eb o o k s e r ie

Solid doSage
and
excipientS
 Solid D o s a g e & E x c i p i e n t s 2015

TableTing

EDITORIAL
4 Advances in Tableting
Editorial Director Rita Peters rpeters@advanstar.com Cynthia A. Challener
Senior Editor Agnes Shanley ashanley@advanstar.com
Managing Editor Susan Haigney shaigney@advanstar.com
Science Editor Adeline Siew, PhD asiew@advanstar.com
Manufacturing Editor Jennifer Markarian jmarkarian@advanstar.com TasTe masking
Science Editor Randi Hernandez rhernandez@advanstar.com
Community Editor Ashley Roberts aroberts@advanstar.com 12 Assessing and Improving
Art Director Dan Ward
Contributing Editors Jill Wechsler jwechsler@advanstar.com; Jim Miller the Palatability of Pharmaceuticals
info@ pharmsource.com; Hallie Forcinio editorhal@cs.com; Susan J.
Schniepp sue.schniepp@mac.com; Eric Langer
Muhammad Ashraf, Frank Holcombe, Jr.,
info@bioplanassociates.com; Vilayat Sayeed, and Siva Vaithiyalingam
and Cynthia A. Challener, PhD challener@vtlink.net
Correspondents Hellen Berger (Latin/South America,
hellen.berger@terra.com.br),
Oral DOsage FOrmulaTiOn
Sean Milmo (Europe, smilmo@btconnect.com), and Jane Wan
(Asia, wanjane@live.com.sg)
Address
24 Using Polymers for More Efficient
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34 Analytical Techniques
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40 Simplify Formulation With PAT
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Tableting

Advances in Tableting
C y n t h i a A. C h a l l e n e r

Innovative equipment,
analytical techniques,
software, and
modeling systems are
improving the
F or many reasons—from ease of administration to dosing
ac-
curacy to manufacturing efficiency—pharmaceutical manu-
facturers 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
tableting process.
technology, including continuous production equipment and the
process analyti- cal 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 improv- ing 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.
Tablet press lubrication
Lubricants (commonly magnesium stearate) affect the tableting
pro- cess 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
L a u r e n B u r k e / G e t t y ImaGes

development manager with Coperion K-Tron Food &

Cynthia A. Challener, PhD,
is a contributing editor to
pharmaceutical technology.
4 Pharmaceutical Technology S o l i d d o S tablet
com
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 lubri- cant. To
compensate, excess lubricant is used, which can negatively affect
a g e & properties.
ex ci pi en t S 2015 PharmTech.
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Tableting
Recently, equipment has been developed that al- the speed of the twin-screw feeder. As a result, ac-
lows for spraying of the lubricant onto the tablet cording to Nowak, the unit can be validated for a
press tooling, allowing for significant reduction in steady and uniform feed of lubricant to the tablet
the quantity of lubricant required. Original sys- press. In addition, because the lubricant is deliv-
tems sprayed powdered lubricants on to the tab- ered to the tools in a fraction of a second, the
let press tooling to prevent sticking of the short- term accuracy is high. “With a nearly
powder to the tool and die of the tablet press, constant feed rate, it is possible to achieve
according to Nowak. Importantly, these uniform coating of the tablet tools and
applications were done primarily volumetrically, eliminate sticking problems, all with reduced
with no measure- ment of the actual weight of the stearate consumption and lower overall operating
lubricant delivered. Magnesium stearate does not costs,” Nowak states.
flow well, which can cause high variations in the Multi-tipped tooling and advanced coatings
feed rate with volu- metric feeders because of The key drivers in tablet manufacturing are the
inconsistent filling of the twin screws. As a need to increase yield and capacity while reduc-
result, there has been an in- creased demand for ing manufacturing costs and minimizing the space
automated tablet press lubrica- tion systems with used and the time spent setting up each press, and
highly accurate gravimetric feed designs, increasing productivity has always been a chal-
according to Nowak. lenge in modern tablet production, according to
“High accuracy twin-screw gravimetric feeders Steve Deakin, owner director of I Holland. That is
quantitatively deliver a specific amount of lubri- why he believes the widespread use of multi-
cant to the tablet. They also allow accurate tipped tooling and the continued development of
deter- mination of the amount of lubricant punch- and-die treatments and coatings have
delivered to each tablet, even though the quantity been great advances in the pharmaceutical
of lubricant that ends up in the tablet granulation industry.
formulation is significantly decreased,” she “Our ongoing development of multi-tip tooling is
observes. As a re- sult, not only are the material specifically driven by the desire to assist our cus-
handling properties of the granulation process tomers in increasing productivity and capacity,”
improved, the overall dissolution rates of tablets he says. Multi-tip punches allow the number of
can be increased. The lower quantities of tablets per turret rotation to be multiplied by the
lubricants required for tablet- ing have also led number of tips on the punch. They also require
to a need for lower and lower feed rate less floor space, because more tablets can be
deliveries, according to Nowak. “For this reason, produced with fewer tablet presses, leading to a
automated lubricant feeding systems today require reduction in overall plant running costs. “The
highly accurate, specialized low-rate feed- ing,” development of a technology like multi-tip tooling
she says. is beneficial to many end users,” says Deakin.
Coperion K-Tron’s solution uses patented load With respect to treatment and coating technol-
cell technology that continuously measures the ogies, I Holland categorizes them based on their
weight
6
of the lubricant and maintains a 2015 PharmTech.
Pharmaceutical Technology S o l i d d o S a g e & ex ci pi en t S function: improving wear resistance, improving
constant
com mass flow (weight per unit of time) by
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Tableting
corrosion resistance, and improving anti-stick ever, requiring the vendors of these singular units
properties. “Treatments and coatings with these to be open to the needs of control engineers so
properties can help preserve the life of our that the movement of the product through the
punches and increase productivity for our process can occur seamlessly with the support of
customers,” Dea- kin comments. “The overall the data required to meet the needs of the
result is reduced press downtime and increased control strategy, according to Kettler.
productivity, which is what every company Nowak notes, for example, that the increase in
wants,” he adds. continuous direct compression tablet manufacture
Continuous manufacturing, QbD, and PAT is requiring high integration between the ingre-
The development of effective equipment for con- dient feeders, PAT instrumentation, and the ad-
tinuous tablet production—from feeders to tablet- ditional system components from the blending
ing machines to coaters—has had a major impact operation and the tablet press. “For this reason,
on the growing adoption of continuous processing. advanced control systems and common protocols,
Pharmaceutical companies are also beginning to PAT technology, and the advanced ingredient
understand the significant benefits that continu- feeder control modules supplied by Coperion K-
ous tableting can bring, from increased produc- Tron that provide totalizer ingredient line control
tivity and quality to increased manufacturing and based on the API feeder performance for multiple
marketing flexibility. “The focus on continuous feeders to a continuous line will be important and
manufacturing of solid oral dosage forms by large require even further innovations,” she says.
pharma companies like Pfizer, Merck, Eli Lilly, and “Putting together the pieces and parts for con-
Vertex is a notable sign that batch process methods tinuous manufacturing will require some new
are waning and the move toward continuous man- players in the systems integration arena,” Ket-
ufacturing is accelerating when the application is tler says. Much of the needed knowledge can be
appropriate,” according to Charles N. Kettler, di- learned from the chemical and food processing in-
rector of Natoli Scientific, a business unit of Na- dustries, which have experience with continuous
toli Engineering Company. He also notes that the manufacturing and addressing these engineering
use of quality-by-design (QbD) concepts and PAT challenges. “Success will depend on making sure
dovetail nicely with the continuous manufacturing that all of the pieces of the puzzle are
architectures that are being developed. PAT has, in communicat- ing with the proper protocols,
fact, advanced to a point where manufacturers can which will require manufacturers of the various
have confidence in the determination of product pieces of equipment used in tableting to open
quality throughout the process. their software enough to enable the development
of overall control strate- gies,” Kettler adds. He
Need for systems integration notes that barriers remain that must be
and data management overcome before integrators will be allowed
The marriage of the unit operations needed to access to the control software for tablet presses
build a continuous manufacturing process is, and other formulation processing units. He
how-Pharmaceutical Technology S o l i d d o S a g e & ex ci pi en t S does
8
believe, however, that market demand
2015 PharmTech.
com
will provide the energy needed to overcome those due to a lack of process understanding with respect
barriers, and that opportunities will present to the impact that raw material properties and
them- selves in 2015. pro- cess conditions have on final tablet
The move to continuous processing also pres- properties. In- creasingly, formulators and process
ents data management challenges. The coupling engineers are turning to predictive process
of complex processes such as high shear wet gran- modeling as a means for increasing process
ulation with fluid bed drying and blending and understanding and reducing variability.
ultimately a tablet press will result in the genera- I Holland, in collaboration with the University
tion of a significant amount of data. Multivariate of Nottingham’s Laboratory of Biophysics and Sur-
measurement technologies (PAT systems) also gen- face Analysis, United Kingdom, recently developed
erate large quantities of data. “The challenge will a predictive model (TSAR≈Predict) that enables
be to evolve a batch record that meets regulatory the identification of the appropriate anti-stick
requirements, thus protecting the patient, but is punch coating solution from I Holland for formu-
not so onerous in size that it cannot be utilized lation-sticking issues without the need to carry
for ongoing process improvement,” Kettler out expensive and time-consuming, full-scale,
observes. He does note that statisticians, trial- and-error experiments with several anti-
chemometricians, and quality assurance experts stick coat- ings. The model considers the
are already work- ing to address this challenge, properties of the API and any excipients, possible
but the industry will need to work with regulators Van der Waals forces, capillary action,
to ultimately develop workable solutions. deformation mechanics, the com- pression
Outside of continuous manufacturing, advances environment, and the chemistries of dif- ferent
in information technology have already been re- coatings.
sponsible for increased tablet press capability and Discrete element and finite element method
controls, according to Deakin. “Modern systems (DEM/FEM) models are more established for the
can provide detailed information relating to the simulation of the behavior of bulk solids during
operation and performance of the tablet presses processing. DEM has been used, for example, to
and help link downstream processes to ensure predict powder packing and flow behaviors. DEM
quality control. The use of these technologies has Solutions offers its EDEM software platform for
both improved tablet quality and enhanced pro- the optimization of bulk solids handling and pro-
duction performance and capacity,” he asserts. cessing equipment, according to the company.
Properties such as the particle size and shape
Modeling for improved performance distribution, mechanical strength and stiffness,
Despite the significant advances in tableting tech- surface roughness, stickiness, chemical reactivity,
nology, including online monitoring with PAT and surface charge are considered in the EDEM
systems and the move to continuous production models.
operations, the tableting process in many ways Other systems that have been applied for the
re- mains inefficient and variable. This predictive modeling of tableting processes
inefficiency is include the population balance equation and
Pharmaceutical Technology S o l i d d o S a g e & ex c ip ie nt S 2015 9
reduced order
Tableting
models that reduce the complexity, and thus the and optimization and the identification of appro-
time and expense required to complete the priate control strategies, often with data from a
calcula- tions (1). This reduction can be achieved reduced number of experiments (1).
with mul- tivariate analysis techniques or lower Despite advances in the development of predic-
dimensional models that are developed by tive models for pharmaceutical tableting
fitting experimen- tal or simulated data using a processes, they still fall short of the desired level
range of techniques, including kriging, response of perfor- mance. Models that better link particle
surface methodology, artificial neural networks, properties to a wider set of bulk powder
or high dimensional model representation (1). properties during processing and more accurately
The company Process Systems Enterprise offers predict the impact of changes in raw materials
its gPROMS modeling platform, which consists and the manufactur- ing process on tablet
of the ModelBuilder model development envi- properties are needed, as are new approaches that
ronment and gSOLIDS and gCRYSTAL specialty enable more complex model- ing without
applications for solids processing. This modeling increasing the computation time and expense (1).
software also offers a process flowsheeting envi-
Reference
ronment, which allows the development of inte- 1. A.J. Rogers, A. Hashemi, and M.G. Ierapetritou,
grated flowsheet models for process simulation Processes 1(2), 67-127 (2013). P T

Excipient Selection for User-Friendly Dosage Forms

Verena Garsuch, pharmacist, senior manager, formulation development at Hermes Pharma discusses how a quality-
by-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 S o l i d d o S a g e & ex c ipi en t S 2015 PharmTech.

