, w/w) as a glidant, sodium starch glycolate
½D CD Slope (1.2%, w/w) as a superdisintegrant and sodium stearyl fumarate
KC ¼ ¼ ð1Þ
½D½CD S0 ð1 SlopeÞ (0.8, w/w) as a lubricant. The manufacturer states that these
For 1:1 drug–CD complexes, the complexation efficiency (CE) components maintain their chemical identities while synergisti-
can be calculated from Eq. (2) [8]. cally providing increased functional performance.
The phenomena that occur during the preparation of tablets are
½D CD Slope
CE ¼ S0 KC ¼ ¼ ð2Þ collectively called compaction and this is divided into two phases:
½CD ð1 SlopeÞ
compression (i.e., volume reduction and particle rearrangement)
Oral delivery is the most common route for drug administra- and consolidation (i.e., interparticulate bond formation) [9]. The
tion. Tablets are solid dosage forms that were discovered in 1843 by major manufacturing processes of tablets are: (i) direct compres-
William Brockedon through the publication of British Patent sion; (ii) wet granulation; (iii) dry granulation; and (iv) other
Number 9977 about ‘‘shaping pills, lozenges and black lead by processes (e.g., lyophilization and moulding technologies). The
Q5 pressure in dies” [9]. This pharmaceutical dosage form is the most aim of this article is to perform a critical review of CDs as excipients
used in the market because it presents high-precision dosing, in tablet formulations. It should be noted that the last review
chemical, physical and microbiological stability, manufacturing article concerning CDs in solid-dosage forms was published in
efficiency and good patient compliance [9,10]. 2007 [12]. In this way, it was our objective to summarize the
According to the European Pharmacopoeia 9 [11], in force since current state of knowledge and to emphasize the prospects for
January 2017, there are ten types of tablets for oral administration: future research.
(i) uncoated tablets; (ii) coated tablets; (iii) effervescent tablets; (iv)
soluble tablets; (v) dispersible tablets; (vi) orodispersible tablets; Functional applications of CDs in tablet formulations
(vii) gastro-resistant tablets; (viii) modified release tablets; (ix) As can be seen in Fig. 2, CDs have enormous potential as
tablets for use in the mouth; and (x) oral lyophilisates. In addition, excipients in tablet formulations, because they can be used with
there are other types of tablets described in the literature such as different pharmaceutical applications. It should be emphasized
bilayer/multilayer tablets and mini-tablets. that the CD principal application is to enhance the dissolution
A medicinal product is a physical system whose properties and bioavailability of poorly soluble drugs belonging to classes II
depend, among others, on the individual contributions of drug (low solubility and high permeability) and IV (low solubility
(s) and excipients. Regarding the tablet formulation process, the and low permeability) of the Biopharmaceutical Classification
pharmaceutical technologist can use several types of excipients System (BCS).
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DRUDIS 2221 1–10
To act as a filler,
To modify/control
binder or
the release of drugs
disintegrant
FIGURE 2
Q15 Principal CD applications in tablet formulations.
Examples of studies with CDs as excipients in tablet formula- previously reported by Miller et al. [12], it is described in the
tions are illustrated in Table 1. Analyzing the literature it is possible literature that often even the physical mixture of drug and CD
to affirm that: (i) these compounds are studied in various types of increases the solubility of the drug owing to the instant complex
tablets such as uncoated tablets, coated tablets, orally disintegrat- formation upon contact with water. Thus, in these cases, the use of
ing tablets (ODTs), effervescent tablets, modified-release tablets, CD as a filler should be considered and a wetting agent (e.g.,
bilayer/multilayer tablets, osmotic pump tablets, mucoadhesive sodium lauryl sulfate and polysorbate 80) and a superdisintegrant
buccal tablets and mini-tablets; and (ii) the principal used CDs are (e.g., croscarmellose sodium, sodium starch glycolate or crospo-
a-CD, b-CD, g-CD, HP-b-CD, randomly methylated b-CD, SBE- vidone) can be added as dissolution enhancers. However, it is
b-CD, b-CD-epichlorohydrin polymer, diethyl-b-CD, triethyl- necessary to study whether there is an interaction between the
b-CD, hydroxyethyl-b-CD, dimethyl-b-CD, triacetyl-b-CD and added excipient and the CD.
