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SOLID DOSAGE AND
EXCIPIENTS
Solid Dosage & Excipients 2015
TABLETING
EDITORIAL
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Community Editor Ashley Roberts [email protected]
Art Director Dan Ward
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[email protected]; Eric Langer [email protected];
and Cynthia A. Challener, PhD [email protected]
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4 Advances in Tableting
Cynthia A. Challener
TASTE MASKING
12 Assessing and Improving
the Palatability of Pharmaceuticals
Muhammad Ashraf, Frank Holcombe, Jr.,
Vilayat Sayeed, and Siva Vaithiyalingam
ORAL DOSAGE FORMULATION
24 Using Polymers for More Efficient
Hot-Melt Extrusion and Spray Drying
Kevin P. O’Donnell, William W. Porter III, and True L. Rogers
ANALYTICAL TECHNIQUES
34 Analytical Techniques
for Oral Solid Dosage Formulation
Paul Kippax and Deborah Huck-Jones
PROCESS ANALYTICAL TECHNOLOGY
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40 Simplify Formulation With PAT
Emil W. Ciurczak
LIPID FORMULATIONS
44
Boosting Solubility in
Lipid-Based Formulations
Agnes Shanley
Tim Cobbold, Chief Executive Officer Andrew Crow, Group Operations Director Robert
Gray, Chief Financial Officer Dame Helen, Alexander Chairman
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NEW TECHNOLOGY
48
Innovations in Solid Dosage Equipment
Ashley Roberts
Issue Editor: Agnes Shanley
On the Cover: Snap Decision/Mandy Disher Photography/Jonathan Kitchen/
Lauren Burke/KidStock/Adam Gault/Getty Images.
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Tableting
Advances in Tableting
Cynthia A. Challener
Innovative equipment,
analytical techniques,
software, and modeling
systems are improving
the tableting process.
F
or many reasons—from ease of administration to dosing accuracy to manufacturing efficiency—pharmaceutical manufacturers prefer to formulate their APIs as solid dosage drugs,
and particularly tablets. There is significant room, however, for
improvement of tableting processes. Advances in tableting technology,
including continuous production equipment and the process analytical technology (PAT) and software required for effective continuous
commercial-scale production, are helping to increase reproducibility,
accuracy, and consistency. These aspects of production impact the
quality, safety, and efficacy of formulated tablets. Modeling systems
designed for use in industry have also been developed that are improving the ability of formulators to better correlate raw material properties
and processing conditions with the properties of the finished tablet.
Key advances for the future will lie in the ability of different equipment
and software suppliers to work together to develop tableting systems
that can be truly integrated for complete continuous processing.
Cynthia A. Challener, PhD,
is a contributing editor to
Pharmaceutical Technology.
4
Lubricants (commonly magnesium stearate) affect the tableting process and the finished tablet. They not only reduce the compression
force during tableting, but also prevent product buildup on tablet
press tools and give the tablet a smooth surface. Too much lubricant
can, however, reduce the hardness of the tablet to an undesired level,
according to Sharon Nowak, business development manager with
Coperion K-Tron Food & Pharmaceutical Industries. Traditionally,
lubricants have been mixed with the solids used to form tablets, but
this approach often leads to non-uniform distribution of the lubricant. To compensate, excess lubricant is used, which can negatively
affect tablet properties.
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
LAUREN BURKE/GETTY IMAGES
Tablet press lubrication
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Tableting
Recently, equipment has been developed that allows for spraying of the lubricant onto the tablet
press tooling, allowing for significant reduction in
the quantity of lubricant required. Original systems sprayed powdered lubricants on to the tablet press tooling to prevent sticking of the powder
to the tool and die of the tablet press, according
to Nowak. Importantly, these applications were
done primarily volumetrically, with no measurement of the actual weight of the lubricant delivered.
Magnesium stearate does not flow well, which can
cause high variations in the feed rate with volumetric feeders because of inconsistent filling of
the twin screws. As a result, there has been an increased demand for automated tablet press lubrication systems with highly accurate gravimetric feed
designs, according to Nowak.
“High accuracy twin-screw gravimetric feeders
quantitatively deliver a specific amount of lubricant to the tablet. They also allow accurate determination of the amount of lubricant delivered to
each tablet, even though the quantity of lubricant
that ends up in the tablet granulation formulation
is significantly decreased,” she observes. As a result, not only are the material handling properties
of the granulation process improved, the overall
dissolution rates of tablets can be increased. The
lower quantities of lubricants required for tableting have also led to a need for lower and lower
feed rate deliveries, according to Nowak. “For this
reason, automated lubricant feeding systems today
require highly accurate, specialized low-rate feeding,” she says.
Coperion K-Tron’s solution uses patented load
cell technology that continuously measures the
weight of the lubricant and maintains a constant
mass flow (weight per unit of time) by adjusting
6
the speed of the twin-screw feeder. As a result, according to Nowak, the unit can be validated for a
steady and uniform feed of lubricant to the tablet
press. In addition, because the lubricant is delivered to the tools in a fraction of a second, the shortterm accuracy is high. “With a nearly constant feed
rate, it is possible to achieve uniform coating of
the tablet tools and eliminate sticking problems,
all with reduced stearate consumption and lower
overall operating costs,” Nowak states.
Multi-tipped tooling and advanced coatings
The key drivers in tablet manufacturing are the
need to increase yield and capacity while reducing manufacturing costs and minimizing the space
used and the time spent setting up each press, and
increasing productivity has always been a challenge in modern tablet production, according to
Steve Deakin, owner director of I Holland. That is
why he believes the widespread use of multi-tipped
tooling and the continued development of punchand-die treatments and coatings have been great
advances in the pharmaceutical industry.
“Our ongoing development of multi-tip tooling is
specifically driven by the desire to assist our customers in increasing productivity and capacity,”
he says. Multi-tip punches allow the number of
tablets per turret rotation to be multiplied by the
number of tips on the punch. They also require less
floor space, because more tablets can be produced
with fewer tablet presses, leading to a reduction in
overall plant running costs. “The development of
a technology like multi-tip tooling is beneficial to
many end users,” says Deakin.
With respect to treatment and coating technologies, I Holland categorizes them based on their
function: improving wear resistance, improving
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
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Bioavailability
Enhancement
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Formulations
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Tableting
corrosion resistance, and improving anti-stick
properties. “Treatments and coatings with these
properties can help preserve the life of our punches
and increase productivity for our customers,” Deakin comments. “The overall result is reduced press
downtime and increased productivity, which is
what every company wants,” he adds.
Continuous manufacturing, QbD, and PAT
The development of effective equipment for continuous tablet production—from feeders to tableting machines to coaters—has had a major impact
on the growing adoption of continuous processing.
Pharmaceutical companies are also beginning to
understand the significant benefits that continuous tableting can bring, from increased productivity and quality to increased manufacturing and
marketing flexibility. “The focus on continuous
manufacturing of solid oral dosage forms by large
pharma companies like Pfizer, Merck, Eli Lilly, and
Vertex is a notable sign that batch process methods
are waning and the move toward continuous manufacturing is accelerating when the application is
appropriate,” according to Charles N. Kettler, director of Natoli Scientific, a business unit of Natoli Engineering Company. He also notes that the
use of quality-by-design (QbD) concepts and PAT
dovetail nicely with the continuous manufacturing
architectures that are being developed. PAT has, in
fact, advanced to a point where manufacturers can
have confidence in the determination of product
quality throughout the process.
Need for systems integration
and data management
The marriage of the unit operations needed to
build a continuous manufacturing process is, how8
ever, requiring the vendors of these singular units
to be open to the needs of control engineers so that
the movement of the product through the process
can occur seamlessly with the support of the data
required to meet the needs of the control strategy,
according to Kettler.
Nowak notes, for example, that the increase in
continuous direct compression tablet manufacture
is requiring high integration between the ingredient feeders, PAT instrumentation, and the additional system components from the blending
operation and the tablet press. “For this reason,
advanced control systems and common protocols,
PAT technology, and the advanced ingredient
feeder control modules supplied by Coperion KTron that provide totalizer ingredient line control
based on the API feeder performance for multiple
feeders to a continuous line will be important and
require even further innovations,” she says.
