GMP: Solid Forms

ebook series 2015
PharmTech.com
Solid Dosage and

Excipients
Solid Dosage & Excipients 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
Art Director Dan Ward
12 Assessing and Improving
Contributing Editors Jill Wechsler jwechsler@advanstar.com; Jim Miller info@ the Palatability of Pharmaceuticals
pharmsource.com; Hallie Forcinio editorhal@cs.com; Susan J. Schniepp
sue.schniepp@mac.com; Eric Langer info@bioplanassociates.com;
Muhammad Ashraf, Frank Holcombe, Jr.,
and Cynthia A. Challener, PhD challener@vtlink.net Vilayat Sayeed, and Siva Vaithiyalingam
Correspondents Hellen Berger (Latin/South America, hellen.berger@terra.com.br),
Sean Milmo (Europe, smilmo@btconnect.com), and Jane Wan (Asia, wanjane@live.com.sg)
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24 Using Polymers for More Efficient
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Tableting
Advances in Tableting
Cynthia A. Challener
F
Innovative equipment, or many reasonsfrom ease of administration to dosing ac-
analytical techniques, curacy to manufacturing efficiencypharmaceutical manu-
software, and modeling facturers prefer to formulate their APIs as solid dosage drugs,
systems are improving
and particularly tablets. There is significant room, however, for
the tableting process.
improvement of tableting processes. Advances in tableting 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 development manager with
Lauren Burke/Getty ImaGes
Coperion K-Tron Food & Pharmaceutical Industries. Traditionally,

lubricants have been mixed with the solids used to form tablets, but
this approach often leads to non-uniform distribution of the lubri-
Cynthia A. Challener, PhD,
is a contributing editor to cant. To compensate, excess lubricant is used, which can negatively
pharmaceutical technology.
affect tablet properties.
4 Pharmaceutical Technology Solid doSage & excipientS 2015 P h a r mTe c h . c o m
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Tableting
Recently, equipment has been developed that 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 short-
let press tooling to prevent sticking of the powder term accuracy is high. With a nearly constant feed
to the tool and die of the tablet press, according rate, it is possible to achieve uniform coating of
to Nowak. Importantly, these applications were the tablet tools and eliminate sticking problems,
done primarily volumetrically, with no measure- all with reduced stearate consumption and lower
ment of the actual weight of the lubricant delivered. overall operating costs, Nowak states.
Magnesium stearate does not flow well, which can
cause high variations in the feed rate with volu- Multi-tipped tooling and advanced coatings
metric feeders because of inconsistent filling of The key drivers in tablet manufacturing are the
the twin screws. As a result, there has been an in- need to increase yield and capacity while reduc-
creased demand for automated tablet press lubrica- ing manufacturing costs and minimizing the space
tion systems with highly accurate gravimetric feed used and the time spent setting up each press, and
designs, according to Nowak. increasing productivity has always been a chal-
High accuracy twin-screw gravimetric feeders lenge in modern tablet production, according to
quantitatively deliver a specific amount of lubri- Steve Deakin, owner director of I Holland. That is
cant to the tablet. They also allow accurate deter- why he believes the widespread use of multi-tipped
mination of the amount of lubricant delivered to tooling and the continued development of punch-
each tablet, even though the quantity of lubricant and-die treatments and coatings have been great
that ends up in the tablet granulation formulation advances in the pharmaceutical industry.
is significantly decreased, she observes. As a re- Our ongoing development of multi-tip tooling is
sult, not only are the material handling properties specifically driven by the desire to assist our cus-
of the granulation process improved, the overall tomers in increasing productivity and capacity,
dissolution rates of tablets can be increased. The he says. Multi-tip punches allow the number of
lower quantities of lubricants required for tablet- tablets per turret rotation to be multiplied by the
ing have also led to a need for lower and lower number of tips on the punch. They also require less
feed rate deliveries, according to Nowak. For this floor space, because more tablets can be produced
reason, automated lubricant feeding systems today with fewer tablet presses, leading to a reduction in
require highly accurate, specialized low-rate feed- overall plant running costs. The development of
ing, she says. a technology like multi-tip tooling is beneficial to
Coperion K-Trons solution uses patented load many end users, says Deakin.