O-carboxymethyl-O-ethyl-b-CD. Concrete examples will be given As for the release of the drug(s), the pharmaceutical dosage
in more detail below. forms are divided into immediate release or conventional release
Temporally, it can be stated that the foundations of dissolution dosage forms and modified release dosage forms. In turn, the
research started in 1897 with the studies performed by Arthur modified-release dosage forms include the sustained-release dos-
Amos Noyes and Willis Rodney Whitney. The development of a age forms, the delayed-release dosage forms and the sequential-
relationship between dissolution and bioavailability occurred be- release dosage forms [11]. Hydrophobic (e.g., diethyl-b-CD and
tween 1950 and 1980, the emphasis on dissolution as a prognostic triacetyl-b-CD) and ionizable (e.g., O-carboxymethyl-O-ethyl-
tool of oral drug absorption occurred between 1980 and 2000, and b-CD) derivatives of b-CD are used in the formulation of sus-
from 2000 to the present day dissolution in the framework of the tained-release or delayed-release tablets, respectively. O-carboxy-
BCS was verified [13]. The drug dissolution process of solid dosages methyl-O-ethyl-b-CD seems to cause delayed dissolution not
is theoretically defined by the Noyes–Whitney equation as dem- because of the presence of the ionizable carboxymethyl groups
onstrated in Eq. (3): but rather because of the presence of the hydrophobic ethyl groups
dC DS [15]. Besides that, CDs are noninvasive platforms for targeted drug
¼ ðCs Ct Þ ð3Þ delivery [16]. Rehman et al. [17] investigated the ability of b-CD
dt h
and chitosan as components in tablet matrix formulations to
where dC/dt is the dissolution rate, D is the diffusion coefficient, S
maximize the release of ibuprofen under conditions simulating
is the surface area, h is the diffusion layer thickness, Cs is the
the colon by employing a wet granulation method. Formulations
solubility of the substance and Ct is the concentration of the
with equal amounts of b-CD and ethylcellulose were the most
dissolved substance at time t.
stable carrier systems and displayed better ibuprofen-release pro-
To enhance the dissolution and bioavailability of carbamaze- files than the formulations containing chitosan.
pine, an anticonvulsant drug with poor aqueous solubility, tablets Recently, the effect of CD complexes on the chemical stability
containing 50 mg of drug complexed with HP-b-CD in the pres- of drugs was reviewed by Popielec and Loftsson [18]. It was
ence of hydroxypropyl methylcellulose were prepared by direct established that CD complexation can hamper hydrolysis, oxida-
compression [14]. The results demonstrated an increased dissolu- tion, photodegradation, isomerization and enzyme-catalyzed deg-
tion rate and a greater and faster absorption of the carbamazepine radation of dissolved drugs in aqueous solution [18]. For instance,
from complex tablets compared with commercial tablets [14]. As the addition of b-CD as an excipient to tablets improved the
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4
REVIEWS
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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REVIEWS
5
REVIEWS
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
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
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
after 5 min
developed
370–420 | 12
200 | 10
| Direct compression
Press-coated | Direct
not added during the studies. The results highlighted the multi-
functional excipient properties of PCD-I/PCD-S polymers (i.e.,
compression
compression
Lyophilization
Kneading
Kneading
Pyridostigmine bromide
Angiotensin II receptor
(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) |
hypnotic
inhibitor
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DRUDIS 2221 1–10
form (bioequivalent). For instance, ODTs of clozapine, a potent water-soluble polymers (e.g., sodium carboxymethylcellulose,
antipsychotic that belongs to class II of the BCS, and complexes hydroxypropyl methylcellulose and polyvinylpyrrolidone); (iv)
with HP-b-CD, were prepared by an evaporation method [29]. use of co-solvents (e.g., ethanol, propylene glycol, glycerine and
Tablets (140 mg) developed by direct compression showed suitable polyethylene glycol) and metal complexes; and (v) combination of
technological characteristics and a higher in vitro dissolution rate two or more of these methods. By way of example, sodium carboxy-
and bioavailability compared with the commercial tablets [29]. methylcellulose was used as a water-soluble polymer to increase the
Regarding future developments, 3D printed tablets can be de- complexation of cefpodoxime proxetil by HP-b-CD [34]. The drug
veloped containing CDs as excipients. This technology has gained dissolution rate and antimicrobial activity of complex tablets were
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more attention in pharmaceutical manufacturing since the FDA higher when compared with commercial tablets [34].
approved the first 3D-printed tablet Spritam1 (levetiracetam) to
treat epilepsy in August 2015 [30]. In addition, 3D printing is a Flow properties of the prepared complexes
layer-by-layer, automated process that can produce complex, per- Analyzing the studies described in the literature, it can be stated
sonalized products on demand [30]. At this moment, there are no that the principal methods used to prepare the CD inclusion
studies published in the literature concerning 3D-printed tablets complexes in tablet formulations are as follows: (i) methods in
with CDs. Another future possibility is the development of tablets the solid state (milling and co-grinding); (ii) methods in the semi-
containing CDs with a sensor that digitally tracks whether patients solid state (kneading); and (iii) methods in solution (co-precipita-
have ingested their medication. For example, the FDA approved tion, solvent evaporation, lyophilization and freeze-drying and
Otsuka Pharmaceutical and Proteus1 a digital medicine system atomization and spray drying). The flow properties are very im-
named Abilify MyCite1 [31] – a drug–device combination product portant in the development of solid dosage forms and are used to
comprising aripiprazole tablets embedded with an ingestible event predict the compression ability of a powder, granule or pellet. A
marker sensor. material shows an excellent flow when presenting the following
characteristics [11]: (i) angle of repose 25–30 ; (ii) flow time
Functional requirements of CD in tablet formulations 10.0 s/100 g; (iii) ability to settle 20 ml; (iv) Carr index or
Drug quantity (therapeutic dose) per tablet compressibility index 10%; and (v) Hausner ratio 1.11. The
According to Jambhekar and Breen [6], there are three require- Carr index and the Hausner ratio can be calculated from Eqs (5)
ments for the formulation of a solid dosage form with CDs: (i) the and (6), respectively, where d0 is the is the apparent density before
dose:solubility ratio must be 250 ml; (ii) the upper limit of the tapping (bulk density), d10 is the apparent density after 10 taps and
drug dose and excipients per tablet is 800 mg; and (iii) drug d500 is the apparent density after 500 taps [65,66].