“Putting together the pieces and parts for continuous manufacturing will require some new
players in the systems integration arena,” Kettler says. Much of the needed knowledge can be
learned from the chemical and food processing industries, which have experience with continuous
manufacturing and addressing these engineering
challenges. “Success will depend on making sure
that all of the pieces of the puzzle are communicating with the proper protocols, which will require
manufacturers of the various pieces of equipment
used in tableting to open their software enough to
enable the development of overall control strategies,” Kettler adds. He notes that barriers remain
that must be overcome before integrators will be
allowed access to the control software for tablet
presses and other formulation processing units.
He does believe, however, that market demand
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
will provide the energy needed to overcome those
barriers, and that opportunities will present themselves in 2015.
The move to continuous processing also presents data management challenges. The coupling
of complex processes such as high shear wet granulation with fluid bed drying and blending and
ultimately a tablet press will result in the generation of a significant amount of data. Multivariate
measurement technologies (PAT systems) also generate large quantities of data. “The challenge will
be to evolve a batch record that meets regulatory
requirements, thus protecting the patient, but is
not so onerous in size that it cannot be utilized for
ongoing process improvement,” Kettler observes.
He does note that statisticians, chemometricians,
and quality assurance experts are already working to address this challenge, but the industry will
need to work with regulators to ultimately develop
workable solutions.
Outside of continuous manufacturing, advances
in information technology have already been responsible for increased tablet press capability and
controls, according to Deakin. “Modern systems
can provide detailed information relating to the
operation and performance of the tablet presses
and help link downstream processes to ensure
quality control. The use of these technologies has
both improved tablet quality and enhanced production performance and capacity,” he asserts.
due to a lack of process understanding with respect
to the impact that raw material properties and process conditions have on final tablet properties. Increasingly, formulators and process engineers are
turning to predictive process modeling as a means
for increasing process understanding and reducing
variability.
I Holland, in collaboration with the University
of Nottingham’s Laboratory of Biophysics and Surface Analysis, United Kingdom, recently developed
a predictive model (TSAR≈Predict) that enables
the identification of the appropriate anti-stick
punch coating solution from I Holland for formulation-sticking issues without the need to carry out
expensive and time-consuming, full-scale, trialand-error experiments with several anti-stick coatings. The model considers the properties of the API
and any excipients, possible Van der Waals forces,
capillary action, deformation mechanics, the compression environment, and the chemistries of different coatings.
Discrete element and finite element method
(DEM/FEM) models are more established for the
simulation of the behavior of bulk solids during
processing. DEM has been used, for example, to
predict powder packing and flow behaviors. DEM
Solutions offers its EDEM software platform for
the optimization of bulk solids handling and processing equipment, according to the company.
Properties such as the particle size and shape
distribution, mechanical strength and stiffness,
Modeling for improved performance
surface roughness, stickiness, chemical reactivity,
Despite the significant advances in tableting tech- and surface charge are considered in the EDEM
nology, including online monitoring with PAT models.
systems and the move to continuous production
Other systems that have been applied for the
operations, the tableting process in many ways re- predictive modeling of tableting processes include
mains inefficient and variable. This inefficiency is the population balance equation and reduced order
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015
9
Tableting
models that reduce the complexity, and thus the
time and expense required to complete the calculations (1). This reduction can be achieved with multivariate analysis techniques or lower dimensional
models that are developed by fitting experimental or simulated data using a range of techniques,
including kriging, response surface methodology,
artificial neural networks, or high dimensional
model representation (1).
The company Process Systems Enterprise offers
its gPROMS modeling platform, which consists
of the ModelBuilder model development environment and gSOLIDS and gCRYSTAL specialty
applications for solids processing. This modeling
software also offers a process flowsheeting environment, which allows the development of integrated flowsheet models for process simulation
and optimization and the identification of appropriate control strategies, often with data from a
reduced number of experiments (1).
Despite advances in the development of predictive models for pharmaceutical tableting processes,
they still fall short of the desired level of performance. Models that better link particle properties
to a wider set of bulk powder properties during
processing and more accurately predict the impact
of changes in raw materials and the manufacturing process on tablet properties are needed, as are
new approaches that enable more complex modeling without increasing the computation time and
expense (1).
Reference
1. A.J. Rogers, A. Hashemi, and M.G. Ierapetritou,
Processes 1(2), 67-127 (2013). PT
Excipient Selection for User-Friendly Dosage Forms
Verena Garsuch, pharmacist, senior manager, formulation development at Hermes Pharma discusses how a qualityby-design approach allows the control of critical quality attributes and critical process parameters in excipient
selection for taste masking, dissolution rate, stability, and processing. Martin Köberle, senior manager, analytical
development at Hermes Pharma describes how hot-melt coating can mask bitter tasting APIs. They also address
technology advances that have improved excipient screening, formulation development, and processing.
10
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
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taste masking
Assessing and Improving the
Palatability of Pharmaceuticals
Muhammad Ashraf, Frank Holcombe, Jr.,
Vilayat Sayeed, and Siva Vaithiyalingam
Muhammad Ashraf is product
quality reviewer; Frank O.
Holcombe, Jr. is chemist; and
Vilayat Sayeed is supervisory
chemist all with FDA’s Office of
Lifecycle Drug Products, OPQ,
CDER. Siva Vaithiyalingam is
director of regulatory affairs with
Teva Pharmaceuticals USA.
Please address all correspondence to
[email protected]
Disclaimer: The views and opinions
presented in this article are those of
the authors and do not necessarily
reflect the views or policies of FDA.
12
T
he Merriam-Webster Dictionary defines palatable as “agreeable to the palate or taste” or “agreeable or acceptable to the
mind” (1). Taste, therefore, depends on both physiological
and psychological phenomena, and is known to vary in humans based on such factors as age, ethnicity, and geographic location.
The human tongue has approximately 10,000 taste buds (2), or receptors, capable of detecting taste. Pharmaceutical product palatability
is generally characterized based on bitterness, saltiness, sourness, and
sweetness (3).
These receptors excite specific neural pathways and, as a result, the
information is processed along with other immediate olfactory, visual,
and somatosensory inputs, as well as those from memory (4). Several
factors influence taste, including experience. Reluctance to take a bitter
medication reflects human evolution, during when humans learned to
reject harmful or poisonous materials, which tend to taste bitter (5).
Developing palatable drugs is key to breaking through this evolutionary barrier, and helps to improve patient compliance with treatment regiments. Currently, palatability is a factor in noncompliance,
which can lead to treatment failure (6) and increased resistance to
drugs, raising overall healthcare costs (7).
Taste is especially important in treatments designed for children.
In one study on children infected with HIV, for example, one third of
the patients failed to comply with the dosage regimen for a particular
drug, due to their perceptions of the drug’s taste (8). In another investigation, pediatric patient compliance with dosage regimen ranged
from 11% to 93%.
Poor compliance or non-compliance typically places children at
risk for such problems as continued recurrence of disease. In addi-
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
KIDSTOCK/BLEND IMAGES/GETTY IMAGES
Taste may be subjective,
but it is crucial to patient
compliance, particularly for
pediatric treatments. This
article reviews methods
used to improve and assess
pharmaceutical palatability.
taste masking
tion, it complicates the physician-patient relationThe European Pediatric Formulation Initiative
ship, and prevents accurate assessment of the qual- (EPFI) was founded in 2007 to address some of
ity of care provided (9).
these issues and raise awareness of the importance
of palatability in drug formulation. The initiative
is focusing on such issues as taste assessment, excipients, delivery devices, and extemporaneous
preparations (12).
This article reviews the various technological
platforms available for taste-masking, taste modification, and taste assessment, and touches on some
Ten years ago, a study published in the Neth- of the risk management challenges associated with
erlands recommended that regulatory authorities making palatable drugs products.
and the pharmaceutical industry ensure that chilTo mask or modify the taste of bitter compounds,
dren have access to more palatable medicines (10). pharmaceutical formulators must understand the
To address this universal concern and to provide chemistry of the API, identify solutions to reincentives to the pharmaceutical industry, the US duce or inhibit the bitter taste of the API without
Congress enacted the following legislation:
changing other flavor modalities (e.g., sweet, salt,
• The Best Pharmaceuticals for Children’s Act
or sour) and then choose the best taste technology
(BPCA 2002)
platform to develop the drug product.