cell technology that continuously measures the With respect to treatment and coating technol-
weight of the lubricant and maintains a constant ogies, I Holland categorizes them based on their
mass flow (weight per unit of time) by adjusting function: improving wear resistance, improving
CAPMUL - Where Formulation Begins
Bioavailability
Enhancement
for BCS
Class II & IV
Formulations
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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 that
properties can help preserve the life of our punches the movement of the product through the process
and increase productivity for our customers, Dea- can occur seamlessly with the support of the data
kin comments. The overall result is reduced press required to meet the needs of the control strategy,
downtime and increased productivity, which is according to Kettler.
what every company wants, he adds. Nowak notes, for example, that the increase in
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 productionfrom feeders to tablet- ditional system components from the blending
ing machines to coatershas 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 communicat-
architectures that are being developed. PAT has, in ing with the proper protocols, which will require
fact, advanced to a point where manufacturers can manufacturers of the various pieces of equipment
have confidence in the determination of product used in tableting to open their software enough to
quality throughout the process. enable the development of overall control strate-
gies, Kettler adds. He notes that barriers remain
Need for systems integration that must be overcome before integrators will be
and data management allowed access to the control software for tablet
The marriage of the unit operations needed to presses and other formulation processing units.
build a continuous manufacturing process is, how- He does believe, however, that market demand
will provide the energy needed to overcome those due to a lack of process understanding with respect
barriers, and that opportunities will present them- to the impact that raw material properties and pro-
selves in 2015. cess conditions have on final tablet properties. In-
The move to continuous processing also pres- creasingly, formulators and process engineers are
ents data management challenges. The coupling turning to predictive process modeling as a means
of complex processes such as high shear wet gran- for increasing process understanding and reducing
ulation with fluid bed drying and blending and 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 Nottinghams 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 (TSARPredict) 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 forlation-sticking issues without the need to carry out
ongoing process improvement, Kettler observes. expensive and time-consuming, full-scale, trial-
He does note that statisticians, chemometricians, and-error experiments with several anti-stick coat-
and quality assurance experts are already work- ings. The model considers the properties of the API
ing to address this challenge, but the industry will and any excipients, possible Van der Waals forces,
need to work with regulators to ultimately develop capillary action, deformation mechanics, the com-
workable solutions. pression environment, and the chemistries of dif-
Outside of continuous manufacturing, advances ferent coatings.
in information technology have already been re- Discrete element and finite element method
sponsible for increased tablet press capability and (DEM/FEM) models are more established for the
controls, according to Deakin. Modern systems simulation of the behavior of bulk solids during
can provide detailed information relating to the processing. DEM has been used, for example, to
operation and performance of the tablet presses predict powder packing and flow behaviors. DEM
and help link downstream processes to ensure Solutions offers its EDEM software platform for
quality control. The use of these technologies has the optimization of bulk solids handling and pro-
both improved tablet quality and enhanced processing equipment, according to the company.
duction performance and capacity, he asserts. Properties such as the particle size and shape
distribution, mechanical strength and stiffness,
Modeling for improved performance surface roughness, stickiness, chemical reactivity,
Despite the significant advances in tableting tech- and surface charge are considered in the EDEM
nology, including online monitoring with PAT models.
systems and the move to continuous production Other systems that have been applied for the
operations, the tableting process in many ways re- predictive modeling of tableting processes include
mains inefficient and variable. This inefficiency is the population balance equation and reduced order
Pharmaceutical Technology Solid doSage & excipientS 2015 9
Tableting
models that reduce the complexity, and thus the and optimization and the identification of appro-
time and expense required to complete the calcula- priate control strategies, often with data from a
tions (1). This reduction can be achieved with mul- reduced number of experiments (1).
tivariate analysis techniques or lower dimensional Despite advances in the development of predic-
models that are developed by fitting experimen- tive models for pharmaceutical tableting processes,
tal or simulated data using a range of techniques, they still fall short of the desired level of perfor-
including kriging, response surface methodology, mance. Models that better link particle properties
artificial neural networks, or high dimensional to a wider set of bulk powder properties during
model representation (1). processing and more accurately predict the impact
The company Process Systems Enterprise offers of changes in raw materials and the manufactur-
its gPROMS modeling platform, which consists ing process on tablet properties are needed, as are
of the ModelBuilder model development envi- new approaches that enable more complex model-
ronment and gSOLIDS and gCRYSTAL specialty ing without increasing the computation time and
applications for solids processing. This modeling 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). PT
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 Kberle, 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.