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taste masking
Assessing and Improving the
Palatability of Pharmaceuticals
M u h a m m a d A s h r a f , F r a n k H o l c o m b e , Jr.,
Vi l a y at S a y e e d , a n d S i v a Va i t h i y a l i n g a m
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.
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
vilayat.sayeed@fda.hhs.gov
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 Pharmaceutical Technology S o l i d d o Srisk
T
he Merriam-Webster Dictionary defines palatable as
“agree-
able 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
mans based on such factors as age, ethnicity, and geographic
hu-
location.
The human tongue has approximately 10,000 taste buds (2), or
recep- tors, 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
evolu- tionary barrier, and helps to improve patient compliance
with treat- ment 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.
imAgES
In one study on children infected with HIV, for example, one third
KiDSTOCK/BLEnD i m A g E S / g E T Ty
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 in- vestigation, pediatric patient compliance with dosage
regimen ranged from 11% to 93%.
Poor compliance or non-compliance typically places children at
for such problems as continued recurrence of disease. In
a g e & e x c i p i e n t S 2015 PharmTech. com
addi-
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taste masking
tion, it complicates the physician-patient relation- The European Pediatric Formulation Initiative
ship, and prevents accurate assessment of the (EPFI) was founded in 2007 to address some of
qual- 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
Taste is especially assessment, ex- cipients, delivery devices, and
important in extemporaneous preparations (12).
treatments designed This article reviews the various technological
platforms available for taste-masking, taste modifi-
for children cation, 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 chil- To mask or modify the taste of bitter
dren have access to more palatable medicines compounds, pharmaceutical formulators must
(10). To address this universal concern and to understand the chemistry of the API, identify
provide incentives to the pharmaceutical solutions to re- duce or inhibit the bitter taste of
industry, the US Congress enacted the following the API without changing other flavor modalities
legislation: (e.g., sweet, salt, or sour) and then choose the best
• The Best Pharmaceuticals for Children’s Act taste technology platform to develop the drug
(BPCA 2002) product.
• The Pediatric Research Equity Act (PREA Some of the most commonly used taste-
2003) masking approaches include:
• The FDA Amendment Act (FDAAA • Natural and artificial flavors and sweeteners
2007). • Polymer coatings
Today, advances in pharmaceutical technology • Multiple emulsion and liposomes
make it easier to design and develop such child- • Inclusion complexes
friendly products as oral films, medical chewing • Ion-exchange complexes
gum, suspensions, and chewable tablets to name • Pro-drugs and salt formation.
a few, wherein taste-masking agents can be incor- The taste-masking technology should be care-
porated to conceal and counter the unpleasant or- fully aligned with the drug product dosage form,
ganoleptic attributes of drug substance. patient population, and duration of therapy.
Finding some common ground for taste- Flavors, sweeteners, and other ingredients Adding
masking and pediatric friendly formulation, flavors and sweeteners is usually the first choice
however, is not an easy task. Standard for improving the taste of a pharmaceutical
combinations of specific sweet- eners with relevant formulation. Liquid flavors are used most often,
flavors may vary by country and target market. For because they diffuse readily into the substrate.
instance, flavors such as “bubble- gum” and “grape” They are available both as oily (e.g., essential oils)
are preferred flavors in the United States, whereas
14 Pharmaceutical Technology S o l i d d o Sa g e & ex c ip ie nt S 2015 PharmTech.
“citrus”
com and “red berries” are popular in Europe,
or non-oily liquids. Their texture generally de- sodium carboxy methylcellulose, gums, or carbo-
pends on the solvent within which they are pre- hydrates can also mask bitter taste by lowering the
pared (13). rate of diffusion of bitter substances from the sa-
Flavor systems, however, can often feature func- liva to the taste buds. Acetaminophen
tional groups, such as aldehydes, ketones, esters, or suspension, for example, has been formulated
terpenes that can interact with actives and other with xanthan gum (0.1-0.2%) and
ingredients in the formulation (14). microcrystalline cellulose (0.6- 1%) to reduce
In addition, f lavors are typically volatile and bitter taste, while the antidepressant mirtazapine
may degrade during the product’s shelf life. They has been formulated as an aqueous suspension
can also be degraded by pH-catalyzed, oxidation- using methionine (stabilizer) and maltitol
reduction, and hydrolytic reactions. (thickening agent). Maltitol, stable in the acidic
To ensure stability and prevent unacceptable pH range of 2 to 3, has the added benefit of
changes in the flavor of a product, flavor systems inhibiting the drug’s undesirable local anesthetic
must be compatible with other ingredients. In effect (17–18).
some cases, for example, flavor systems may be Flavors and sweeteners have also been used to
combined with antioxidants to reduce free mask unpleasant taste in orally disintegrating
radical autoxidation. tablets (ODTs) (19) and rapidly dissolving films
Besides traditional sweeteners and f lavors, (RDFs). For example, mannitol and licorice, and
other additives can be used to improve the taste sugar-based excipients, using glucose, sucrose, su-
of pharmaceutical formulations. These include cralose, and fructose and other ingredients have
amino acids and their salts (e.g., alanine, taurine, been used to improve the flavor of ODT formula-
glutamic acid, and glycine), which are known tions (20–22).
to reduce the bitterness of drugs. Some patients, Sucralose, which is 600 times sweeter than
for example, found that the taste of ampicillin sugar, has been used with mint and licorice
improved markedly when its granules had been flavors to mask the taste of diclofenac sodium
prepared with glycine and mixed with additional maltodextrin RDFs (23). The films were prepared
quantity of glycine, sweeteners, flavors, and finally by casting and drying aqueous mixtures of
compressed into tablets (15). maltodextrin, glycerin, sorbitan oleate, and
Lipoproteins can also be effective in suppress- diclofenac sodium. The taste- masking agents
ing the bitter taste of basic and hydrophobic were added in very low concentra- tion
drugs. Incorporating it into a liposomal (sucralose, mint, and licorice at 1%, 6%, and 3%
formulation with egg phyosphotydyl choline (16), w/w) and did not significantly affect the tensile
for example, suc- cessfully masked the bitter properties and film disintegration time.
taste of chloroquine phosphate in HEPES (N-2- In addition, sucralose, citric acid, aspartame,
Hydroxyethylpipera- zine -N’-2) -ethane sulfonic and passion fruit flavor have been used in an RDF
acid) buffer at pH 7.2 formulation of cetirizine hydrochloride, a water-
Increasing the viscosity of liquid formulations soluble drug with bitter taste. This dosage form
with thickening agents such as polyethylene was developed specifically for patients who have
Pharmaceutical Technology S o l i d d o S a g e & ex c ip ie nt S 2015 15
glycol, difficulty swallowing tablets (24).
taste masking
Polymeric coatings
Polymers that are insoluble in saliva are fre-
quently 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, how-
ever, can rupture during compression or tablet
chewing, and patient tests show that they can
contribute to a gritty feel in the mouth. Micro-
spheres 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 pre-
vent 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
sus- pension of finely ground famotidine (5
micron) in an aqueous dispersion of Eudragit EPO for the manufacture of granulations of bitter tast-
(15%, w/v). The microspheres were then mixed ing drugs. The taste-masked granulations can be
with other tableting ingredients suitable for
ODT and com- pressed into tablets (27).
Techniques such as solvent diffusion, precipita-
tion, and multiple emulsion have also been used
to process polymer-coated pharmaceuticals. For
instance:
16 Pharmaceutical Technology S o l i d d o S a g e
& ex c ipi en t S 2015 PharmTech.
com
• Eudragit E100 has been used to coat micro-
particles of Indinavir, a bitter-tasting HIV
drug, by using a double emulsion solvent dif-
fusion 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-poly-
mer ratio of 8:2, and results were evaluated
by dissolution in simulated salivary fluid of
pH
6.2 and then in human volunteers. The taste-
masked drug-polymer complex was then for-
mulated into an ODT using spray-dried man-
nitol, 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 molecu-
lar 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
further formulated into various types of tablet
dos- age forms such as ODTs and chewable
tablets. In tests, tablets of Zidovudine, a bitter-
tasting antiret- roviral 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
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taste masking
using extrusion and compression (33). Eudragit E, stants for α and γ cyclodextrin were found lower
which dissolves in acidic environments, has been when compared to the association constant of
used with Fattibase, a mixture of palm, palm ker- β-cyclodextrin (36).
nel, and coconut oil triglycerides that melt at body Similar results were reported in studies of the
temperature, to develop coatings for drug particles taste-masking effect of cyclodextrins on such an-
that mask bitter flavors. The coated particles tihistamines as hydroxyzine, cetirizine, and dl-
were used to make liquid suspensions, and testing chlorpheniramine. The taste-masking was found
found that flavor had been masked completely related to the respective association constant de-
(34). creasing in the following order: Hydroxy propyl β
Multiple emulsions cyclodextrin, β cyclodextrin, α cyclodextrin, and
Taste-masking can be also be achieved by incor- γ cyclodextrins. Studies found that primaquine
porating drugs into the inner aqueous phase of phosphate’s bitter taste was completely masked by
water-oil-water (W/O/W) multiple emulsions, in formation of inclusion complex with β cyclodex-
which either the oil layer or the water layer masks trin (37–39).
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 therefore are safe for oral use. These polymers
substances. Cyclodextrins are cyclic have extensively charged cationic and anionic
oligosaccharides, which have the ability to form a functional groups, which can form complexes
host/guest inclusion com- plex both in solution with ionizable drugs via ion-exchange. The
and in solid phase. Molecules or functional resulting drug-resinate possesses the properties
groups causing unpleasant taste can be of resin.
encapsulated within the cyclodextrin cavity, so Because the resins are insoluble in water, the
that they do not come in contact with the taste ex- posure of drug to the taste buds in the oral
bud. Once the drug substance forms an inclusion cavity is limited. Once swallowed, however, the
complex with cyclodextrin, it exhibits properties drug is released from the resinate due to high
different than those of the parent drug substance, ionic con- centration in the gastrointestinal tract,