• The Pediatric Research Equity Act (PREA
Some of the most commonly used taste-masking
2003)
approaches include:
• The FDA Amendment Act (FDAAA 2007).
• Natural and artificial flavors and sweeteners
Today, advances in pharmaceutical technology
• Polymer coatings
make it easier to design and develop such child• Multiple emulsion and liposomes
friendly products as oral films, medical chewing
• Inclusion complexes
gum, suspensions, and chewable tablets to name
• Ion-exchange complexes
a few, wherein taste-masking agents can be incor• Pro-drugs and salt formation.
porated to conceal and counter the unpleasant orThe taste-masking technology should be careganoleptic attributes of drug substance.
fully aligned with the drug product dosage form,
Finding some common ground for taste-masking patient population, and duration of therapy.
and pediatric friendly formulation, however, is not an
easy task. Standard combinations of specific sweet- Flavors, sweeteners, and other ingredients
eners with relevant flavors may vary by country and Adding flavors and sweeteners is usually the first
target market. For instance, flavors such as “bubble- choice for improving the taste of a pharmaceutical
gum” and “grape” are preferred flavors in the United formulation. Liquid flavors are used most often,
States, whereas “citrus” and “red berries” are popular because they diffuse readily into the substrate.
in Europe, and licorice in Scandinavia (11).
They are available both as oily (e.g., essential oils)
Taste is especially
important in treatments
designed for children
14
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
or non-oily liquids. Their texture generally depends on the solvent within which they are prepared (13).
Flavor systems, however, can often feature functional groups, such as aldehydes, ketones, esters, or
terpenes that can interact with actives and other
ingredients in the formulation (14).
In addition, flavors are typically volatile and
may degrade during the product’s shelf life. They
can also be degraded by pH-catalyzed, oxidationreduction, and hydrolytic reactions.
To ensure stability and prevent unacceptable
changes in the flavor of a product, flavor systems
must be compatible with other ingredients. In
some cases, for example, flavor systems may be
combined with antioxidants to reduce free radical
autoxidation.
Besides traditional sweeteners and f lavors,
other additives can be used to improve the taste
of pharmaceutical formulations. These include
amino acids and their salts (e.g., alanine, taurine,
glutamic acid, and glycine), which are known
to reduce the bitterness of drugs. Some patients,
for example, found that the taste of ampicillin
improved markedly when its granules had been
prepared with glycine and mixed with additional
quantity of glycine, sweeteners, flavors, and finally
compressed into tablets (15).
Lipoproteins can also be effective in suppressing the bitter taste of basic and hydrophobic drugs.
Incorporating it into a liposomal formulation with
egg phyosphotydyl choline (16), for example, successfully masked the bitter taste of chloroquine
phosphate in HEPES (N-2-Hydroxyethylpiperazine -N’-2) -ethane sulfonic acid) buffer at pH 7.2
Increasing the viscosity of liquid formulations
with thickening agents such as polyethylene glycol,
sodium carboxy methylcellulose, gums, or carbohydrates can also mask bitter taste by lowering the
rate of diffusion of bitter substances from the saliva to the taste buds. Acetaminophen suspension,
for example, has been formulated with xanthan
gum (0.1-0.2%) and microcrystalline cellulose (0.61%) to reduce bitter taste, while the antidepressant
mirtazapine has been formulated as an aqueous
suspension using methionine (stabilizer) and
maltitol (thickening agent). Maltitol, stable in the
acidic pH range of 2 to 3, has the added benefit of
inhibiting the drug’s undesirable local anesthetic
effect (17–18).
Flavors and sweeteners have also been used to
mask unpleasant taste in orally disintegrating
tablets (ODTs) (19) and rapidly dissolving films
(RDFs). For example, mannitol and licorice, and
sugar-based excipients, using glucose, sucrose, sucralose, and fructose and other ingredients have
been used to improve the flavor of ODT formulations (20–22).
Sucralose, which is 600 times sweeter than sugar,
has been used with mint and licorice flavors to
mask the taste of diclofenac sodium maltodextrin
RDFs (23). The films were prepared by casting and
drying aqueous mixtures of maltodextrin, glycerin,
sorbitan oleate, and diclofenac sodium. The tastemasking agents were added in very low concentration (sucralose, mint, and licorice at 1%, 6%, and
3% w/w) and did not significantly affect the tensile
properties and film disintegration time.
In addition, sucralose, citric acid, aspartame,
and passion fruit flavor have been used in an RDF
formulation of cetirizine hydrochloride, a watersoluble drug with bitter taste. This dosage form
was developed specifically for patients who have
difficulty swallowing tablets (24).
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015
15
taste masking
Polymeric coatings
Polymers that are insoluble in saliva are frequently used to mask the bitter taste of some
drugs. The cationic copolymer, Eudragit E100
amino methacrylate copolymer, for example,
can be used to coat the microspheres used
in suspensions, and the granulations used in
ODTs. The polymer’s pH profile helps ensure
that active ingredient is released in the stomach
and not in the mouth, because Eudragit E100
is soluble below a pH of 5 in the stomach, but
insoluble in saliva, where the average pH is 6.4
(25). Granulations coated by the polymer, however, can rupture during compression or tablet
chewing, and patient tests show that they can
contribute to a gritty feel in the mouth. Microspheres coated with the same material did not
rupture.
Eudragit E100 can also be used in spray drying
processes. In one process, the polymer was used
to coat microspheres of donepezil hydrochloride,
using spray-drying technology (26). In this study,
a drug-to-polymer ratio of 1:2 was found to prevent drug release in simulated salivary fluid. The
taste-masked microspheres were then formulated
into an ODT.
In another example, taste-masked microspheres
of famotidine were prepared by spray drying a suspension of finely ground famotidine (5 micron) in
an aqueous dispersion of Eudragit EPO (15%, w/v).
The microspheres were then mixed with other
tableting ingredients suitable for ODT and compressed into tablets (27).
Techniques such as solvent diffusion, precipitation, and multiple emulsion have also been used
to process polymer-coated pharmaceuticals. For
instance:
16
• Eudragit E100 has been used to coat microparticles of Indinavir, a bitter-tasting HIV
drug, by using a double emulsion solvent diffusion technique. The microparticles were
then used to make a pediatric suspension (28).
• Eudragit EPO, an aminoalkyl methacrylate
copolymer was complexed with Ondansetron
HCl, a bitter-tasting drug using precipitation.
The best results were seen at a drug-to-polymer ratio of 8:2, and results were evaluated by
dissolution in simulated salivary fluid of pH
6.2 and then in human volunteers. The tastemasked drug-polymer complex was then formulated into an ODT using spray-dried mannitol, microcrystalline cellulose, and
Polyplasdone XL-10 (29).
• The natural polymer, chitosan, has also been
used to mask bitter taste in microspheres of
Ondansetron HCl. Chitosan, a high molecular weight, polycationic polyamine, linear
polysaccharide derived from crustacean
shells, readily dissolves in inorganic acids but
is insoluble approximately above pH 6.5 (30).
A 1:1 drug-to-polymer ratio successfully
achieved taste-masking without any chemical
interaction and loss of crystallinity (31).
These polymers have also been used as binders
for the manufacture of granulations of bitter tasting drugs. The taste-masked granulations can be
further formulated into various types of tablet dosage forms such as ODTs and chewable tablets. In
tests, tablets of Zidovudine, a bitter-tasting antiretroviral drug prepared by a wet granulation method
using Surelease as binder, were found to taste better
than tablets prepared by direct compression (32).
Eudragit E-100 has also been used to mask the
flavor of bitter tasting pirenzepine and oxybutynin,
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taste masking
using extrusion and compression (33). Eudragit E,
which dissolves in acidic environments, has been
used with Fattibase, a mixture of palm, palm kernel, and coconut oil triglycerides that melt at body
temperature, to develop coatings for drug particles
that mask bitter flavors. The coated particles were
used to make liquid suspensions, and testing found
that flavor had been masked completely (34).
Multiple emulsions
stants for α and γ cyclodextrin were found lower
when compared to the association constant of
β-cyclodextrin (36).
Similar results were reported in studies of the
taste-masking effect of cyclodextrins on such antihistamines as hydroxyzine, cetirizine, and dlchlorpheniramine. The taste-masking was found
related to the respective association constant decreasing in the following order: Hydroxy propyl β
cyclodextrin, β cyclodextrin, α cyclodextrin, and
γ cyclodextrins. Studies found that primaquine
phosphate’s bitter taste was completely masked by
formation of inclusion complex with β cyclodextrin (37–39).