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taste masking
Assessing and Improving the

Palatability of Pharmaceuticals
Muhammad Ashraf, Frank Holcombe, Jr.,
Vilayat Sayeed, and Siva Vaithiyalingam
T
Taste may be subjective, he Merriam-Webster Dictionary defines palatable as agree-
but it is crucial to patient able to the palate or taste or agreeable or acceptable to the
compliance, particularly for mind (1). Taste, therefore, depends on both physiological
pediatric treatments. This
and psychological phenomena, and is known to vary in hu-
article reviews methods
mans based on such factors as age, ethnicity, and geographic location.
used to improve and assess
pharmaceutical palatability. 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,
Muhammad Ashraf is product which can lead to treatment failure (6) and increased resistance to
quality reviewer; Frank O.
Holcombe, Jr. is chemist; and drugs, raising overall healthcare costs (7).
Vilayat Sayeed is supervisory Taste is especially important in treatments designed for children.
chemist all with FDAs Office of
KidStock/Blend Images/Getty Images
Lifecycle Drug Products, OPQ, In one study on children infected with HIV, for example, one third of
CDER. Siva Vaithiyalingam is the patients failed to comply with the dosage regimen for a particular
director of regulatory affairs with
Teva Pharmaceuticals USA. drug, due to their perceptions of the drugs taste (8). In another in-
Please address all correspondence to vestigation, pediatric patient compliance with dosage regimen ranged
vilayat.sayeed@fda.hhs.gov
Disclaimer: The views and opinions from 11% to 93%.
presented in this article are those of
the authors and do not necessarily Poor compliance or non-compliance typically places children at
reflect the views or policies of FDA.
risk for such problems as continued recurrence of disease. In addi-
12 Pharmaceutical Technology Solid Dosage & Excipients 2015 P h a r mTe c h . c o m
taste masking
tion, it complicates the physician-patient relation- The European Pediatric Formulation Initiative
ship, and prevents accurate assessment of the qual- (EPFI) was founded in 2007 to address some of
ity of care provided (9). these issues and raise awareness of the importance
of palatability in drug formulation. The initiative
is focusing on such issues as taste assessment, ex-
Taste is especially cipients, delivery devices, and extemporaneous
important in treatments preparations (12).
designed for children This article reviews the various technological
platforms available for taste-masking, taste modifi-
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 compounds,
dren have access to more palatable medicines (10). pharmaceutical formulators must understand the
To address this universal concern and to provide chemistry of the API, identify solutions to re-
incentives to the pharmaceutical industry, the US duce or inhibit the bitter taste of the API without
Congress enacted the following legislation: changing other flavor modalities (e.g., sweet, salt,
The Best Pharmaceuticals for Childrens Act or sour) and then choose the best taste technology
(BPCA 2002) platform to develop the drug product.
The Pediatric Research Equity Act (PREA Some of the most commonly used taste-masking
2003) approaches include:
The FDA Amendment Act (FDAAA 2007). Natural and artificial flavors and sweeteners
Today, advances in pharmaceutical technology Polymer coatings
make it easier to design and develop such child- Multiple emulsion and liposomes
friendly products as oral films, medical chewing Inclusion complexes
gum, suspensions, and chewable tablets to name Ion-exchange complexes
a few, wherein taste-masking agents can be incor- Pro-drugs and salt formation.
porated to conceal and counter the unpleasant or- The taste-masking technology should be care-
ganoleptic attributes of drug substance. fully aligned with the drug product dosage form,
Finding some common ground for taste-masking patient population, and duration of therapy.
and pediatric friendly formulation, however, is not an
easy task. Standard combinations of specific sweet- Flavors, sweeteners, and other ingredients
eners with relevant flavors may vary by country and Adding flavors and sweeteners is usually the first
target market. For instance, flavors such as bubble- choice for improving the taste of a pharmaceutical
gum and grape are preferred flavors in the United formulation. Liquid flavors are used most often,
States, whereas citrus and red berries are popular because they diffuse readily into the substrate.