such as improved dissolution and taste. which de- pends on several factors such as, the
The taste-masking effect of various types of cy- nature of the reaction between drug ion and
clodextrin complexes may be correlated to their resin, drug load- ing, type of ion (cation vs
respective association constants. It is reported that anion), ionic strength, and other formulation
β-cyclodextrin provides the highest taste-masking factors. Tests have shown that ion-exchange
effect for cetirizine, while α and γ cyclodextrin resins can be effective in taste- masking for
provide
18 the poorest
cal Techresults.
Pharmaceuti nology S o lThe
i d d oassociation
S a g e & e xccon-
i pie nt Sseveral drugs such
2015 PharmTech. as Etoricoxib, dex-
com
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taste masking
Prodrugs and salt formation The use of analytical devices in the drug-
It is postulated that bitter taste is perceived when develop- ment phase has improved the taste-
a bitter-tasting drug binds directly to taste assessment pro- cess, and this has led to a more
recep- tors. This binding, however, depends on robust, reproducible taste assessment method
molecular geometry. Changing this geometry by using objective electronic devices such as
derivative formation will alter the affinity of the electronic tongues. These are es- sentially
drug mol- ecule to the taste receptor. Several analytical instruments made of chemical sensors
antibiotics such as Chloramphenicol palmitate or with specificity to different compounds in the
phosphate esters for pediatric suspension and solution. These sensors are non-specific, low
alkyl esters of Clinda- mycin and Erythromycin selective chemical sensors with partial specificity
show how prodrugs can be used for bitter taste- for cross-sensitivity to a range of organic and inor-
masking. ganic substances in solution, and they are coupled
Conversion of a drug to a salt has also been with chemometric data processing tools (48).
found to mask bitter drug taste by altering the A typical electronic tongue is based on
chemical group that is responsible for the bitter potentio- metric or voltametric sensors; however,
taste. An ex- ample of this approach is in theory, any kind of sensor could be built into
chlorpheniramine male- ate, a taste-masked salt an electronic tongue. What is more important is
of chlorpheniramine base. Testing has shown that that an appro- priate set of sensors responds to
the alkyloxy alkyl carbon- ates of clarithromycin a range of com- pound taste attributes, and takes
have remarkably drecreased bitterness and into account such interactions as suppression as
Measuringbioavailability
improved palatability: Art(43–46).
or science? well as synergetic effects, so that sensor
Taste assessment for pharmaceutical products is responses represent human perception end points
complicated, due to the qualitative measurement (49).
and the inherent differences and preferences Several studies have utilized electronic tongues to
among the subjects. It becomes even more dif- assess the taste of the pharmaceutical product. In
ficult when the taste assessment involves the pedi- one case, an electronic tongue was used to select a
atric population. For instance, in one such study, taste-masking agent in the manufacture of diclofe-
the end point-of-taste assessment was based on nac fast-dissolving film (27). The authors concluded
se- lecting a face from a list of five faces that that the electronic tongue allowed them to discern
portrayed happiness to sadness progressively (47). the effect of a taste-masking agent in the presence
Such an assessment rating scale, as concluded of other hydrosoluble constituents of the film.
by the study authors, has the following limita- Other studies suggest that the e-Tongue can be
tions. First, the taste was assessed indirectly, and a useful tool in taste assessment, enhancement,
secondly, the subjects can be influenced by their and masking studies for such intensely bitter sub-
own perception of the odor or taste of the stances as epinephrine bitartarate, where the de-
product, and finally, there is no universal vice has been used to screen different
standard used in the study. sweetening and/or flavoring ingredients and to
20 Pharmaceutical Technology S o l i d d o S a g e
determine the agent that best masks the
& ex c ipi en t S 2015 PharmTech.
com unpleasant taste of the API (50).
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taste masking
The electronic tongue is often used to screen the compliance concern, it is necessary to address the
taste-masking effect of sweetening agents in phar- issue of palatability through proper selection of in-
maceutical formulations. In one case, the electronic gredients during development of the drug product
tongue was used to investigate the taste-masking formulation. Presently a number of approaches are
effect of glucose, sucrose, sucralose, fructose, man- used for taste-masking such as inclusion of sweet-
nitol, sodium saccharin, acesulfame potassium, eners and flavors, coating with pH sensitive poly-
monoammonium glycyrrhizinate, and other sweet- mers which are insoluble in the mouth but dissolve
ening agents, to formulate liquid quinine readily in the stomach, inclusion complexes, and
hydrochlo- ride (51) as well as other drugs (52– complex of drug with ion-exchange resins. These
54). 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 popu-
lation, duration of therapy, and the levels of these References
1. Webster’s Ninth Collegiate Dictionary (Merriam-
ingredients listed in the CDER approved products.
Webster Inc., 1988).
This information is available in the Inactive In- 2. E.T. Rolls, et al., Annals of the New York Academy of
gredients Database (IID) of CDER approved drugs. Sciences 855 (1), 426-437 (1998).
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
the levels listed in the IID, or if the amount listed (2012).
5. J.I.M. Glendinning, Physiology & Behavior. 56(6),
in the database is used in a therapeutic category
1217-1227 (1994).
that would not support the use of the same ingredi- 6. WHO, “Drug Resistance: HIV/AIDS,” World Health
ent in the proposed therapeutic oral dosage form, Organization, www.who.int/drugresistance/hivaids/en/
7. B. Hovstadius and G. Petersson, BMC Health Ser-
may require additional studies. vices Research 11: 326 (2011).
Aspartame (methyl ester of phenylalanine) is an 8. D. Lin, J.A. Seabrook, D.M. Matsui, S.M. King,
artificial sweetener used in a number of CDER- M.J. Rieder and Y. Finkelstein,
Pharmacoepidemiology and Drug Safety, 20(12):
approved oral drug products but requires a warn- 1246–1252 (2011).
ing on the label, because it is a source of 9. S. Winnick, et al, Pediatrics, 115(6), e718-e724
(2005).
phenylala- nine and a possible concern for 10. E. Schirm, et al, Acta Padeiatr. 92(12), 1486-1489
phenylketoneurics. Thus its use should be (2003).
carefully assessed in the product development 11. Committee for Medicinal Products for Human Use:
Reflection Paper: Formulations of Choice for the
and should be avoided where possible to mitigate Pediatric Population. EMEA/CHMP/
this risk to a sub-set of the general population PEG/194810/2005.
12. A. Cram, et al, Int. J. Pharm. 365 (1-2), 1–3 (2009).
(55–57).
13. T.L. Reiland and J.M. Lipari, “Flavors and Flavor
Bitter or unpleasant taste of pharmaceuticals Modifiers” in Encyclopedia of Pharmaceutical Tech-
is one of the causes of non-compliance and often nology, James Swarbrick Ed. (informa healthcare,
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
tient populations.
22 Pharmaceutical TBecause
echnology Sof
o l ithis
d d ocrucial
S a g e &patient chemistry
ex c ipi en t S 2015 and Manufacturing Controls,” in Pediat-
PharmTech.
com
 ric Drug Development: Concepts and Applications, An-
drew 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. Blase, and M.N. Shah, “Taste masked
pharmaceu- tical suspensions for pharmaceutical
actives,” Eur. Pat. Appl. EP0556057, August 1993.
18.A.T.P. Skraanga, and R.E. Tully/ Akzo Nobel,
N.V., “Oral liquid antidepressant solution,” U.S.
Patent 6,040,301, March 2000.
19. Y. Fu, S. Yang, et al., Therapeutic Drug Carrier
Sys- tem,21(6), 433-475 (2004).
20. R.K. Chang, et al, Pharm. Technol. N. Am. 24(6), 52–
58 (2000).
21. R.K. Khankari, et al., Cima Labs. Inc., “Rapidly
dissolv- ing tablet dosage form,” US Patent 6,221,392,
April 2001.
22. T. Mizumoto, Y. Masuda, and M. Fukui, Yamanouchi
Pharmaceutical Co., Ltd., “Intrabuccally dissolving
compressed moldings and production process
thereof,” US Patent 5,576,014, November 1996.
23. F. Cilurzo, et al, Drug Dev. Ind. Pharm. 37(3), 252–
259 (2011).
24. R. Mishra, and A. Amin, Pharm. Tech. 33(2), 48-
56 (2009).
25. J.C. McElnay and C.M. Hughes, “Drug Delivery:
Buc- cal Route,” in Encyclopedia of Pharmaceutical
Technol- ogy, J. Swarbrick, Ed. (Marcel Dekker Inc.,
New York, NY, 3rd ed., 2006), pp. 1071-1081.
26. Y.D. Yan et al., Biol. Pharm. Bull. 33 (8), 1364-
1370 (2010).
27. J. Xu, L. Bovet, and K. Zhao, Int. J. Pharm. 359 (1-
2), 63–69 (2008).
28. D.A. Chiappetta, et al., AAPS PharmSciTech, 10 (1), 1-
6 (2009).
29. S. Khan, P. Kataria, P. Nakhat, and P. Yeole,
AAPS PharmSciTech, 8(2), E127-E133 (2007).
30. D.S. Jones, “Chitosan” in Handbook of
Pharmaceutical Excipients, R.C. Rowe, P.J. Sheskey,
and M.E. Quinn Eds. (Pharmaceutical Press and the
American Pharma- cists Association, Washington DC., (2007).
6th ed. 2009), pp. 159-161.
31. D. Bora, et al, AAPS PharmSciTech, 9(4), 1159 –
1164 (2008).
32. Y. Paul, S. Tyagi, and B. Singh, Int. J. Pharma and
Bio Sciences, 2 (2), 20-30 (2011).
Pharmaceutical tionOnDrugs/ucm113978.htm
33. T. Ishikawa, et al, Chem. Pharm. Bull. 47(10), 1451‐
1454 (1999).
34. J.W. Mauger, and D.H. Robinson, The Board of Re-
gents of the University of Nebraska, “Coating tech-
nology for taste-masking orally administered bitter
drugs,” US patent 5728403 A, Oct. 1994.
35. A. Vaziri, and B. Warburton, J. Microencapsul. 11(6),
641-648 (1994).
36. M. Stojanov et al, J. Pharm. Sci. 100(8), 3177-
3185 (2011).
37. N. Ono, et al, J. Pharm. Sci. 100(5), 1935 –
1943
(2011).
38. P. P. Shah and R. C. Mashru, AAPS
PharmSciTech, 9(3), 1025-1030 (2008).
DOI: 10.1208/s12249-008-9137-6
39. G. M. Roy, Pharm. Tech. 18, 84-99 (1994).
40. W. Samprasit, et al, Pharm. Dev. and Tech. 17(3)
315- 320 (2012).
41. S. Patra, et al, Pharm. Dev. and Tech. 15(5), 511–
517 (2010).
42. R.B. Shah, et al, Drug Dev. Ind. Pharm. 35(12),
1409– 1418 (2009).
43. E.P. Taylor, J. Pharm. Pharmacol. 5(1), 254‐256
(1953).
44. A.A. Sinkula, and S.H. Yalkowsky, J. Pharm. Sci. 64,
200‐203 (1975).
45. M.A. Hussain, et al, Pharm Res. 5(9), 615-618
(1988).
46. D. Yu and E. Roche, “Taste masked pharmaceutical
liquid formulations” US Patent 6586012, Jul. 2003.
47. R. Cohen, et al, Eur. J. Pediatr. 168, 851–857 (2009).
48. A. Legin, et al, “Electronic tongues: new analytical
perspective for chemical sensors,” In Integrated Ana-
lytical Systems, S. Alegret, Ed. (Elsevier, Amsterdam,
Vol. 39, 2003), pp. 437-486.
49. L.M. Schmidtke, et al., J. Agric. Food Chem., 58
(8), 5026–5033 (2010).
50. O. Rachid, et al, AAPS PharmSciTech, 11 (2), 550-
557 (2010). DOI:10.1208/S12249-010-9402-3
51. K. Woertz, et al, Int. J. Pharm. 400 (1-2):114-23
(2010).
52. Z. Rahman, et al, Int. J. Pharm. 422 (1-2), 91-
100 (2012).
53. L. Li, V. Naini, et al, J. Pharm. Sci. 96 (10),
2723–2734
54. M. Maniruzzaman, et al, Eur. J. Pharm.
Biopharm.
80(2), 433-442 (2012).
55. Title 21 CFR 201.21
56. FDA, Drugs, FDA.org, www.fda.gov/Drugs/Informa-
Technology S o l i d d o S a g e & e xc i pie nt S 2015 23
57. FDA, Guidance for Industry, Orally Disintegrating
Oral Dosage Formulation