Taste-masking can be also be achieved by incorporating drugs into the inner aqueous phase of
water-oil-water (W/O/W) multiple emulsions, in
which either the oil layer or the water layer masks
the test. This approach has reportedly worked for
formulations of chloroquin phosphate and chlor- Ion-exchange resins
promazine (35).
Ion-exchange resins have also been used to mask
flavor in pharmaceuticals. These resins are high
Inclusion complexes
molecular weight, water-insoluble polyelectrolyte
Inclusion complexes with cyclodextrins have been polymers that are not absorbed by the body and
used to improve the palatability of drug substances. therefore are safe for oral use. These polymers
Cyclodextrins are cyclic oligosaccharides, which have extensively charged cationic and anionic
have the ability to form a host/guest inclusion com- functional groups, which can form complexes with
plex both in solution and in solid phase. Molecules ionizable drugs via ion-exchange. The resulting
or functional groups causing unpleasant taste can drug-resinate possesses the properties of resin.
be encapsulated within the cyclodextrin cavity, so
Because the resins are insoluble in water, the exthat they do not come in contact with the taste posure of drug to the taste buds in the oral cavity
bud. Once the drug substance forms an inclusion is limited. Once swallowed, however, the drug is
complex with cyclodextrin, it exhibits properties released from the resinate due to high ionic condifferent than those of the parent drug substance, centration in the gastrointestinal tract, which desuch as improved dissolution and taste.
pends on several factors such as, the nature of the
The taste-masking effect of various types of cy- reaction between drug ion and resin, drug loadclodextrin complexes may be correlated to their ing, type of ion (cation vs anion), ionic strength,
respective association constants. It is reported that and other formulation factors. Tests have shown
β-cyclodextrin provides the highest taste-masking that ion-exchange resins can be effective in tasteeffect for cetirizine, while α and γ cyclodextrin masking for several drugs such as Etoricoxib, dexprovide the poorest results. The association con- tromethorphan, and Risperidone (40–42).
18
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taste masking
Prodrugs and salt formation
It is postulated that bitter taste is perceived when
a bitter-tasting drug binds directly to taste receptors. This binding, however, depends on molecular
geometry. Changing this geometry by derivative
formation will alter the affinity of the drug molecule to the taste receptor. Several antibiotics such
as Chloramphenicol palmitate or phosphate esters
for pediatric suspension and alkyl esters of Clindamycin and Erythromycin show how prodrugs can
be used for bitter taste-masking.
Conversion of a drug to a salt has also been found
to mask bitter drug taste by altering the chemical
group that is responsible for the bitter taste. An example of this approach is chlorpheniramine maleate, a taste-masked salt of chlorpheniramine base.
Testing has shown that the alkyloxy alkyl carbonates of clarithromycin have remarkably drecreased
bitterness and improved bioavailability (43–46).
Measuring palatability: Art or science?
Taste assessment for pharmaceutical products is
complicated, due to the qualitative measurement
and the inherent differences and preferences
among the subjects. It becomes even more difficult when the taste assessment involves the pediatric population. For instance, in one such study,
the end point-of-taste assessment was based on selecting a face from a list of five faces that portrayed
happiness to sadness progressively (47).
Such an assessment rating scale, as concluded
by the study authors, has the following limitations. First, the taste was assessed indirectly, and
secondly, the subjects can be influenced by their
own perception of the odor or taste of the product,
and finally, there is no universal standard used in
the study.
20
The use of analytical devices in the drug-development phase has improved the taste-assessment process, and this has led to a more robust, reproducible
taste assessment method using objective electronic
devices such as electronic tongues. These are essentially analytical instruments made of chemical
sensors with specificity to different compounds in
the solution. These sensors are non-specific, low
selective chemical sensors with partial specificity
for cross-sensitivity to a range of organic and inorganic substances in solution, and they are coupled
with chemometric data processing tools (48).
A typical electronic tongue is based on potentiometric or voltametric sensors; however, in theory,
any kind of sensor could be built into an electronic
tongue. What is more important is that an appropriate set of sensors responds to a range of compound taste attributes, and takes into account such
interactions as suppression as well as synergetic
effects, so that sensor responses represent human
perception end points (49).
Several studies have utilized electronic tongues to
assess the taste of the pharmaceutical product. In
one case, an electronic tongue was used to select a
taste-masking agent in the manufacture of diclofenac fast-dissolving film (27). The authors concluded
that the electronic tongue allowed them to discern
the effect of a taste-masking agent in the presence of
other hydrosoluble constituents of the film.
Other studies suggest that the e-Tongue can be
a useful tool in taste assessment, enhancement,
and masking studies for such intensely bitter substances as epinephrine bitartarate, where the device has been used to screen different sweetening
and/or flavoring ingredients and to determine the
agent that best masks the unpleasant taste of the
API (50).
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taste masking
The electronic tongue is often used to screen the
taste-masking effect of sweetening agents in pharmaceutical formulations. In one case, the electronic
tongue was used to investigate the taste-masking
effect of glucose, sucrose, sucralose, fructose, mannitol, sodium saccharin, acesulfame potassium,
monoammonium glycyrrhizinate, and other sweetening agents, to formulate liquid quinine hydrochloride (51) as well as other drugs (52–54).
compliance concern, it is necessary to address the
issue of palatability through proper selection of ingredients during development of the drug product
formulation. Presently a number of approaches are
used for taste-masking such as inclusion of sweeteners and flavors, coating with pH sensitive polymers which are insoluble in the mouth but dissolve
readily in the stomach, inclusion complexes, and
complex of drug with ion-exchange resins. These
taste-masking techniques have been successfully
Risk considerations
exploited in several dosage forms such as liquids,
The choice of flavors, sweeteners, and polymers fast dissolving films, matrix formulations, and wet
used in the taste-masking platform should be care- granulated formulations.
fully aligned with the dosage form, patient population, duration of therapy, and the levels of these References
ingredients listed in the CDER approved products. 1. Webster’s Ninth Collegiate Dictionary (MerriamWebster Inc., 1988).
This information is available in the Inactive In- 2. E.T. Rolls, et al., Annals of the New York Academy of
Sciences 855 (1), 426-437 (1998).
gredients Database (IID) of CDER approved drugs.
3. Umami Information Center, www.umamiinfo.com
Amounts used in the product formulations beyond 4. D. Baguley, et al, Arch. Dis. Child. 97, 293-297 (2012).
the levels listed in the IID, or if the amount listed 5. J.I.M. Glendinning, Physiology & Behavior. 56(6),
1217-1227 (1994).
in the database is used in a therapeutic category
6. WHO, “Drug Resistance: HIV/AIDS,” World Health
that would not support the use of the same ingrediOrganization, www.who.int/drugresistance/hivaids/en/
7.
B.
Hovstadius and G. Petersson, BMC Health Serent in the proposed therapeutic oral dosage form,
vices Research 11: 326 (2011).
may require additional studies.
8. D. Lin, J.A. Seabrook, D.M. Matsui, S.M. King, M.J.
Aspartame (methyl ester of phenylalanine) is an
Rieder and Y. Finkelstein, Pharmacoepidemiology
and
Drug Safety, 20(12): 1246–1252 (2011).
artificial sweetener used in a number of CDER9. S. Winnick, et al, Pediatrics, 115(6), e718-e724
approved oral drug products but requires a warn(2005).
ing on the label, because it is a source of phenylala- 10. E. Schirm, et al, Acta Padeiatr. 92(12), 1486-1489
(2003).
nine and a possible concern for phenylketoneurics.
11. Committee for Medicinal Products for Human Use:
Thus its use should be carefully assessed in the
Reflection Paper: Formulations of Choice for the
Pediatric
Population. EMEA/CHMP/
product development and should be avoided where
PEG/194810/2005.
possible to mitigate this risk to a sub-set of the 12. A. Cram, et al, Int. J. Pharm. 365 (1-2), 1–3 (2009).
general population (55–57).