in Europe, and licorice in Scandinavia (11). They are available both as oily (e.g., essential oils)
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 suspension,
tional groups, such as aldehydes, ketones, esters, or for example, has been formulated with xanthan
terpenes that can interact with actives and other gum (0.1-0.2%) and microcrystalline cellulose (0.6-
ingredients in the formulation (14). 1%) to reduce bitter taste, while the antidepressant
In addition, flavors are typically volatile and mirtazapine has been formulated as an aqueous
may degrade during the products shelf life. They suspension using methionine (stabilizer) and
can also be degraded by pH-catalyzed, oxidation- maltitol (thickening agent). Maltitol, stable in the
reduction, and hydrolytic reactions. acidic pH range of 2 to 3, has the added benefit of
To ensure stability and prevent unacceptable inhibiting the drugs undesirable local anesthetic
changes in the flavor of a product, flavor systems effect (1718).
must be compatible with other ingredients. In Flavors and sweeteners have also been used to
some cases, for example, flavor systems may be mask unpleasant taste in orally disintegrating
combined with antioxidants to reduce free radical tablets (ODTs) (19) and rapidly dissolving films
autoxidation. (RDFs). For example, mannitol and licorice, and
Besides traditional sweeteners and f lavors, sugar-based excipients, using glucose, sucrose, su-
other additives can be used to improve the taste cralose, and fructose and other ingredients have
of pharmaceutical formulations. These include been used to improve the flavor of ODT formula-
amino acids and their salts (e.g., alanine, taurine, tions (2022).
glutamic acid, and glycine), which are known Sucralose, which is 600 times sweeter than sugar,
to reduce the bitterness of drugs. Some patients, has been used with mint and licorice flavors to
for example, found that the taste of ampicillin mask the taste of diclofenac sodium maltodextrin
improved markedly when its granules had been RDFs (23). The films were prepared by casting and
prepared with glycine and mixed with additional drying aqueous mixtures of maltodextrin, glycerin,
quantity of glycine, sweeteners, flavors, and finally sorbitan oleate, and diclofenac sodium. The taste-
compressed into tablets (15). masking agents were added in very low concentra-
Lipoproteins can also be effective in suppress- tion (sucralose, mint, and licorice at 1%, 6%, and
ing the bitter taste of basic and hydrophobic drugs. 3% w/w) and did not significantly affect the tensile
Incorporating it into a liposomal formulation with properties and film disintegration time.
egg phyosphotydyl choline (16), for example, suc- In addition, sucralose, citric acid, aspartame,
cessfully masked the bitter taste of chloroquine and passion fruit flavor have been used in an RDF
phosphate in HEPES (N-2-Hydroxyethylpipera- formulation of cetirizine hydrochloride, a water-
zine -N-2) -ethane sulfonic acid) buffer at pH 7.2 soluble drug with bitter taste. This dosage form
Increasing the viscosity of liquid formulations was developed specifically for patients who have
with thickening agents such as polyethylene glycol, difficulty swallowing tablets (24).
taste masking
Polymeric coatings Eudragit E100 has been used to coat micro-
Polymers that are insoluble in saliva are fre- particles of Indinavir, a bitter-tasting HIV
quently used to mask the bitter taste of some drug, by using a double emulsion solvent dif-
drugs. The cationic copolymer, Eudragit E100 fusion technique. The microparticles were
amino methacrylate copolymer, for example, then used to make a pediatric suspension (28).
can be used to coat the microspheres used Eudragit EPO, an aminoalkyl methacrylate
in suspensions, and the granulations used in copolymer was complexed with Ondansetron
ODTs. The polymers pH profile helps ensure HCl, a bitter-tasting drug using precipitation.
that active ingredient is released in the stomach The best results were seen at a drug-to-poly-
and not in the mouth, because Eudragit E100 mer ratio of 8:2, and results were evaluated by
is soluble below a pH of 5 in the stomach, but dissolution in simulated salivary fluid of pH
insoluble in saliva, where the average pH is 6.4 6.2 and then in human volunteers. The taste-
(25). Granulations coated by the polymer, how- masked drug-polymer complex was then for-
ever, can rupture during compression or tablet mulated into an ODT using spray-dried man-
chewing, and patient tests show that they can nitol, microcrystalline cellulose, and
contribute to a gritty feel in the mouth. Micro- Polyplasdone XL-10 (29).