Using Polymers for

More Efficient Hot-Melt
Extrusion and Spray Drying

O
K e v i n P. O ’Do n ne ll, Willia m W. P o r t e r III, a n d Tr ue L. R o g e r s

New cellulosic polymers ral drug delivery is the preferred route of

have been shown to administration
because it is convenient, relatively painless, and ame-
improve solubility in
nable to patients varying in age and cultural
these key amorphous background
solid dispersion (1). However, a challenge in formulating oral dosage
processes. forms results from a growing prevalence of higher molecular
weight, poorly soluble compounds designed during drug
discovery screen- ing. The coupling of combinatorial chemistry
with high-throughput screening of ligand candidates for lipophilic
receptor therapies has resulted in a predominance of poorly soluble
new chemical entities (NCEs) and APIs (2–4).
Solubility is crucial for any oral solid dosage form as the API
must be released, dissolve in aqueous gastrointestinal media,
traverse the endothelial barrier, and bypass metabolic enzymes to
reach systemic circulation and deliver the drug’s intended
pharmacotherapeutic ef- fect. If the API does not dissolve, it will be
wasted, passing through the gastrointestinal tract without serving
its intended pharmacologi- cal purpose. The development of safe
and efficacious dosage forms containing poorly soluble APIs,
therefore, represents a formidable challenge for formulation
scientists.
Within the past 29 years, the amorphous solid dispersion (ASD)
ADAm G A ult / O JO I mA G e S / G e t t y ImAGeS

platform has gained popularity. An ASD is a metastable system that

Kevin O’Donnell is associate
research scientist, R&D; William
“Trey” Porter III is associate
research scientist, R&D; and True
Rogers is technologies leader,
R&D, all at Dow Pharma and
Food Solutions.
24 Pharmaceutical Technology S o l i d
d o S a g e & e xc i pie nt S 2015 PharmTech.
com
enables supersaturated dissolution of the API above its equilibrium
solubility, making more of the delivered dose available for systemic
absorption. Cellulose derivatives have emerged as leading polymeric
excipients in ASD formulations, because they provide a matrix into
which the amorphous API is dispersed and stabilized. They also in-
hibit precipitation, maintaining the API at a supersaturated
concen-
Oral Dosage Formulation
tration once dissolved, which is referred to as the Spray-dried dispersions are produced by
“spring-and-parachute” phenomenon (5). In addi- dissolv- ing the API and cellulose derivative in an
tion, cellulose derivatives are sustainable polymers organic solvent or co-solvent mixture, then
derived from wood and cotton linters, and most atomizing the solution into fine droplets in a
are generally regarded as safe (GRAS) for human drying chamber. The drying medium, typically
consumption. heated nitrogen gas, evaporates the organic
solvent, leaving the dry ASD to be collected in the
Spray drying, like cyclone.
Due to rapid solvent evaporation, spray-dried
hot-melt extrusion, offers dispersions achieve intimate mixing of API and
benefits in the formation of polymer, ideally delivering a molecular dispersion.
solid dispersions. These dispersions are also flowable and compress-
ible for downstream processing, for example, com-
Hot-melt extrusion and spray drying have pression to tablets.
emerged as the leading ASD technologies. For HME, Spray-dried dispersions achieve
the polymer must be brought to a softened or
mol- ten state, so that the API can be dispersed
intimate mixing of API and
within the polymer matrix while the combination polymer, ideally delivering a
of heat and shear render it amorphous. molecular dispersion.
Ideally, the API melts or dissolves in the molten
polymer and is intimately mixed into the mass as Considering the challenges of making higher
it traverses through the conveying and kneading quality, safer, and more efficacious medicines
zones. The mixture then exits the extruder and available to a growing global population, ASD
can be pelletized, milled, calendared, or left as a manufacturing processes must be robust and
strand or film. sus- tainable. Hydroxypropyl methylcellulose
In addition to softening or melting, the (HPMC) and hydroxypropyl methyl cellulose
polymer used in hot-melt extrusion must be acetate suc- cinate (HPMCAS) polymers
able to with- stand high shear and elevated developed to work in hot-melt extrusion, spray
temperature environ- ments. Once softened or drying, and other ASD processes are examined in
molten, the polymer must also provide sufficient this article.
melt viscosity to create work- ability and some of Hot-melt extrusion
the structural resistance neces- sary to knead and The scale of hot-melt extrusion technology allows
traverse the mass through the extruder and to for rapid throughput at production level, with a
mold the final form. The polymer should also small manufacturing footprint. The number of
allow the API to supersaturate in aque- ous media. available excipients for hot-melt extrusion is lim-
Few polymers are available that are melt ited, however, due to the aforementioned high
processable, stable during extrusion, stabilize the tem- perature and shear exposure during the
amorphous
26 API,caland
Pharmaceuti Technenable
ology S oAPI supersaturation. process.
l i d d o Sa g e & ex c ip ie nt S 2015 PharmTech.
com
 HPMC has historically been Figure 1: Dissolution of Griseofulvin from milled extrudate (low-viscosity HPMC HME)
disadvantaged in hot-melt polymers.

extrusion due to a narrow

processing range between the
glass transition temperature
(Tg) and degradation temper-
ature and high-melt viscosity
(6), resulting in low through-
put and typically requiring
significant plasticization.
Affinisol H P M C (Dow
Chemical) for hot-melt ex-
Figure 2: Griseofulvin release from pelletized extrudates of various viscosity grades.
trusion has a Tg of approxi-
mately 115 °C, a lower melt
viscosity and is stable to 200
°C while exhibiting minimal
color change (7) allowing it
to be extruded without plas-
ticizer over a range of pro-
cessing conditions at higher
throughput. This perfor-
mance was demonstrated
by extruding neat polymer
of varying viscosity grades,
from 100- to 4000-cP on a 26-mm Coperion hot- The binary mixtures were extruded on a Leis-
melt extruder at 155 °C into a translucent strand tritz Nano 16 hot-melt extruder at 180 °C, and the
while utilizing 50% of system pressure and 30% of extrudate, using a low viscosity grade, was milled
torque limits. This variance of polymer viscosity into a fine powder, while the extrudates contain-
allows f lexibility and control of the dissolution ing the 100 cP, 4M, and experimental high viscos-
profile, as well as significant nucleation inhibition ity grade were pelletized. All extrudates were vis-
A l l FIGuReS ARe c O u R t e S y OF t h e A uthORS.

and supersaturation. ibly clear, and determined to contain amorphous

Griseofulvin (GRIS), a BCS Class II antifungal GRIS by differential scanning calorimetry, pow-
with a high melting point of 220 °C, was formu- der x-ray diffraction, and Raman spectroscopy.
lated with the 100 and 4M cP viscosity grades of The presence of a single Tg indicated a single-
Affinisol HPMC for hot-melt extrusion, as well as phase system.
high and low experimental viscosity grades at a Figure 1 shows that the low viscosity grade
drug load of 10%. extru- date provided immediate release and
Pharmaceutisupersatura-
cal Technology S o l i d d o S a g e & ex c ipi en t S 2015 27
Oral Dosage Formulation
Figure 3: Processing drive load on a Leistritz Nano 16 extruded of formulations with
HPMC to produce solid dis-
25% Itraconazole in AFFINISOLTM HPMC HME polymers of various viscosity persions. Although the litera-
grades.
ture indicates that the API can
plasticize the polymer, these
formulations still required
elevated processing tempera-
tures of 180 °C (8, 9).
Affinisol hot-melt extrusion
polymers were formulated
with ITZ at a 25% drug load
and extruded at temperatures
as low as 155
°C into translucent strands
with experimental viscosity
grades. As demonstrated in
Figure 4: Dissolution release rate of Itraconazole solid dispersions in acidic media.
Figure 3, drive load was low for
all formulations.
All strands were milled to
fine powder, and the charac-
terizations mentioned in the
GRIS case study confirmed
that ASDs were obtained.
Similar to GRIS, the viscosity
grade controlled the rate of
ITZ supersaturation in acidic
media, as shown in Figure 4.
Ultimately, ~17X supersatu-
ration of the equilibrium ITZ
solubility
tion of the poorly soluble API and that the all milled extrudates wasofattained
regardless with
the viscosity
polymer successfully held the drug in solution for grade of polymer used.
six hours. Figure 2 shows how viscosity grade Itraconazole solubility is pH-dependent, and
selection impacts the supersaturated dissolution maintaining the drug in solution upon transition
profile, from immedi- ate- to sustained-release. In from simulated gastric to intestinal media is criti-
all cases, the polymer not cal for bioavailability improvement (10).
only controlled GRIS release but also maintained Therefore, a pH change dissolution study was
the dissolved drug in solution for up to 24 hours. performed on ITZ formulated with relevant
Itraconazole (ITZ), another poorly soluble BSC grades of Affinisol polymers and compared to an
Class IIPharmaceuti
28 compound,cal Techhas
nologybeen
S o l imelt
d doSextruded
a g e & exwith equivalent
c ipi en t S dose of
2015 PharmTech.
com
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Oral Dosage Formulation
Figure 5: Dissolution of Itraconazole following a pH transition dissolution method.
viscosities to enable success-
Buffer addition point is denoted by the vertical red line. ful extrusion of ASDs that
can deliver immediate and
sustained supersaturation of
poorly soluble APIs.