13. T.L. Reiland and J.M. Lipari, “Flavors and Flavor
Modifiers” in Encyclopedia of Pharmaceutical TechBitter or unpleasant taste of pharmaceuticals
nology, James Swarbrick Ed. (informa healthcare,
is one of the causes of non-compliance and often
3rd ed., 2006), pp. 1763-1772.
leads to failure of the treatment in a variety of pa- 14. G. P. McNally, and A. M. Railkar, “Formulation
chemistry and Manufacturing Controls,” in Pediattient populations. Because of this crucial patient
22
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
ric Drug Development: Concepts and Applications, Andrew E. Mulberg, Dianne Murphy, Julia Dunne, and
Lisa L. Mathis, Eds. (John Wiley & Sons. 2nd ed., 2013),
pp. 565-575.
15. S. Niazi, and A. Shamesh, “Chewing gum containing a
medicament and taste maskers,” US Patent 04639368,
Jan. 1987.
16. Y. Katsuragi, et al, Pharm. Res. 12 (5), 658-662 (1995).
17. C.M
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TABLETING
EDITORIAL
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4 Advances in Tableting
Cynthia A. Challener
TASTE MASKING
12 Assessing and Improving
the Palatability of Pharmaceuticals
Muhammad Ashraf, Frank Holcombe, Jr.,
Vilayat Sayeed, and Siva Vaithiyalingam
ORAL DOSAGE FORMULATION
24 Using Polymers for More Efficient
Hot-Melt Extrusion and Spray Drying
Kevin P. O’Donnell, William W. Porter III, and True L. Rogers
ANALYTICAL TECHNIQUES
34 Analytical Techniques
for Oral Solid Dosage Formulation
Paul Kippax and Deborah Huck-Jones
PROCESS ANALYTICAL TECHNOLOGY
UBM ADVANSTAR
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40 Simplify Formulation With PAT
Emil W. Ciurczak
LIPID FORMULATIONS
44
Boosting Solubility in
Lipid-Based Formulations
Agnes Shanley
Tim Cobbold, Chief Executive Officer Andrew Crow, Group Operations Director Robert
Gray, Chief Financial Officer Dame Helen, Alexander Chairman
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NEW TECHNOLOGY
48
Innovations in Solid Dosage Equipment
Ashley Roberts
Issue Editor: Agnes Shanley
On the Cover: Snap Decision/Mandy Disher Photography/Jonathan Kitchen/
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Tableting
Advances in Tableting
Cynthia A. Challener
Innovative equipment,
analytical techniques,
software, and modeling
systems are improving
the tableting process.
F
or many reasons—from ease of administration to dosing accuracy to manufacturing efficiency—pharmaceutical manufacturers prefer to formulate their APIs as solid dosage drugs,
and particularly tablets. There is significant room, however, for
improvement of tableting processes. Advances in tableting technology,
including continuous production equipment and the process analytical technology (PAT) and software required for effective continuous
commercial-scale production, are helping to increase reproducibility,
accuracy, and consistency. These aspects of production impact the
quality, safety, and efficacy of formulated tablets. Modeling systems
designed for use in industry have also been developed that are improving the ability of formulators to better correlate raw material properties
and processing conditions with the properties of the finished tablet.
Key advances for the future will lie in the ability of different equipment
and software suppliers to work together to develop tableting systems
that can be truly integrated for complete continuous processing.
Cynthia A. Challener, PhD,
is a contributing editor to
Pharmaceutical Technology.
4
Lubricants (commonly magnesium stearate) affect the tableting process and the finished tablet. They not only reduce the compression
force during tableting, but also prevent product buildup on tablet
press tools and give the tablet a smooth surface. Too much lubricant
can, however, reduce the hardness of the tablet to an undesired level,
according to Sharon Nowak, business development manager with
Coperion K-Tron Food & Pharmaceutical Industries. Traditionally,
lubricants have been mixed with the solids used to form tablets, but
this approach often leads to non-uniform distribution of the lubricant. To compensate, excess lubricant is used, which can negatively
affect tablet properties.
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
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Tableting
Recently, equipment has been developed that allows for spraying of the lubricant onto the tablet
press tooling, allowing for significant reduction in
the quantity of lubricant required. Original systems sprayed powdered lubricants on to the tablet press tooling to prevent sticking of the powder
to the tool and die of the tablet press, according
to Nowak. Importantly, these applications were
done primarily volumetrically, with no measurement of the actual weight of the lubricant delivered.
Magnesium stearate does not flow well, which can
cause high variations in the feed rate with volumetric feeders because of inconsistent filling of
the twin screws. As a result, there has been an increased demand for automated tablet press lubrication systems with highly accurate gravimetric feed
designs, according to Nowak.
“High accuracy twin-screw gravimetric feeders
quantitatively deliver a specific amount of lubricant to the tablet. They also allow accurate determination of the amount of lubricant delivered to
each tablet, even though the quantity of lubricant
that ends up in the tablet granulation formulation
is significantly decreased,” she observes. As a result, not only are the material handling properties
of the granulation process improved, the overall
dissolution rates of tablets can be increased. The
lower quantities of lubricants required for tableting have also led to a need for lower and lower
feed rate deliveries, according to Nowak. “For this
reason, automated lubricant feeding systems today
require highly accurate, specialized low-rate feeding,” she says.
Coperion K-Tron’s solution uses patented load
cell technology that continuously measures the
weight of the lubricant and maintains a constant
mass flow (weight per unit of time) by adjusting
6
the speed of the twin-screw feeder. As a result, according to Nowak, the unit can be validated for a
steady and uniform feed of lubricant to the tablet
press. In addition, because the lubricant is delivered to the tools in a fraction of a second, the shortterm accuracy is high. “With a nearly constant feed
rate, it is possible to achieve uniform coating of
the tablet tools and eliminate sticking problems,
all with reduced stearate consumption and lower
overall operating costs,” Nowak states.
Multi-tipped tooling and advanced coatings
The key drivers in tablet manufacturing are the
need to increase yield and capacity while reducing manufacturing costs and minimizing the space
used and the time spent setting up each press, and
increasing productivity has always been a challenge in modern tablet production, according to
Steve Deakin, owner director of I Holland. That is
why he believes the widespread use of multi-tipped
tooling and the continued development of punchand-die treatments and coatings have been great
advances in the pharmaceutical industry.
“Our ongoing development of multi-tip tooling is
specifically driven by the desire to assist our customers in increasing productivity and capacity,”
he says. Multi-tip punches allow the number of
tablets per turret rotation to be multiplied by the
number of tips on the punch. They also require less
floor space, because more tablets can be produced
with fewer tablet presses, leading to a reduction in
overall plant running costs. “The development of
a technology like multi-tip tooling is beneficial to
many end users,” says Deakin.
With respect to treatment and coating technologies, I Holland categorizes them based on their
function: improving wear resistance, improving
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
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Tableting
corrosion resistance, and improving anti-stick
properties. “Treatments and coatings with these
properties can help preserve the life of our punches
and increase productivity for our customers,” Deakin comments. “The overall result is reduced press
downtime and increased productivity, which is
what every company wants,” he adds.
Continuous manufacturing, QbD, and PAT
The development of effective equipment for continuous tablet production—from feeders to tableting machines to coaters—has had a major impact
on the growing adoption of continuous processing.
Pharmaceutical companies are also beginning to
understand the significant benefits that continuous tableting can bring, from increased productivity and quality to increased manufacturing and
marketing flexibility. “The focus on continuous
manufacturing of solid oral dosage forms by large
pharma companies like Pfizer, Merck, Eli Lilly, and
Vertex is a notable sign that batch process methods
are waning and the move toward continuous manufacturing is accelerating when the application is
appropriate,” according to Charles N. Kettler, director of Natoli Scientific, a business unit of Natoli Engineering Company. He also notes that the
use of quality-by-design (QbD) concepts and PAT
dovetail nicely with the continuous manufacturing
architectures that are being developed. PAT has, in
fact, advanced to a point where manufacturers can
have confidence in the determination of product
quality throughout the process.
Need for systems integration
and data management
The marriage of the unit operations needed to
build a continuous manufacturing process is, how8
ever, requiring the vendors of these singular units
to be open to the needs of control engineers so that
the movement of the product through the process
can occur seamlessly with the support of the data
required to meet the needs of the control strategy,
according to Kettler.