spheres coated with the same material did not The natural polymer, chitosan, has also been
rupture. used to mask bitter taste in microspheres of
Eudragit E100 can also be used in spray drying Ondansetron HCl. Chitosan, a high molecu-
processes. In one process, the polymer was used lar weight, polycationic polyamine, linear
to coat microspheres of donepezil hydrochloride, polysaccharide derived from crustacean
using spray-drying technology (26). In this study, shells, readily dissolves in inorganic acids but
a drug-to-polymer ratio of 1:2 was found to pre- is insoluble approximately above pH 6.5 (30).
vent drug release in simulated salivary fluid. The A 1:1 drug-to-polymer ratio successfully
taste-masked microspheres were then formulated achieved taste-masking without any chemical
into an ODT. interaction and loss of crystallinity (31).
In another example, taste-masked microspheres These polymers have also been used as binders
of famotidine were prepared by spray drying a sus- for the manufacture of granulations of bitter tast-
pension of finely ground famotidine (5 micron) in ing drugs. The taste-masked granulations can be
an aqueous dispersion of Eudragit EPO (15%, w/v). further formulated into various types of tablet dos-
The microspheres were then mixed with other age forms such as ODTs and chewable tablets. In
tableting ingredients suitable for ODT and com- tests, tablets of Zidovudine, a bitter-tasting antiret-
pressed into tablets (27). roviral drug prepared by a wet granulation method
Techniques such as solvent diffusion, precipita- using Surelease as binder, were found to taste better
tion, and multiple emulsion have also been used than tablets prepared by direct compression (32).
to process polymer-coated pharmaceuticals. For Eudragit E-100 has also been used to mask the
instance: flavor of bitter tasting pirenzepine and oxybutynin,
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taste masking
using extrusion and compression (33). Eudragit E, stants for and 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- -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 were tihistamines as hydroxyzine, cetirizine, and dl-
used to make liquid suspensions, and testing found chlorpheniramine. The taste-masking was found
that flavor had been masked completely (34). related to the respective association constant de-
creasing in the following order: Hydroxy propyl
Multiple emulsions cyclodextrin, cyclodextrin, cyclodextrin, and
Taste-masking can be also be achieved by incor- cyclodextrins. Studies found that primaquine
porating drugs into the inner aqueous phase of phosphates bitter taste was completely masked by
water-oil-water (W/O/W) multiple emulsions, in formation of inclusion complex with cyclodex-
which either the oil layer or the water layer masks trin (3739).
the test. This approach has reportedly worked for
formulations of chloroquin phosphate and chlor- Ion-exchange resins
promazine (35). Ion-exchange resins have also been used to mask
flavor in pharmaceuticals. These resins are high
Inclusion complexes molecular weight, water-insoluble polyelectrolyte
Inclusion complexes with cyclodextrins have been polymers that are not absorbed by the body and
used to improve the palatability of drug substances. therefore are safe for oral use. These polymers
Cyclodextrins are cyclic oligosaccharides, which have extensively charged cationic and anionic
have the ability to form a host/guest inclusion com- functional groups, which can form complexes with
plex both in solution and in solid phase. Molecules ionizable drugs via ion-exchange. The resulting
or functional groups causing unpleasant taste can drug-resinate possesses the properties of resin.
be encapsulated within the cyclodextrin cavity, so Because the resins are insoluble in water, the ex-
that they do not come in contact with the taste posure of drug to the taste buds in the oral cavity
bud. Once the drug substance forms an inclusion is limited. Once swallowed, however, the drug is
complex with cyclodextrin, it exhibits properties released from the resinate due to high ionic con-
different than those of the parent drug substance, centration in the gastrointestinal tract, which de-
such as improved dissolution and taste. pends on several factors such as, the nature of the
The taste-masking effect of various types of cy- reaction between drug ion and resin, drug load-
clodextrin complexes may be correlated to their ing, type of ion (cation vs anion), ionic strength,
respective association constants. It is reported that and other formulation factors. Tests have shown
-cyclodextrin provides the highest taste-masking that ion-exchange resins can be effective in taste-
effect for cetirizine, while and cyclodextrin masking for several drugs such as Etoricoxib, dex-
provide the poorest results. The association con- tromethorphan, and Risperidone (4042).