Spray-drying applications
Spray drying, like hot-melt
extrusion, offers benefits in
the formation of solid dis-
persions: minimal thermal
exposure, tunable particle
morphology, solvent f lex-
ibility, and the ability to post
Figure 6: Comparison of the concentration dependent viscosity at a shear rate of 100
s-1 between Methocel E3 and Affinisol HP HPMC, demonstrating that the Affinisol HP process the powder into the
HPMC can achieve significant increase in dissolved solids content at the same desired dosage form.
viscosity.
Despite these advantages,
the operation in pharmaceu-
tical development has been
mired by scalability issues,
with commercial spray dryers
requiring large manufactur-
ing footprints and substantial
resources for production. One
factor determining a large
footprint is that spray drying
is a viscosity-limited process
commercial ITZ (Sporanox). The formulations with solution viscosity primarily controlled by
were first exposed to acidic media for two hours the enabling excipient.
and then buffer was added to raise the pH to 6.8. Hypromellose is available in a number of sub-
Figure 5 demonstrates that both the commercial stitution chemistries and viscosity grades. HPMC
ITZ formulation and the Affinisol extrudate pro- 2910 is the most commonly used grade of HPMC
vided significant supersaturation in acidic media for spray drying, as it has the highest organic
and maintained that supersaturation following the sol- ubility of the pharmacopeial substitution
pH transition. grades. Low viscosity HPMC 2910 is typically
These case studies demonstrate Affinisol utilized to prevent viscosity associated
HPMC’s ability to be extruded over a range of atomization issues.
30 Affinisol
Pharmaceutical Technology S o l i d d o S a g e & ex ci pi en t S 2015 HP polymers were developed
PharmTech.
com with
lower viscosity than standard
Figure 7: Comparison of dissolution of spray dried dispersion formed with Affinisol HP
HPMC 2910, to increase the HPMC and Methocel E3 and (a) 10% ketoconazole and (b) 10% phenytoin
bymicrocentrifuge dissolution test.
dissolved solids concentration
while still achieving a solution
viscosity that can be atomized.
Figure 6 shows the concen-
tration-dependent viscosity
of Affinisol HP HPMC and
Methocel E3 at shear rate of
100 s-1, demonstrating that
up to 1.5 times more solids
could be dissolved in the
spray solu- tion, thus
increasing product payload
during spray drying.
Affinisol HP HPMC main-
tained its ability to supersat-
urate and inhibit nucleation
of poorly soluble APIs to
the same degree as standard
HPMC 2910 in tests. Spray-
dried dispersions contain-
ing 10% ketoconazole or
10% phenytoin were made
with Methocel E3 and Af-
finisol HP HPMC on a Bend
miniSD spray dryer, and
evaluated by a microcentri-
fuge dissolution test (MCT) (11) to compare su- Although traditionally used for enteric applica-
persaturation performance. The spray solutions tions, HPMCAS has found utility as a solubility-
containing Affinisol HP HPMC contained 1.5 enabling excipient and is available in three grades
times the amount of solids as the solutions con- that vary by acetate and succinate substitution.
taining Methocel E3. Unlike HPMC, standard HPMCAS has no varia-
The M CT dissolution plots, Figure 7, dem- tion within each grade based on viscosity of the
onstrate that the dispersions created with Af- polymer.
finisol HP HPMC achieve the same level of su- The reduced viscosity of Affinisol HP HPMCAS
persaturation and nucleation inhibition as the compared to standard HPMCAS (Figure 8) allows
standard grade. for an increase in solids loading in the spray so-
Pharmaceutical Technology S o l i d d o S a g e & ex c ipi en t S 2015 31
Oral Dosage Formulation
were compared for each com-
Figure 8: Rheology of acetone solutions containing 20% (w/w) Affinisol HP
HPMCAS polymers needed and Affinisol HPMCAS. pound. As shown in Figure 9,
Affinisol HP HPMCAS and
standard HPMCAS deliver
nearly identical supersatura-
tion for each model API. Vari-
ations seen in Figure 9 highlight
that formulation optimization
may be required when switch-
ing from standard HPMCAS
to Affinisol HP HPMCAS.
The reduced viscosity of the
spray solution when a one-to-
one substitution of standard
Figure 9: MCT dissolution AUC90 results for SDDs containing Affinisol HP HPMCAS
polymers or standard HPMCAS with phenytoin, itraconazole or ketoconazole. All data is HPMCAS with Affinisol HP
normalized to the standard HPMCAS for each drug to account for variation in drug HPMCAS will impact atomi-
loading for each API.
zation at the spray nozzle and,
thus, particle formation.
While spray drying is tradi-
tionally a process with a large
footprint and low through-
put, excipients designed spe-
cifically for this operation
can reduce the footprint, cost,
or even scale of spray dryer
needed.

lution of up to 1.7 times the standard HPMCAS References

1. D.W.A Bourne, PHAR 7633, Chapter 7: Routes of drug adminis-
material. tration (2010) pp. 1-14.
Spray-dried dispersions were formed as de- 2. M.A. Repka, American Pharm Rev. Volume 1-10 (2009).
3. M. Maniruzzaman, et al., ISRN Pharm, 1-9 (2012).
scribed previously using either Affinisol HP HPM- 4.T. Bee. and N. Neub, Manuf Chem Pharm, April, 1-7 (2011).
CAS or standard HPMCAS and phenytoin, itra- 5. H.R. Guzman et al., J Pharm Sci, 96 (10), 2686-2702
(2007).
conazole, and ketoconazole as model APIs, with all 6. O.A. Abu-Diak, D.S. Jones, and G.P. Andrews, Molecular Phar-
maceutics 8(4) 1362-1371 (2011).
spray solutions made at 2% solids with 25% (w/w)
7. K.A. Coppens, et al., Pharm Tech, January, 62-70 (2006).
API loading. 8. K. P. O’Donnell and W.H.H. Woodward, Drug Dev Ind Pharm.
May 20:1-10 (2014).
The spray-dried dispersions were analyzed by 9. K. Six, et al., Pharmaceutical Research 20(7) 1047-1054 (2003).
MCT dissolution testing, and the AUC90 values 10.D.A. Miller, et al., Drug Dev Ind Pharm. 34, 890-902 (2008).
11. D.T. Friesen, et al., Mol. Pharm. 5 (6) 1003-1019 (2008). P T
32 Pharmaceutical Technology S o l i d d o Sa g e & ex c ip ie nt S 2015 PharmTech.
com
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Analytical Techniques
Analytical Techniques for
Oral Solid Dosage Formulation
Pa ul K i p p a x a n d D e b o r a h H u c k - J o n e s
Analytical technologies
must accurately identify
and measure the critical
material attributes of APIs
and excipients, separately
and when combined
during
oral solid dosage
formulation and
development.
Paul Kippax is product group
manager and Deborah Huck-
Jones is product manager, ana-
lytical imaging, both with Malvern
Instruments.
34 Pharmaceutical Technology S o l i d d o S a g e & ex ci pi en t S 2015 PharmTech.
com
T
he workflows associated with the development of an
oral
solid dosage (OSD) product, whether innovator or
generic,
focus on detailed characterization of the API and excipi-
ents, both individually and then in combination, within
the
blended formulation. Processing steps such as blending can alter
the characteristics of an API, thereby affecting the efficiency of a
drug’s delivery or its clinical efficacy. The ability to identify and
measure the critical material attributes of the API and the excipients
separately prior to processing, and also within a multicomponent
blend, is essential.
This article considers the analytical information required to drive
formulation workflows, focusing on the use of laser diffraction par-
ticle size analysis, gel permeation/size exclusion chromatography
(GPC/SEC), and morphologically directed Raman spectroscopy
(MDRS). These techniques play a role in the efficient characteriza-
tion of APIs and excipients, separately and when blended.
Regulatory framework for OSD formulation
The OSD form is the most widely used drug delivery vehicle, and the
workflows associated with its development are well defined.
Interna- tional Conference on Harmonization (ICH) Q8 (R2)
Pharmaceutical Development (1) describes these workflows and
highlights the steps needed to ensure success, which include:
J o n a t h a n K I t c h e n / P h o t o d I s c / G e t t y IMaGes
• Definition of the quality target product profile (QTPP)
• Identification of the critical quality attributes (CQAs)
of the product
• Determination of the CQAs of the drug substance
and excipients
• Selection of an appropriate manufacturing
process
• Definition of a control strategy.
 The starting point for formulation is definition cessed. At this stage, the focus shifts from look-
of the performance that the product must deliver, ing at individual ingredients to characterization
the QTPP. This definition relates to clinical effi- of the blend and the development of an
cacy, quality, and safety, and involves the consid- appropri- ate manufacturing process. Putting in
eration of such issues as drug strength, bioavail- place the monitoring and control strategies needed
ability, and the rate of drug delivery. The CQAs of to ensure consistent manufacture marks the
the product are the product variables that have a endpoint of the development process.
direct impact on the QTPP, and, for an OSD prod- The prevailing influence of quality by design
uct, might include such parameters as (QbD) is evident from the language used to define
disintegra- tion rate, dose uniformity, and this workflow. However, there is no regulatory re-
hardness. quirement to apply QbD when working toward
The ability to identify and a new drug application (NDA). For abbreviated
new drug applications (ANDAs), basic QbD prin-
measure the critical ciples, as set forth in FDA’s question-based review
material attributes of the approach, are required. Applying QbD does not
API and change the underlying formulation workflow, but
it does influence the rigor with which each stage is
the excipients separately implemented.
prior to processing, and also A QbD approach to investigating the CQAs of
within a multicomponent the API, for example, might extend to develop-
ing functional relationships between these CQAs
blend, is essential.
Delivering the CQAs of the product relies on es- and critical material attributes (CMAs) and criti-
tablishing the CQAs of the drug substance and ex- cal process parameters (CPPs), rather than simply
cipients of the formulation, the individual compo- identifying appropriate ranges for the CQAs. A
nents of the formulation. Systematic investigation QbD approach to process development is based on
of the individual excipients and APIs is required scoping the design space—an operating window
to determine which of their properties is linked in which success is assured—rather than simply
with control of the product CQAs and/or delivery defining a fixed set of processing conditions. This
to the QTPP. A CQA for the product, for example, rigor creates a requirement for more extensive in-
might be its disintegration characteristics, while an formation gathering and intensifies the need for
a l l fIGures a re c o u r t e s y o f th e a ut ho rs.