Nowak notes, for example, that the increase in
continuous direct compression tablet manufacture
is requiring high integration between the ingredient feeders, PAT instrumentation, and the additional system components from the blending
operation and the tablet press. “For this reason,
advanced control systems and common protocols,
PAT technology, and the advanced ingredient
feeder control modules supplied by Coperion KTron that provide totalizer ingredient line control
based on the API feeder performance for multiple
feeders to a continuous line will be important and
require even further innovations,” she says.
“Putting together the pieces and parts for continuous manufacturing will require some new
players in the systems integration arena,” Kettler says. Much of the needed knowledge can be
learned from the chemical and food processing industries, which have experience with continuous
manufacturing and addressing these engineering
challenges. “Success will depend on making sure
that all of the pieces of the puzzle are communicating with the proper protocols, which will require
manufacturers of the various pieces of equipment
used in tableting to open their software enough to
enable the development of overall control strategies,” Kettler adds. He notes that barriers remain
that must be overcome before integrators will be
allowed access to the control software for tablet
presses and other formulation processing units.
He does believe, however, that market demand
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
will provide the energy needed to overcome those
barriers, and that opportunities will present themselves in 2015.
The move to continuous processing also presents data management challenges. The coupling
of complex processes such as high shear wet granulation with fluid bed drying and blending and
ultimately a tablet press will result in the generation of a significant amount of data. Multivariate
measurement technologies (PAT systems) also generate large quantities of data. “The challenge will
be to evolve a batch record that meets regulatory
requirements, thus protecting the patient, but is
not so onerous in size that it cannot be utilized for
ongoing process improvement,” Kettler observes.
He does note that statisticians, chemometricians,
and quality assurance experts are already working to address this challenge, but the industry will
need to work with regulators to ultimately develop
workable solutions.
Outside of continuous manufacturing, advances
in information technology have already been responsible for increased tablet press capability and
controls, according to Deakin. “Modern systems
can provide detailed information relating to the
operation and performance of the tablet presses
and help link downstream processes to ensure
quality control. The use of these technologies has
both improved tablet quality and enhanced production performance and capacity,” he asserts.
due to a lack of process understanding with respect
to the impact that raw material properties and process conditions have on final tablet properties. Increasingly, formulators and process engineers are
turning to predictive process modeling as a means
for increasing process understanding and reducing
variability.
I Holland, in collaboration with the University
of Nottingham’s Laboratory of Biophysics and Surface Analysis, United Kingdom, recently developed
a predictive model (TSAR≈Predict) that enables
the identification of the appropriate anti-stick
punch coating solution from I Holland for formulation-sticking issues without the need to carry out
expensive and time-consuming, full-scale, trialand-error experiments with several anti-stick coatings. The model considers the properties of the API
and any excipients, possible Van der Waals forces,
capillary action, deformation mechanics, the compression environment, and the chemistries of different coatings.
Discrete element and finite element method
(DEM/FEM) models are more established for the
simulation of the behavior of bulk solids during
processing. DEM has been used, for example, to
predict powder packing and flow behaviors. DEM
Solutions offers its EDEM software platform for
the optimization of bulk solids handling and processing equipment, according to the company.
Properties such as the particle size and shape
distribution, mechanical strength and stiffness,
Modeling for improved performance
surface roughness, stickiness, chemical reactivity,
Despite the significant advances in tableting tech- and surface charge are considered in the EDEM
nology, including online monitoring with PAT models.
systems and the move to continuous production
Other systems that have been applied for the
operations, the tableting process in many ways re- predictive modeling of tableting processes include
mains inefficient and variable. This inefficiency is the population balance equation and reduced order
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015
9
Tableting
models that reduce the complexity, and thus the
time and expense required to complete the calculations (1). This reduction can be achieved with multivariate analysis techniques or lower dimensional
models that are developed by fitting experimental or simulated data using a range of techniques,
including kriging, response surface methodology,
artificial neural networks, or high dimensional
model representation (1).
The company Process Systems Enterprise offers
its gPROMS modeling platform, which consists
of the ModelBuilder model development environment and gSOLIDS and gCRYSTAL specialty
applications for solids processing. This modeling
software also offers a process flowsheeting environment, which allows the development of integrated flowsheet models for process simulation
and optimization and the identification of appropriate control strategies, often with data from a
reduced number of experiments (1).
Despite advances in the development of predictive models for pharmaceutical tableting processes,
they still fall short of the desired level of performance. Models that better link particle properties
to a wider set of bulk powder properties during
processing and more accurately predict the impact
of changes in raw materials and the manufacturing process on tablet properties are needed, as are
new approaches that enable more complex modeling without increasing the computation time and
expense (1).
Reference
1. A.J. Rogers, A. Hashemi, and M.G. Ierapetritou,
Processes 1(2), 67-127 (2013). PT
Excipient Selection for User-Friendly Dosage Forms
Verena Garsuch, pharmacist, senior manager, formulation development at Hermes Pharma discusses how a qualityby-design approach allows the control of critical quality attributes and critical process parameters in excipient
selection for taste masking, dissolution rate, stability, and processing. Martin Köberle, senior manager, analytical
development at Hermes Pharma describes how hot-melt coating can mask bitter tasting APIs. They also address
technology advances that have improved excipient screening, formulation development, and processing.
10
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
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taste masking
Assessing and Improving the
Palatability of Pharmaceuticals
Muhammad Ashraf, Frank Holcombe, Jr.,
Vilayat Sayeed, and Siva Vaithiyalingam
Muhammad Ashraf is product
quality reviewer; Frank O.
Holcombe, Jr. is chemist; and
Vilayat Sayeed is supervisory
chemist all with FDA’s Office of
Lifecycle Drug Products, OPQ,
CDER. Siva Vaithiyalingam is
director of regulatory affairs with
Teva Pharmaceuticals USA.
Please address all correspondence to
[email protected]
Disclaimer: The views and opinions
presented in this article are those of
the authors and do not necessarily
reflect the views or policies of FDA.
12
T
he Merriam-Webster Dictionary defines palatable as “agreeable to the palate or taste” or “agreeable or acceptable to the
mind” (1). Taste, therefore, depends on both physiological
and psychological phenomena, and is known to vary in humans based on such factors as age, ethnicity, and geographic location.
The human tongue has approximately 10,000 taste buds (2), or receptors, capable of detecting taste. Pharmaceutical product palatability
is generally characterized based on bitterness, saltiness, sourness, and
sweetness (3).
These receptors excite specific neural pathways and, as a result, the
information is processed along with other immediate olfactory, visual,
and somatosensory inputs, as well as those from memory (4). Several
factors influence taste, including experience. Reluctance to take a bitter
medication reflects human evolution, during when humans learned to
reject harmful or poisonous materials, which tend to taste bitter (5).
Developing palatable drugs is key to breaking through this evolutionary barrier, and helps to improve patient compliance with treatment regiments. Currently, palatability is a factor in noncompliance,
which can lead to treatment failure (6) and increased resistance to
drugs, raising overall healthcare costs (7).
Taste is especially important in treatments designed for children.
In one study on children infected with HIV, for example, one third of
the patients failed to comply with the dosage regimen for a particular
drug, due to their perceptions of the drug’s taste (8). In another investigation, pediatric patient compliance with dosage regimen ranged
from 11% to 93%.
Poor compliance or non-compliance typically places children at
risk for such problems as continued recurrence of disease. In addi-
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
KIDSTOCK/BLEND IMAGES/GETTY IMAGES
Taste may be subjective,
but it is crucial to patient
compliance, particularly for
pediatric treatments. This
article reviews methods
used to improve and assess
pharmaceutical palatability.
taste masking
tion, it complicates the physician-patient relationThe European Pediatric Formulation Initiative
ship, and prevents accurate assessment of the qual- (EPFI) was founded in 2007 to address some of
ity of care provided (9).
these issues and raise awareness of the importance
of palatability in drug formulation. The initiative
is focusing on such issues as taste assessment, excipients, delivery devices, and extemporaneous
preparations (12).
This article reviews the various technological
platforms available for taste-masking, taste modification, and taste assessment, and touches on some
Ten years ago, a study published in the Neth- of the risk management challenges associated with
erlands recommended that regulatory authorities making palatable drugs products.
and the pharmaceutical industry ensure that chilTo mask or modify the taste of bitter compounds,
dren have access to more palatable medicines (10). pharmaceutical formulators must understand the
To address this universal concern and to provide chemistry of the API, identify solutions to reincentives to the pharmaceutical industry, the US duce or inhibit the bitter taste of the API without
Congress enacted the following legislation:
changing other flavor modalities (e.g., sweet, salt,
• The Best Pharmaceuticals for Children’s Act
or sour) and then choose the best taste technology
(BPCA 2002)
platform to develop the drug product.