dissolution from the tablet must be satisfactorily quick to avoid d500 d0
dissolution rate-limited drug absorption. The major drawback of Carr index ¼ 100 ð5Þ
d500
CDs in tablet formulations is their formulation bulk [1]. This
aspect limits the use of CDs in these delivery systems to potent
d500
drugs (low-dose drugs). The formulation bulk, resulting from CDs Hausner ratio ¼ ð6Þ
d10
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 Salústio et al. [45] studied the flow properties of inclusion
single-dose tablet [8]. The relative increase in formulation bulk complexes of ibuprofen and b-CD obtained by two complexation
(RIFB) increases when the molecular weight of the CD (MWCD) methods, namely suspension/solution (with water removed by air
increases and the CE decreases, as can be seen from Eq. (4) where stream, spray- and freeze-drying) and kneading. All studied mate-
rials have shown poor flow properties and a glidant had to be
Q6 MWD is the molecular weight of the drug [63].
added to the formulations to prepare mini-tablets. Another study
MWCD 1
RIFB ¼ 1þ ð4Þ indicated good compressibility and flow properties of the loraze-
MWD CE
pam complexes with HP-b-CD prepared by kneading, spray-drying
In general, the tablet weight ranges from 60–100 mg (diameter and lyophilization [50]. Thus, in our opinion, the flow properties
6 mm) to 900–1000 mg (diameter 16 mm). Tablets with high of the prepared inclusion complex should be evaluated to predict
weights and diameters cause difficulties in swallowing, which the compressibility and to avoid tabletting problems (e.g., varia-
leads to a decrease in therapeutic compliance, especially in pedi- tion in tablet weight and drug content).
atrics and geriatrics and chronic treatments. In addition, some Direct compression is the preferred manufacture method of tablets
types of tablets should present low weight such as, for instance, by the pharmaceutical industry because it has fewer steps compared
buccal tablets (150 mg) [64]. In this way, for medium-dose drugs with granulation processes, is the most economical and can be used
and/or when the CE is low, the main methods that can be used to for moisture or heat-sensitive materials. However, this method
increase the CE play a key part in reducing the CD amount in the requires that materials present the following properties: (i) sufficient
pharmaceutical formulation. These methods are as follows [8]: (i) density; (ii) constant flow; (iii) agglutination and cohesion capacity;
pH adjustment of the complexation medium; (ii) formation of and (iv) absence of friction (i.e., no adherence to the surfaces).
multicomponent complexes with hydroxy acids (e.g., tartaric, Therefore, direct compression can only be used for inclusion com-
lactic, citric and a-ketoglutaric acids), hydroxylamines (e.g., plexes with good flow properties and compressibility or in situations
monoethanolamine, diethanolamine and triethanolamine) and by adding a direct compression filler (e.g., microcrystalline cellulose,
amino acids (e.g., lysine, cysteine, valine, glycine, isoleucine and lactose monohydrate, calcium hydrogen phosphate and mannitol)
arginine); (iii) formation of multicomponent complexes with or a co-processed excipient (for example, MicroceLac1 100 that
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DRUDIS 2221 1–10
comprises 75% alpha-lactose monohydrate and 25% microcrystal- three CDs are present (i.e., b-CD – the CD with higher pharma-
line cellulose). It should be noted that direct compression is the ceutical application, a-CD and HP-b-CD); and (ii) the first phar-
manufacturing process described most in the literature to prepare maceutical product containing CDs was approved in Japan in 1976
tablets containing CDs. Nevertheless, sometimes the compression as sublingual tablets with PGE2-b-CD (Prostarmon E1).
Q7 chamber (die) filling is done by manual mode and this is not suitable
for industrial application. Concluding remarks
If the complex does not show good flow properties and com- CDs are complexing excipients in tablet formulations mainly for
pressibility, other manufacturing processes should be considered potent drugs. For medium-dose drugs and/or when the CE is low,
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