associated CQA for the API could be particle size, appropriate analytical strategies.
since this influences the bioavailability of an API
when it is released from the tablet matrix. Focusing on the API
Once the performance of the individual API and In the early stages of formulation, the focus is
excipient has been investigated, there is a require- very much on the API and how its therapeutic
ment to assess whether the individual effect can be most efficiently delivered to the
components are changed as the blend is patient. ICH Q6A, Specifications: Test
formulated and pro- PharmaceutiProcedures and
cal Technology S o l i dAccep-
d o S a g e & ex c ip ie nt S 2015 35
Analytical Techniques
Figure 1: Particle images captured for two different API
Assessing the impact of these properties helps
crystal polymorphs using automated image analysis. with the development of a detailed specification
for the API. Some of these properties are
relatively easy to measure, but for others analysis
is more dif- ficult. For example, particle size can
be measured quickly and easily for all types of
pharmaceutical products using the technique of
laser diffraction. Polymorphic form, on the other
hand, is less read- ily characterized.
Many APIs exist in multiple crystal forms and
these have the potential to exhibit different clini-
cal performance. If a certain polymorph is identi-
fied as having desirable characteristics, then it is
Figure 2: Raman spectra for polymorphs A (orange line) and essential to verify that the correct polymorphic
B (red line) show clear differences between 1120–1300 form is used in the formulation and is delivered
cm-1.
by the manufacturing process. Manual micros-
copy is one technique for differentiating crystal
forms but it can be both time-consuming and
subject to operator variability. Morphologically
directed Raman spectroscopy (MDRS), a rela-
tively new technique, enables quicker and more
accurate polymorph detection.
MDRS involves using morphological data to
guide the application of Raman spectroscopy,
tance Criteria For New Drug Substances and New which in turn provides chemical identification.
Drug Products: Chemical Substances (2) details the The process is implemented using an automated
biological and physicochemical properties that can imaging system with spectroscopy capabilities.
influence the pharmacological profile of an API,
which include: Differentiating API polymorphs
• Physical properties such as pH, refractive Automated imaging (Morphologi G3-ID) was
index, melting point used to characterize two different polymorphic
• Particle size forms of an API. Polymorph A was found to
• Polymorphic form/amorphous content have a square-like crystalline form, while poly-
• Chiral identity morph B exhibited a needle-like structure (see
• Water content Figure 1). This difference in morphology meant
• Inorganic impurity levels that by applying size and shape classification to
• Microbial content. the automated imaging data, it was possible to
36 Pharmaceutical Technology S o l i d d o Sa g e & ex c ip ie nt S 2015 PharmTech.
com
identify the majority of in- Figure 3: Molecular weight distributions reported using a size-exclusion chromatography
dividual particles in a blend triple- detector system for hypromellose and three hypromellose acetate succinate polymer
grades.
as either polymorph A or B,
with a high degree of accu-
racy. However, a small popu-
lation of particles could not
be securely classified on this
basis alone.
For these particles, the
additional use of Raman
spectroscopy ensured secure
characterization as differ-
ent polymorphs are associ-
ated with different Raman
spectra (see Figure 2). Poly-
morphs A and B exhibit clear differences within tential impact of the CMAs of each excipient is
the 1120–1300 cm-1 region; focusing analysis here therefore essential.
allows the classification of particles as being ei- For example, the particle size of a bulk
ther one polymorph or the other. This approach excipient can influence the flow properties of the
can be used to validate the data generated with blend and its propensity to segregate. Neither
automated imaging and to provide additional property di- rectly affects the QTPP; however,
information about the crystal structure of the both can be asso- ciated with poor content
polymorphs, which supports the elucidation and uniformity and/or poorly controlled mechanical
control of formation mechanisms. properties in the finished tablet, in which case
effective control measures are needed. Laser
Optimizing excipient properties diffraction particle sizing covers the size range of
The simplest use of an excipient is as a bulking interest and provides sufficient reso- lution to
agent to make tableting of a high-potency API that accurately quantify both fine and coarse material
is administered in very small quantities a practical within a blend, thereby supporting a com-
proposition. Blending with an excipient also helps prehensive assessment of the grades available (3).
enhance the bulk properties of a fine micronized In more sophisticated controlled-release formu-
API—properties such as flow behavior, bulk den- lations, excipients control the rate at which the
sity, or compressibility—to improve the efficiency API is released in vivo; their properties are more
of manufacturing. Though the properties of such readily identified as CQAs. For example, proper-
ingredients may be expected to have little impact ties of a polymeric controlled-release agent, such
on the QTPP, they can, in some instances, be de- as its molecular weight (MW), have a direct im-
fined as CQAs. Systematic investigation of the po- pact on the rate of drug delivery, itself a CQA of
the
cal Tproduct.
Pharmaceuti echnology S o l i d d o S a g e & e xc ip ie nt S 2015 37
Analytical Techniques
Table I: Comparison of molecular weight data reported using triple detection and conventional gel permeation/size-exclusion
chromatography. Data reported by the triple detector array system include the molecular size (R (w) and R (w)) and intrinsic viscosity
(ηw).
Triple Detector Array (TDA) Conventional Results
Sample
Mw (Da) R (w) (nm) R (w) (nm) η(w) (dL/g) Mw (Da)
g h

hPMc 88,100 18.54 14.24 2.493 98,100

hPMcas-l f 162,300 13.49 10.36 0.87 83,400

hPMcas-Mf 167,500 13.5 10.36 0.882 74700

hPMcas-h f 360,900 15.95 12.25 0.792 72500

Figure 4: Particle elongation distributions reported for API particles before and after ple-detector array (Viscotek
blending with different excipients. Blending causes a reduction in elongation, suggesting TDAMax).
the API particles become more regular in shape following blending.
GPC/SEC involves separa-
tion of the dissolved sample
solution followed by detec-
tion of the resulting size-
fractionated eluent stream
using one or more detectors.
The results in Table I show that
with a single, conventional
GPC/SEC system employing
a single refractive index (RI)
(concentration) detector, the
MW data are inaccurate. This
problem is encountered with
Multi-detector GPC/SEC can provide the differ- a GPC/SEC set-up that relies on calibration with
entiation needed to reliably control the a relevant standard to deliver acceptable accuracy.
properties of such excipients (4). In contrast, the triple-detector array, which in-
corporates a light-scattering detector, enables the
Selecting an excipient measurement of absolute MW without
for controlled drug release calibration. While the single detector suggests
Figure 3 shows molecular weight distribution data that the sam- ples have closely similar MW, the
for four samples of polymers routinely used for triple-detector system reveals that two of the
con- trolled drug release: hypromellose derivatives have a weight-averaged MW
(hydroxypropyl methylcellulose, HPMC) and three approximately double that of the HPMC, and
different forms of hypromellose acetate succinate that the MW of the other de-
(HPMCAS). The MW data were generated using a rivative is approximately four times higher. These
GPC/SEC system with a single RI detector, and differences would lead to different controlled
separately
38 Technology S o l i d d o S a g e & ex c ipi en t Sdrug-
with caaltri-
Pharmaceuti 2015 release performance.
PharmTech.
com
Combining API(s) and excipient(s) fect is more pronounced in blends containing
Optimizing the properties of the constituent com- MCC. This finding, which can be attributed to
ponents of the formulation in isolation does not the relative hardness of lactose and MCC, could
ensure their delivery to the patient in these forms. have a direct bearing on excipient choice. Both
Processing steps can alter CQAs, especially those excipients are routinely used as bulking agents,
of the fine, fragile API particles. Therefore, the but the data measured here reveals an overlooked
CQAs of all ingredients must be closely monitored pathway by which they could influence the CQAs
during blending and to the point of drug delivery. of the product. Increasing the level of API fines
At this stage in the process, analysis is compli- in the blend could increase processing problems,
cated because gathering information specifically such as the risk of adhesion to equipment sur-
for the API requires its differentiation from other faces, but, more importantly, could have a direct
components in the blend. MDRS can be a use- impact on content uniformity (by influencing the
ful technique for this application; it provides the risk of segregation) and bioavailability.
chemical identification needed to securely identify
an API, and consequently can provide component- Conclusion
specific particle size and shape data. These capabil- OSD formulation, especially within the framework
ities can be used to assess the impact of of QbD, calls for detailed and systematic study of
processing, the properties of APIs and excipients, and of these
in this case blending (5). components within the finished blend. Laser dif-
Monitoring process-induced changes in an API fraction particle sizing, GPC/SEC, and MDRS have
An experimental study was conducted to deter- a role to play in the meeting the associated infor-
mine whether blending with different excipients mational need. The ability of MDRS to provide
had any impact on the morphology of API parti- component-specific morphological data has con-
cles. Tests were carried out with three different ex- siderable value for API characterization pre- and
cipients: lactose, microcrystalline cellulose (MCC), post-blending.
and a mixture of lactose and MCC. Figure 4 shows
particle shape data for the API, before and after References
1. ICH, Q8(R2) Pharmaceutical Development, Step 4
blending. The shape parameter used is elongation,
version (2009).
a normalized measure of form derived from the 2. ICH Q6A, Specifications: Test Procedures and Accep-
ratio of the width and length of the particle. Nee- tance Criteria for New Drug Substances and New
dle-shaped particles have an elongation of close Drug Products: Chemical Substances, Step 4 version
(1999).
to 1, while the elongation of those that are more 3. Malvern Instruments, Pharmaceutical Excipient
regular is closer to 0. Characterization, Application Note (Malvern, UK,
The results show clearly that the impact of 2015).
4. R. Chen, Intl Journal of Polymer Anal. Charact.,14,
blending is linked to the excipient chosen. In 617-630 (2009).
each case, the API particles becomes more regu- 5. J. Gamble, et al., Intl Journal Pharmaceutics,
larly shaped as a result of blending but the ef- 470, 77-87 (2014). PT

Pharmaceutical Technology S o l i d d o S a g e & ex c ipi en t S 2015 39

Process Analytical Technology

Simplify Formulation With PAT

Emil W. C i u r c z a k

PAT has aided formulation,

both pre-and post-filing, by
reducing costs and time
frames. Contrary to popular
beliefs, it doesn’t require big
investments.
T to
he term PAT (process analytical technology) was
introduced
by FDA in 2002 (with final guidance published two years
later)
encourage pharmaceutical producers to better
understand
and control their production of solid and other dosage
forms.
During the past decade, the idea has expanded in many, often
unantici- pated ways.
The idea of examining all incoming raw materials (APIs and
excipi- ents) began as a suggestion by the European Medicines
Agency (EMA) to European pharma companies.
Since supplies in Europe are largely delivered by railcar,
examining raw materials was seen as no problem. In the United
States, however, raw materials are delivered by truck. So what, in
Switerland, might involve two-1000kg containers, in New Jersey could
mean more than 100 20-kg containers. Using compendial methods of
analysis, such staples as lactose, for example, could have taken
hundreds of analyst-hours per batch, at a huge cost.
In 1984, Sandoz developed a near-infrared (NIR) method for
analyzing materials, not just for the sake of science, but to prevent
massive costs to the division (which had already more than doubled
headcount). However, what started out as a mere rapid identity
method, quickly morphed into a qualification technique. In
developing the libraries, it rapidly became apparent that every
S n a p D e C i S i o n / p h o t o D i S C / G e t t y imaGeS