• The Pediatric Research Equity Act (PREA
Some of the most commonly used taste-masking
2003)
approaches include:
• The FDA Amendment Act (FDAAA 2007).
• Natural and artificial flavors and sweeteners
Today, advances in pharmaceutical technology
• Polymer coatings
make it easier to design and develop such child• Multiple emulsion and liposomes
friendly products as oral films, medical chewing
• Inclusion complexes
gum, suspensions, and chewable tablets to name
• Ion-exchange complexes
a few, wherein taste-masking agents can be incor• Pro-drugs and salt formation.
porated to conceal and counter the unpleasant orThe taste-masking technology should be careganoleptic attributes of drug substance.
fully aligned with the drug product dosage form,
Finding some common ground for taste-masking patient population, and duration of therapy.
and pediatric friendly formulation, however, is not an
easy task. Standard combinations of specific sweet- Flavors, sweeteners, and other ingredients
eners with relevant flavors may vary by country and Adding flavors and sweeteners is usually the first
target market. For instance, flavors such as “bubble- choice for improving the taste of a pharmaceutical
gum” and “grape” are preferred flavors in the United formulation. Liquid flavors are used most often,
States, whereas “citrus” and “red berries” are popular because they diffuse readily into the substrate.
in Europe, and licorice in Scandinavia (11).
They are available both as oily (e.g., essential oils)
Taste is especially
important in treatments
designed for children
14
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
or non-oily liquids. Their texture generally depends on the solvent within which they are prepared (13).
Flavor systems, however, can often feature functional groups, such as aldehydes, ketones, esters, or
terpenes that can interact with actives and other
ingredients in the formulation (14).
In addition, flavors are typically volatile and
may degrade during the product’s shelf life. They
can also be degraded by pH-catalyzed, oxidationreduction, and hydrolytic reactions.
To ensure stability and prevent unacceptable
changes in the flavor of a product, flavor systems
must be compatible with other ingredients. In
some cases, for example, flavor systems may be
combined with antioxidants to reduce free radical
autoxidation.
Besides traditional sweeteners and f lavors,
other additives can be used to improve the taste
of pharmaceutical formulations. These include
amino acids and their salts (e.g., alanine, taurine,
glutamic acid, and glycine), which are known
to reduce the bitterness of drugs. Some patients,
for example, found that the taste of ampicillin
improved markedly when its granules had been
prepared with glycine and mixed with additional
quantity of glycine, sweeteners, flavors, and finally
compressed into tablets (15).
Lipoproteins can also be effective in suppressing the bitter taste of basic and hydrophobic drugs.
Incorporating it into a liposomal formulation with
egg phyosphotydyl choline (16), for example, successfully masked the bitter taste of chloroquine
phosphate in HEPES (N-2-Hydroxyethylpiperazine -N’-2) -ethane sulfonic acid) buffer at pH 7.2
Increasing the viscosity of liquid formulations
with thickening agents such as polyethylene glycol,
sodium carboxy methylcellulose, gums, or carbohydrates can also mask bitter taste by lowering the
rate of diffusion of bitter substances from the saliva to the taste buds. Acetaminophen suspension,
for example, has been formulated with xanthan
gum (0.1-0.2%) and microcrystalline cellulose (0.61%) to reduce bitter taste, while the antidepressant
mirtazapine has been formulated as an aqueous
suspension using methionine (stabilizer) and
maltitol (thickening agent). Maltitol, stable in the
acidic pH range of 2 to 3, has the added benefit of
inhibiting the drug’s undesirable local anesthetic
effect (17–18).
Flavors and sweeteners have also been used to
mask unpleasant taste in orally disintegrating
tablets (ODTs) (19) and rapidly dissolving films
(RDFs). For example, mannitol and licorice, and
sugar-based excipients, using glucose, sucrose, sucralose, and fructose and other ingredients have
been used to improve the flavor of ODT formulations (20–22).
Sucralose, which is 600 times sweeter than sugar,
has been used with mint and licorice flavors to
mask the taste of diclofenac sodium maltodextrin
RDFs (23). The films were prepared by casting and
drying aqueous mixtures of maltodextrin, glycerin,
sorbitan oleate, and diclofenac sodium. The tastemasking agents were added in very low concentration (sucralose, mint, and licorice at 1%, 6%, and
3% w/w) and did not significantly affect the tensile
properties and film disintegration time.
In addition, sucralose, citric acid, aspartame,
and passion fruit flavor have been used in an RDF
formulation of cetirizine hydrochloride, a watersoluble drug with bitter taste. This dosage form
was developed specifically for patients who have
difficulty swallowing tablets (24).
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015
15
taste masking
Polymeric coatings
Polymers that are insoluble in saliva are frequently used to mask the bitter taste of some
drugs. The cationic copolymer, Eudragit E100
amino methacrylate copolymer, for example,
can be used to coat the microspheres used
in suspensions, and the granulations used in
ODTs. The polymer’s pH profile helps ensure
that active ingredient is released in the stomach
and not in the mouth, because Eudragit E100
is soluble below a pH of 5 in the stomach, but
insoluble in saliva, where the average pH is 6.4
(25). Granulations coated by the polymer, however, can rupture during compression or tablet
chewing, and patient tests show that they can
contribute to a gritty feel in the mouth. Microspheres coated with the same material did not
rupture.
Eudragit E100 can also be used in spray drying
processes. In one process, the polymer was used
to coat microspheres of donepezil hydrochloride,
using spray-drying technology (26). In this study,
a drug-to-polymer ratio of 1:2 was found to prevent drug release in simulated salivary fluid. The
taste-masked microspheres were then formulated
into an ODT.
In another example, taste-masked microspheres
of famotidine were prepared by spray drying a suspension of finely ground famotidine (5 micron) in
an aqueous dispersion of Eudragit EPO (15%, w/v).
The microspheres were then mixed with other
tableting ingredients suitable for ODT and compressed into tablets (27).
Techniques such as solvent diffusion, precipitation, and multiple emulsion have also been used
to process polymer-coated pharmaceuticals. For
instance:
16
• Eudragit E100 has been used to coat microparticles of Indinavir, a bitter-tasting HIV
drug, by using a double emulsion solvent diffusion technique. The microparticles were
then used to make a pediatric suspension (28).
• Eudragit EPO, an aminoalkyl methacrylate
copolymer was complexed with Ondansetron
HCl, a bitter-tasting drug using precipitation.
The best results were seen at a drug-to-polymer ratio of 8:2, and results were evaluated by
dissolution in simulated salivary fluid of pH
6.2 and then in human volunteers. The tastemasked drug-polymer complex was then formulated into an ODT using spray-dried mannitol, microcrystalline cellulose, and
Polyplasdone XL-10 (29).
• The natural polymer, chitosan, has also been
used to mask bitter taste in microspheres of
Ondansetron HCl. Chitosan, a high molecular weight, polycationic polyamine, linear
polysaccharide derived from crustacean
shells, readily dissolves in inorganic acids but
is insoluble approximately above pH 6.5 (30).
A 1:1 drug-to-polymer ratio successfully
achieved taste-masking without any chemical
interaction and loss of crystallinity (31).
These polymers have also been used as binders
for the manufacture of granulations of bitter tasting drugs. The taste-masked granulations can be
further formulated into various types of tablet dosage forms such as ODTs and chewable tablets. In
tests, tablets of Zidovudine, a bitter-tasting antiretroviral drug prepared by a wet granulation method
using Surelease as binder, were found to taste better
than tablets prepared by direct compression (32).
Eudragit E-100 has also been used to mask the
flavor of bitter tasting pirenzepine and oxybutynin,
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
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taste masking
using extrusion and compression (33). Eudragit E,
which dissolves in acidic environments, has been
used with Fattibase, a mixture of palm, palm kernel, and coconut oil triglycerides that melt at body
temperature, to develop coatings for drug particles
that mask bitter flavors. The coated particles were
used to make liquid suspensions, and testing found
that flavor had been masked completely (34).