physical nuance (e.g., particle size, polymorphic form, crystallinity, and

moisture) affected the spectrum of the material. Thus, the materials
could simply be identified, but, with a tad more effort, all the materials’
other physical and chemical properties could be cataloged, too. These
traits were useful in showing, for example, that a supplier wasn’t
Emil Ciurczak is principal of
Doramaxx Consulting, emil.ciurczak@ changing grades, or material particle sizes. As the supply chain
gmail.com.
expanded from local, US-based suppliers to overseas suppliers, these
40 Pharmaceutical Technology S o l i d extras became ever more important. With large pharma companies
d o S a g e & e xc i pie nt S 2015 PharmTech.
com resorting more and
more to outsourcing packaging, production, and cessity for a finished product and can shave time off
even R&D, it became increasingly obvious that the process, it is also quite good for development
PAT and quality-by-design (QbD) controls were work. While formulating for initial clinical trials,
becoming cru- cial, and not just a cost-saving blend uniformity is essential. However, since, at
approach. that point, the drug company is dealing with both
The tools for PAT need not merely be part of an a new drug and a new formulation, it does not yet
integrated system; as the NIR qualification have a validated assay method with which to assure
showed, several new techniques/instruments may blend uniformity. Using light-induced fluorescence
be used for individual quality checks. The (LIF) for low con- centration formulations (less
wireless NIR spec- trometer was developed than 1-2% w/w) or NIR to show completeness of
(primarily) for blend unifor- mity (in real time). It blending is an extremely fast approach instead of
is an excellent example of how just one tool may waiting for a day (if lucky) or a week for analytical
be used for both production and development. results. This speed allows several
IFPACblend
While 2015uniformity
ShowCASES PAT SoluTIoNS
is, indeed, a ne-
There were some interesting trends at the • Fourier-Transform Molecular Rotational Resonance
International Foundation for Process Analytical Chemistry (FTMRR) spectroscopy, introduced by Brightspec. It
(IFPAC) meeting held in Alexandria, VA from Jan. 25–28, imposes a frequency in the microwave-to-teraHerz (THz)
2015. range, measuring the degree that it is rotated by a
For one thing, several sessions were dedicated to single molecule or mixture of molecules. It is used for
generic- drug producers, and generic industry issues were both trace gases and major components, with the only
addressed in greater depth than in previous meetings: requirement being that they be in vapor phase.
• Lawrence Yu, deputy director of FDA’s Office of Product • TimeGate Instruments described a time-resolved Raman
Quality called on the generic-drug industry to be held to instrument, using a visible (532-nm) laser for maximum
the same standards as innovator companies as far as Raman signal, applying a 100-ps “time-gate,” to
submitting risk assessments and so forth. Because his capture the Raman spectrum while shutting out the
office now includes oversight of both new drug and interfering fluorescence signal. The software allows for
abbreviated new drug applications (NDAs and ANDAs), 2-D graphics to determine optimum gating times v.
reviews will become more similar (and comprehensive) Raman shift or 3-D graphics to optimize gating time v.
than ever. Raman shift v. maximum detection wavelengths.
• An entire session was devoted to risk management, and EMA guideline
all the speakers were either FDA officials or The European Medicines Agency (EMA) near-infrared
representatives from generic-drug companies. A guideline was presented by Sean Jones, pharma assessor
number of detailed risk- management programs were at the UK’s Medicines and Healthcare products
presented by professionals from generic drug Regulatory Agency (MRHA; London). An entire evening
companies, and were indistinguishable from others session was devoted to it, and some repeating themes
presented by speakers from Big Pharma companies. were evident:
• Continuous manufacturing (CM) was addressed as a • It was encouraging that the 2004 guideline has finally
cost- saving and quality management tool for contract been updated and codified.
manufacturing organizations (CMOs) and generics, and • There were some obvious difficulties, however, because it
was no longer discussed as a “large innovator” tool. is largely based on International Conference on
NIR and Raman instruments Harmonization (ICH) Q2 (R1), which is a blueprint for
There were a huge number of near-infrared (NIR) and chromatographic analyses, rather than spectroscopic
Raman instrument booths at the show. Some of the more methods. Some updates are needed.
interesting were: • Sample selection (e.g., synthetic vs. production samples)
• JDSU’s new wireless NIR, based on its linear variable should be more reflective of the RM guidances (e.g., ICH
filter (LVF) technology Q9) and not be “fixed” for all levels of API and type of
• Brimrose’s smaller, Acousto-Optic Tuneable Filter drug (e.g., high vs. low toxicity).
(AOTF)- based, wireless device for blend uniformity.
Pharmaceutical Technology S o l i d d o S a g e & e xc ip ie nt S 2015 41
Process Analytical Technology
formulations to be made in short order, so that with the indigenous raw materials, then scale up
tablets or capsules can be made for quality control to production levels. But, the time involved (and
or clinical purposes, and in vivo-in vitro (IVIVC) time means longer time to market and cost
testing in less time than it took with previous overruns) can make the project come close to
cGMP-based methods. In addition, the final losing money.
formulation chosen would now have a “process One answer to these problems is continuous
signature,” divined from the initial blending work. manu- facturing (CM). In CM, there is a series of
Within a company, the scale-up of a new material dispensers for the various ingredients (API
product from pilot batches to production-sized lots and excipi- ents) where the materials are dispensed
can be ex- pensive and take up to 18 months. The (into a mixing chamber) by weight (or volume) in
ability to gauge, in real time, the uniformity of the proper stoi- chiometric ratios. The mixer,
larger sized batches, speeds up the process. Tech usually a screw-driven blender, brings the powders
transfer (e.g., of an entire production line) from one to a well-blended mixture. The powder blend can be
location (even domestically) to a second site can granulated, compressed to a ribbon, or used as is in
sometimes take as long as the first scale-up direct compression. Another screw unit is used to
procedure. Using PAT-based monitor- ing tools, lubricate the blend and it is then compressed into
this time can be reduced substantially (the concept tablets or filledofinCM
Advantages capsules.
of design space enters here). This time lag occurs, At each step of the process, there are controlling
even though the company is using the same Master monitors: weight/volume dispensers, NIR/Raman,
Manufacturing Formula (MMF), operational LIF, and so forth. These monitors assure the staff
standard operating procedures, and (essentially) the that every step of the process is under control.
exact same sources of raw materials and, on the • The amounts of each ingredient is controlled
sur- face, often the same models of production at all times, assuring the proper materials are
equipment. Just imagine the difficulty of transferring being added to the blender (weight,
a method to a subsidiary or a contract solenoids).
manufacturing organization (CMO) in a developing • The mixture is shown to be well-blended
country. There will be differ- ent equipment, and have the correct material ratios (NIR,
different API and excipient suppliers (it would not Raman).
be economically feasible to import aspi- rin, lactose, • The granulation or ribbon is shown to have
or talc, for example, and most countries wouldn’t the proper moisture and particle sizes
allow it, anyway), and different training and (gran- ulation) or proper mix and physical
language of the staff. proper- ties (ribbon) (NIR, Raman).
Despite oversight from members of the develop- • The tablets and/or capsules are monitored for
ment staff, different materials and equipment make weight and/or API and some physical
for potentially long (and expensive) delays before full proper- ties (prediction of dissolution
production is achieved. Quite often, a series of test profile), usually up to 100% (NIR, Raman).
batches must be run before the quality of the • Coating levels may be controlled and
finished
42
product is good enough for sales. As with moni-
Pharmaceutical Technology S o l i d d o S a g e & ex ci pi en t S 2015 tored, in real time (NIR, Raman).
PharmTech.
the initial formulation, the CMO could run a series
com
 The two most important advantages of CM have Miscellaneous applications
to do with waste of materials. In a production Several other applications of the same PAT tools
set- ting, at any given time, only a few used for production may be applied to other parts
kilograms of material are being processed. That of the system:
means, should there be an “event” that causes • Clinical packaging. Currently, the double-
an out of speci- fication (OOS) incident, blind nature of a clinical study can frustrate
manufacturing can be stopped (remember, it is any attempt at true control. The patient cards
continuously monitored for product quality) are made up and several are sacrificed to the
and, at the worst case, only a few kilos of material QC lab for analyses. If the QC results match
are lost. These OOS materials may be discarded up with the coded identities for those cards,
and the process restarted. the batch is considered “validated.” In the
Because there is no actual batch size stated, the real world, mistakes can be made, and all
lost materials may be made up by simply running that the QC tests prove is that the cards that
the unit longer, with raw materials being added to were sacrificed were or were not properly
the hoppers at the beginning of the run, as made.
needed. Indeed, when a campaign is run, i.e., a Using NIR or Raman or chemical imaging,
long run of a product, either for product the packaging line may check the identity of
introduction or stock shortages, there are no limits every blister in the packaging line, assuring a
on the size of a batch. In fixed batch sizes, there proper trial.
may be a need for mul- tiple discrete lots to be • Packaging materials. The polymeric materials
run with the required clean- ing and cleaning used in packaging do not lend themselves to
validation between each lot. That means more easy compendial spot tests or, for that matter,
hardware used, tying up production units away to simple lab tests. Assuring the packaging
from other products. The end result is higher facility that they are using the correct bottles
overhead. (i.e., HDPE of MDPE or LDPE), that the
Because the unit uses much smaller blister pack- aging polymer is correct wound
quantities of materials, a design of experiment on the roll (one side melts in multi-layer
(DoE) may be run to optimize the product for polymer covering), or that the line is actually
the local raw materials, using far less material. packaging the drug that is shown on the label
There would not be a need to run production- (a cause for recalls), are some of the benefits of
sized lots, because the formulation, pilot, and a simple NIR unit on the shop floor.
production lots are all the same size. In short, a company can utilize any or all the
Another obvious advantage is, when you have tools available for PAT/QbD. Despite what some
an expensive (or even moderately priced) API, a people may claim, you do not have to spend mil-
DoE in a CM unit takes far less material, and a lions, all at once, to achieve cost savings with PAT.
typical series may be run in days, not weeks, with The task of formulating dosage forms can be
results immediately available. The reduction in made simpler by adopting some or all of the
costs could be as much as 75–80% over conven- tools avail- able for PAT in the production arena.
Pharmaceutical Technology S o l i d d o S a g e & e xc i pie nt S 2015 43
tional means. PT
Lipid Formulations

Boosting Solubility in
Lipid-Based Formulations
Higher API loading can mean smaller daily

I
doses.
A g n e s Sh an le y

Ionic liquid technologies
offer a new way to improve
bioavailability and
potentially shrink patients’
daily dose requirements
Keith Hutchison, PhD,
senior vice-president of
R&D for Capsugel, describes
the technology.
n January, Capsugel (Morristown, NJ) acquired proprietary ionic
liquids technology from Australia’s Monash Institute of Phar-
maceutical Sciences. The technology uses lipid-like counter-
ion
salts to improve the solubility of lipid-based liquid, semi-solid,
and multiparticulate formulations.
Ionic liquids offer formulators the potential to increase drug
solu- bility, reduce absorption variability, decrease excipient levels,
and reduce pill burden, according to Capsugel’s senior vice-
president of R&D, Keith Hutchison, who recently shared some
insights into the technology and its significance with
Pharmaceutical Technology.
Significance of ionic liquids technology
PharmTech: What exactly is ionic liquids technology (ILT), and why
is it significant?
Hutchison: ILT is a patented technology developed by Monash
Institute of Pharmaceutical Sciences (MIPS) in Australia, which uti-
lizes ionic liquids, lipid-like counter-ions in a liquid state, to enhance
the solubility of APIs in lipid vehicles. ILT fills an existing need for
technology that significantly improves drug solubility in lipid-based
M a n d y d i s h e r P h o t o g r a P h y / M o M e n t / g e t t y iMag e s

formulas across several markets—not only for new chemical entities

(NCE), but for orphan drugs, approved under 505(b)2, and over-
the- counter formulas.
Lipid-based formulation (LBF) technology is often used to address
poor bioavailability and may be important when biological obstacles
such as drug efflux and/or drug metabolism are present. An
ongoing challenge with lipid-based formulations, however, has been
Agnes Shanley is senior editor of relatively low drug loading, which can translate into a commercially
pharmaceutical technology.
unaccept- able daily dose requirement. Higher solubility with ILT
44 Pharmaceutical Technology S o l i d d owill result
Sa g e & e xcin
i pie nt S 2015 PharmTech.
com
 Achieving
Faster Time to
First in
Xcelolab® Powder Dispenser
Human™ Provides fast, flexible, precision powder dispensing
for any laboratory. Performs accurate, closed loop,
weight dispensing that is difficult and potentially
inaccurate by hand or by other laboratory
methods.

Xcelodose® S Precision
Powder Micro-Dosing
System
Precisely dispenses drug substances alone, as
low as 100μg, into capsules without excipients
or
bulking agents. This allows companies to
eliminate costly and time-consuming
compatibility, stability and preformulation
studies during early stage
drug development.

CFS 1200™ and the CFS

1500 C™ Liquid Filling &
Sealing Machines
These fully automatic cGMP compliant
machines fill and seal liquids/semi-solids into
two-piece hard
capsules at speeds of 1,200 and 1,500 capsules
per hour. This helps scientists exploit the potential
of lipid- based formulations for poorly soluble
compounds.