Multiple emulsions
stants for α and γ cyclodextrin were found lower
when compared to the association constant of
β-cyclodextrin (36).
Similar results were reported in studies of the
taste-masking effect of cyclodextrins on such antihistamines as hydroxyzine, cetirizine, and dlchlorpheniramine. The taste-masking was found
related to the respective association constant decreasing in the following order: Hydroxy propyl β
cyclodextrin, β cyclodextrin, α cyclodextrin, and
γ cyclodextrins. Studies found that primaquine
phosphate’s bitter taste was completely masked by
formation of inclusion complex with β cyclodextrin (37–39).
Taste-masking can be also be achieved by incorporating drugs into the inner aqueous phase of
water-oil-water (W/O/W) multiple emulsions, in
which either the oil layer or the water layer masks
the test. This approach has reportedly worked for
formulations of chloroquin phosphate and chlor- Ion-exchange resins
promazine (35).
Ion-exchange resins have also been used to mask
flavor in pharmaceuticals. These resins are high
Inclusion complexes
molecular weight, water-insoluble polyelectrolyte
Inclusion complexes with cyclodextrins have been polymers that are not absorbed by the body and
used to improve the palatability of drug substances. therefore are safe for oral use. These polymers
Cyclodextrins are cyclic oligosaccharides, which have extensively charged cationic and anionic
have the ability to form a host/guest inclusion com- functional groups, which can form complexes with
plex both in solution and in solid phase. Molecules ionizable drugs via ion-exchange. The resulting
or functional groups causing unpleasant taste can drug-resinate possesses the properties of resin.
be encapsulated within the cyclodextrin cavity, so
Because the resins are insoluble in water, the exthat they do not come in contact with the taste posure of drug to the taste buds in the oral cavity
bud. Once the drug substance forms an inclusion is limited. Once swallowed, however, the drug is
complex with cyclodextrin, it exhibits properties released from the resinate due to high ionic condifferent than those of the parent drug substance, centration in the gastrointestinal tract, which desuch as improved dissolution and taste.
pends on several factors such as, the nature of the
The taste-masking effect of various types of cy- reaction between drug ion and resin, drug loadclodextrin complexes may be correlated to their ing, type of ion (cation vs anion), ionic strength,
respective association constants. It is reported that and other formulation factors. Tests have shown
β-cyclodextrin provides the highest taste-masking that ion-exchange resins can be effective in tasteeffect for cetirizine, while α and γ cyclodextrin masking for several drugs such as Etoricoxib, dexprovide the poorest results. The association con- tromethorphan, and Risperidone (40–42).
18
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 P h a r mTe c h . c o m
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taste masking
Prodrugs and salt formation
It is postulated that bitter taste is perceived when
a bitter-tasting drug binds directly to taste receptors. This binding, however, depends on molecular
geometry. Changing this geometry by derivative
formation will alter the affinity of the drug molecule to the taste receptor. Several antibiotics such
as Chloramphenicol palmitate or phosphate esters
for pediatric suspension and alkyl esters of Clindamycin and Erythromycin show how prodrugs can
be used for bitter taste-masking.
Conversion of a drug to a salt has also been found
to mask bitter drug taste by altering the chemical
group that is responsible for the bitter taste. An example of this approach is chlorpheniramine maleate, a taste-masked salt of chlorpheniramine base.
Testing has shown that the alkyloxy alkyl carbonates of clarithromycin have remarkably drecreased
bitterness and improved bioavailability (43–46).
Measuring palatability: Art or science?
Taste assessment for pharmaceutical products is
complicated, due to the qualitative measurement
and the inherent differences and preferences
among the subjects. It becomes even more difficult when the taste assessment involves the pediatric population. For instance, in one such study,
the end point-of-taste assessment was based on selecting a face from a list of five faces that portrayed
happiness to sadness progressively (47).
Such an assessment rating scale, as concluded
by the study authors, has the following limitations. First, the taste was assessed indirectly, and
secondly, the subjects can be influenced by their
own perception of the odor or taste of the product,
and finally, there is no universal standard used in
the study.
20
The use of analytical devices in the drug-development phase has improved the taste-assessment process, and this has led to a more robust, reproducible
taste assessment method using objective electronic
devices such as electronic tongues. These are essentially analytical instruments made of chemical
sensors with specificity to different compounds in
the solution. These sensors are non-specific, low
selective chemical sensors with partial specificity
for cross-sensitivity to a range of organic and inorganic substances in solution, and they are coupled
with chemometric data processing tools (48).
A typical electronic tongue is based on potentiometric or voltametric sensors; however, in theory,
any kind of sensor could be built into an electronic
tongue. What is more important is that an appropriate set of sensors responds to a range of compound taste attributes, and takes into account such
interactions as suppression as well as synergetic
effects, so that sensor responses represent human
perception end points (49).
Several studies have utilized electronic tongues to
assess the taste of the pharmaceutical product. In
one case, an electronic tongue was used to select a
taste-masking agent in the manufacture of diclofenac fast-dissolving film (27). The authors concluded
that the electronic tongue allowed them to discern
the effect of a taste-masking agent in the presence of
other hydrosoluble constituents of the film.
Other studies suggest that the e-Tongue can be
a useful tool in taste assessment, enhancement,
and masking studies for such intensely bitter substances as epinephrine bitartarate, where the device has been used to screen different sweetening
and/or flavoring ingredients and to determine the
agent that best masks the unpleasant taste of the
API (50).
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taste masking
The electronic tongue is often used to screen the
taste-masking effect of sweetening agents in pharmaceutical formulations. In one case, the electronic
tongue was used to investigate the taste-masking
effect of glucose, sucrose, sucralose, fructose, mannitol, sodium saccharin, acesulfame potassium,
monoammonium glycyrrhizinate, and other sweetening agents, to formulate liquid quinine hydrochloride (51) as well as other drugs (52–54).
compliance concern, it is necessary to address the
issue of palatability through proper selection of ingredients during development of the drug product
formulation. Presently a number of approaches are
used for taste-masking such as inclusion of sweeteners and flavors, coating with pH sensitive polymers which are insoluble in the mouth but dissolve
readily in the stomach, inclusion complexes, and
complex of drug with ion-exchange resins. These
taste-masking techniques have been successfully
Risk considerations
exploited in several dosage forms such as liquids,
The choice of flavors, sweeteners, and polymers fast dissolving films, matrix formulations, and wet
used in the taste-masking platform should be care- granulated formulations.
fully aligned with the dosage form, patient population, duration of therapy, and the levels of these References
ingredients listed in the CDER approved products. 1. Webster’s Ninth Collegiate Dictionary (MerriamWebster Inc., 1988).
This information is available in the Inactive In- 2. E.T. Rolls, et al., Annals of the New York Academy of
Sciences 855 (1), 426-437 (1998).
gredients Database (IID) of CDER approved drugs.
3. Umami Information Center, www.umamiinfo.com
Amounts used in the product formulations beyond 4. D. Baguley, et al, Arch. Dis. Child. 97, 293-297 (2012).
the levels listed in the IID, or if the amount listed 5. J.I.M. Glendinning, Physiology & Behavior. 56(6),
1217-1227 (1994).
in the database is used in a therapeutic category
6. WHO, “Drug Resistance: HIV/AIDS,” World Health
that would not support the use of the same ingrediOrganization, www.who.int/drugresistance/hivaids/en/
7.
B.
Hovstadius and G. Petersson, BMC Health Serent in the proposed therapeutic oral dosage form,
vices Research 11: 326 (2011).
may require additional studies.
8. D. Lin, J.A. Seabrook, D.M. Matsui, S.M. King, M.J.
Aspartame (methyl ester of phenylalanine) is an
Rieder and Y. Finkelstein, Pharmacoepidemiology
and
Drug Safety, 20(12): 1246–1252 (2011).
artificial sweetener used in a number of CDER9. S. Winnick, et al, Pediatrics, 115(6), e718-e724
approved oral drug products but requires a warn(2005).
ing on the label, because it is a source of phenylala- 10. E. Schirm, et al, Acta Padeiatr. 92(12), 1486-1489
(2003).
nine and a possible concern for phenylketoneurics.
11. Committee for Medicinal Products for Human Use:
Thus its use should be carefully assessed in the
Reflection Paper: Formulations of Choice for the
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