Capsugel Ultra™ III

A cGMP-compliant capsule filling machine
with numerous innovative operational and
safety features that streamline production
with
To find out more about our R&D portfolio of New Yorkspeeds
processing City of up to 33,000 capsules
Aprilhour.
per 21-23, 2015for high-speed semi-
Designed
products, services, and equipment, call 888-783-
Booth #1453
automatic filling applications, it introduces
6361 or send an email to cost-effective quality and performance.
solutions@capsugel.com
© 2015 Capsugel Belgium NV All rights reserved.
Learn more at
Lipid Formulations
a decrease in excipient levels and therefore both a salt form of the compound with higher aqueous
smaller capsule size and reduced daily pill solubility.
burden for patients across a range of low MIPS researchers took an alternative approach
solubility drugs. for ILT—utilizing salt formation to intentionally
“Lipid-based formulation reduce aqueous solubility while increasing lipid
solubility or lipophilicity. The ILT salt forms of the
... is often used to address compound are often liquid or semi-solid at room
poor bioavailability ... an temperature, and this lower melting point results
ongoing challenge with in much greater solubility in commonly used li-
pidic excipients.
it, though, is relatively Small-scale solubility screening has confirmed
low drug loading, which several-fold increases in compound lipidic excipi-
can translate into a ent solubility when ILT forms are used. It was also
determined that ILT forms are effectively solu-
commercially unacceptable bilized in mixed micelles upon dispersion and
daily dose requirement.” digestion, which helps promote drug absorption.
Further, the ILT APIs are readily formulated in
Lipid salts can already be used in certain self-emulsifying systems (SEDDS or SMEDDS)
spray- dried formulations to help design the that are well known to improve oral bioavailabil-
best prod- ucts for ‘brick dust’ low solubility ity in vivo.
drugs—very poorly water soluble compounds
that are easily wetted in water, but seem to be ILT and existing technology
insoluble in almost everything else. The ionic PharmTech: How does ILT complement or
liquids technology from Monash represents the expand existing technology?
first time that the solution is made available for a Hutchison: Solubility challenges are a major
wide range of ‘grease ball’ lipophilic low problem for customers today. ILT broadens the
solubility drugs, which show very poor water range of solutions that can be used, including
solubility but are more easily wetted by oil. This amorphous dispersions based on either spray dry-
means that patients might, for example, only ing or hot-melt extrusion (HME), nanocrystal
need to take one or two capsules formulated tech- nology options, and a range of liquid, semi-
with ILT instead of 5 to 10 using conventional solid, and multiparticulate lipid formulation
technology. approaches. Proprietary ILT expands the
PharmTech: Can you explain the chemistry be- potential use of lipid formulation across a
hind ILT? broader range of drugs and lipophilicity profiles.
Hutchison: Salt-screening strategies are rou- ILT can be utilized for ionizable compounds and
tinely utilized as an initial approach for address- enhances many lipid- based formulations (i.e.,
ing low solubility. In this approach, one combines liquid, semi-solid or solid lipid multiparticulate
a compound
46 with
cal Teachncounter-ion
Pharmaceuti ology S o l i d d otoS aproduce the
g e & ex ci pi en t S 2015 PharmTech. [LMP] technologies). As
com
such, ILT creates additional technology options tial or ‘enabling’ formulation to clinic. Our invest-
and flexibility for product development teams to ments in technology options and infrastructure
advance APIs with low bioavailability. for design, development, and commercial manu-
PharmTech: Will ILT make lipid-based formula- facture of finished dosage forms allow our clients
tions preferable to other technologies in to choose one partner for the science of product
addressing low solubility challenges? development, thereby reducing time to clinic, cost,
Hutchison: The most important step is to and project complexity.
select the right dosage form technology for each
API. No specific technology or finished dosage Technology collaboration
format can be utilized for all compounds, and it PharmTech: What is the nature of Capsugel’s on-
is critical to access a range of technologies, going collaboration with Monash University?
know-how, and track record across compound Hutchison: Monash and Capsugel have a long
types and applica- tions. To address a low history of collaboration in LBF technology and
bioavailability challenge, the physicochemical its applications, including co-founding the Lipid
and/or biological obstacles must be well Formulation Classification System (LFCS) Con-
understood in order to choose the right sortium to advance a common understanding of
technology in meeting target product profile and lipid formulations in order to facilitate the
commercial objectives. technol- ogy’s broad adoption. Capsugel has
Capsugel Dosage Form Solutions has developed acquired all of MIPS’ intellectual property
a proprietary technology selection methodology, pertaining to ILT, and the transfer of know-how.
based on modeling more than 1000 compounds ILT-based LBF internal and ‘lead user’ product
across technologies, to rapidly select the optimal development projects with clients are currently
technology for a specific API and advance an ini- being evaluated. PT

Call for papers on apis and exCipients

The editors of Pharmaceutical Technology are looking for
article submissions for the APIs, Excipients, and
Manufacturing September 2015 supplement.
Topics addressed in the supplement will include
developments in the synthesis of APIs and
pharmaceutical intermediates, formulation development,
finished product manufacturing, and advances in small-
molecule synthesis and biologics manufacturing.
Contribution types
Contributions may include:
• Technical case studies that describe problem resolution
with technical data and analysis
• Review of new or enhanced technologies and related
applications that provides technical analysis with
specific case studies of the technology at work
• Topical literature review or analysis of industry
developments that inform the reader of the latest
scientific advances in the field
• Industry or regulatory analysis of the latest
developments in regulations and industry guidelines
• Viewpoint papers on topics affecting the industry.
How to contribute
The due date for abstracts is July 1, 2015. Articles should
be non-promotional, technical in nature, original, and
not previously published elsewhere.
Please send submissions to Editorial Director, Rita Peters,
at rpeters@advanstar.com.
For more information on how to contribute to
Pharmaceutical Technology, visit the Contribute page at
PharmTech.com.

Pharmaceutical Technology S o l i d d o S a g e & e x ci pie n t S 2015 47

New Technology

Innovations in
Solid Dosage Equipment

G
Ashley R obe r t s

The increasing complexity rowth in solid-dosage products and use of high-

of manufacturing potency APIs are driving equipment innovation.
pharmaceuticals has
Operator safety and cost efficiency head the list
necessitated more
complex manufacturing of issues that are top of mind for tablet producers.
options and has been the Single rotary presses or rotary punches meet a variety of output
driving force behind the needs, depending on individual company production. In turn,
creation of a wider array of manufacturers have introduced more options for high-volume
equipment, including
and small-batch production.
high-, medium-, and small-
volume tablet presses.
High-volume presses
For high-volume production of single- and bi-layer tablets, Korsch
introduced the XT 600, a double-rotary press designed with a
60-kN or 100-kN compression column for precompression and
main compression and proven compression dwell bar. An ex-
changeable turret offers the flexibility to produce a tablet of virtu-
ally any size and shape. The carrier plate design isolates vibration
in the compression zone, reducing noise during output. The ergo-
nomic system features the Smart-Touch human machine interface
(HMI) with 19-inch display for ease of use in the laboratory.
Romaco’s high volume double-sided press, the KTP 720X, is de-
signed for single-layer and bi-layer tablets and can produce up to
For more information,
please visit: 1,020,000 tablets per hour. The system features a brushless torque
Bosch motor, Windows 7-based HMI panel, and can be equipped with a
CRISTINA PEDRAZZINI/GETTY IMAGES

GEA Group continuous weight control in-line scale to measure the weight of
Fette the tablets and adjust the press accordingly. The weight control
Korsch
addition eliminates the need for manual sampling and reduces
Natoli
Pharma Technology Inc. product waste.
Roeltgen Fette Compacting America’s FE75 Tablet Press can be equipped
Romaco Group with up to 115 punch stations to produce more than 1.6 million
48 Pharmaceutical Technology S o l i d tab-
d o Sa g e & e xc i pie nt S 2015 PharmTech.
com
 lets per hour. The FE75 features four Figure 1: The PERFORMA Lite is GEA’s compact tablet
compression rollers with a control system for press, capable of production rates up to 320,000 tablets
per hour.
direct com- pression, enabling the machine to
operate with two intermediate pressures.
Similar to Romaco and Korsch, the press is
a double-sided rotary press that measures two
square meters, the system can be used to press
single- and double-layer tablets and powder.
The FE75 includes pneumatically controlled
tablet scrapers, conical filling units, tubeless
extraction unit, and chassis complete with a Figure 2: Natoli’s medium-scale press NP-155 features
touch screen HMI for ease of use in the laboratory.
two-part frame structure and a pneumatic sus-
pension system.

Medium-volume presses
For the manufacturer that requires a balance be-
tween high-volume and small-batch production,
economical options are available. GEA’s PER-
FORMA Lite (Figure 1) is a medium-scale tablet
press with rates up to 320,000 tablets per hour.
The compact system gives the user the ability
to adjust the precompression dwell time by up
to 300%. The GEA Air Compensator is fitted to
the precompression station and enables shorter
set-up times, high yield, improved tablet qual-
ity, and greater product output. An exchange-
IMAGES CouRTESY o F Bo SCh, GEA, NATolI, AND PhARMA TEChNoloGY

able turret allows product changeover in just 30

minutes, and the standard model comes with a
constant-level feeding system, replaceable upper
guides, removable scraper seals, and die seats. manual weight, thickness, and overload adjust-
The NP-155 (Figure 2) is Natoli’s cost-effi- ments; automatically lubricated punch guides;
cient, medium-output rotary press with hard- and adjustable punch penetration.
ened-steel die table, auto-lubricated turret, The TPR 500 (Figure 3) is Bosch’s answer to
touch screen HMI, optional force feeders, and the need for medium-output tablet presses. The
direct drive design. The cGMP- and Confor- system features a 56-station die table, torque
mité Européene-compliant press can produce drive, and tablet discharge chute, as well as
more than 280,000 tablets per hour and features a 21-inch HMI. The press can produce up to
Pharmaceutical Technology S o l i d d o S a g e & ex c ipi en t S 2015 49
New Technology
Figure 3: Bosch’s TPR 500 is designed with separated
production and mechanical areas to reduce powder
contamination.
Figure 4: Pharma Technology Inc. and Roeltgen’s
FlexiTab tablet press can operate with powder quantities
up to 1 kg.
Laboratory and small-scale presses
New small-scale equipment can be used in R&D.
Na- toli’s NP-RD20 is designed for formulation
develop- ment and produces tablets in small
quantities for test- ing purposes. The automated,
single-station mobile laboratory press can
manufacture single tablets or test tablet parameters
and dwell time. The system has data acquisition
capabilities that can collect and track test results,
including compression curve and elasticity in single-
and bi-layer tablets.
Pharma Technology Inc. and Roeltgen introduced
a collaboratively developed core-coating module for
the FlexiTab Tablet Press (Figure 4). The freely-
con- trollable single-punch press is designed for
Galenics development and small-batch production
in single- layer, bi-layer, tri-layer, and externally
lubricated tab- lets. The system can be operated in
manual or auto- matic modes with powder
quantities as low as 500 mg and up to 1 kg, with

Ad Index
operating forces up to 100 kN. P T

COMPANY
PAGE

Abitec Corp...........................................................................................7
Capsugel, A Div Of
Pfizer ....................................................................45
Coating
CMIC CMOPlaceUSA
Inc Corporation................................................................
..................................................................................5
400,000 tablets per hour, and a Ò True FlowÓ tab- 11
Federal Equipment Co ........................................................................17
let discharge chute with an optimized take-off
angle reduces product damage and increases Jost Chemical Co ................................................................................13
output, especially with shaped or friable tab- Metrics Inc .........................................................................................33
lets. A Siemens torque drive connected to the Mikart ..................................................................................................3
turret is able to achieve high torque at low rpm.
MPI Research .....................................................................................21
The system is designed with no wear parts to
Natoli Engineer Co Inc ........................................................................19
reduce maintenance, and the production area is
separated from the mechanical area to prevent Ropack ...............................................................................................25
powder contamination. Sonneborn, LLC ..................................................................................29
50 Pharmaceutical Technology S o l i d d o Sa g e & ex c ip ie nt S 2015 PharmTech.
com