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taste masking
Prodrugs and salt formation The use of analytical devices in the drug-develop-
It is postulated that bitter taste is perceived when ment phase has improved the taste-assessment pro-
a bitter-tasting drug binds directly to taste recep- cess, and this has led to a more robust, reproducible
tors. This binding, however, depends on molecular taste assessment method using objective electronic
geometry. Changing this geometry by derivative devices such as electronic tongues. These are es-
formation will alter the affinity of the drug mol- sentially analytical instruments made of chemical
ecule to the taste receptor. Several antibiotics such sensors with specificity to different compounds in
as Chloramphenicol palmitate or phosphate esters the solution. These sensors are non-specific, low
for pediatric suspension and alkyl esters of Clinda- selective chemical sensors with partial specificity
mycin and Erythromycin show how prodrugs can for cross-sensitivity to a range of organic and inor-
be used for bitter taste-masking. ganic substances in solution, and they are coupled
Conversion of a drug to a salt has also been found with chemometric data processing tools (48).
to mask bitter drug taste by altering the chemical A typical electronic tongue is based on potentio-
group that is responsible for the bitter taste. An ex- metric or voltametric sensors; however, in theory,
ample of this approach is chlorpheniramine male- any kind of sensor could be built into an electronic
ate, a taste-masked salt of chlorpheniramine base. tongue. What is more important is that an appro-
Testing has shown that the alkyloxy alkyl carbon- priate set of sensors responds to a range of com-
ates of clarithromycin have remarkably drecreased pound taste attributes, and takes into account such
bitterness and improved bioavailability (4346). interactions as suppression as well as synergetic
effects, so that sensor responses represent human
Measuring palatability: Art or science? perception end points (49).
Taste assessment for pharmaceutical products is Several studies have utilized electronic tongues to
complicated, due to the qualitative measurement assess the taste of the pharmaceutical product. In
and the inherent differences and preferences one case, an electronic tongue was used to select a
among the subjects. It becomes even more dif- taste-masking agent in the manufacture of diclofe-
ficult when the taste assessment involves the pedi- nac fast-dissolving film (27). The authors concluded
atric population. For instance, in one such study, that the electronic tongue allowed them to discern
the end point-of-taste assessment was based on se- the effect of a taste-masking agent in the presence of
lecting a face from a list of five faces that portrayed other hydrosoluble constituents of the film.
happiness to sadness progressively (47). Other studies suggest that the e-Tongue can be
Such an assessment rating scale, as concluded a useful tool in taste assessment, enhancement,
by the study authors, has the following limita- and masking studies for such intensely bitter sub-
tions. First, the taste was assessed indirectly, and stances as epinephrine bitartarate, where the de-
secondly, the subjects can be influenced by their vice has been used to screen different sweetening
own perception of the odor or taste of the product, and/or flavoring ingredients and to determine the
and finally, there is no universal standard used in agent that best masks the unpleasant taste of the
the study. 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 hydrochlo- readily in the stomach, inclusion complexes, and
ride (51) as well as other drugs (5254). complex of drug with ion-exchange resins. These
taste-masking techniques have been successfully
Risk considerations exploited in several dosage forms such as liquids,
The choice of flavors, sweeteners, and polymers fast dissolving films, matrix formulations, and wet
used in the taste-masking platform should be care- granulated formulations.
fully aligned with the dosage form, patient popu-
lation, duration of therapy, and the levels of these References
ingredients listed in the CDER approved products. 1. Websters Ninth Collegiate Dictionary (Merriam-
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 (2012).
the levels listed in the IID, or if the amount listed 5. J.I.M. Glendinning, Physiology & Behavior. 56(6),
in the database is used in a therapeutic category 1217-1227 (1994).
6. WHO, Drug Resistance: HIV/AIDS, World Health
that would not support the use of the same ingredi- Organization, www.who.int/drugresistance/hivaids/en/
ent in the proposed therapeutic oral dosage form, 7. B. Hovstadius and G. Petersson, BMC Health Ser-
vices Research 11: 326 (2011).
may require additional studies.
8. D. Lin, J.A. Seabrook, D.M. Matsui, S.M. King, M.J.
Aspartame (methyl ester of phenylalanine) is an Rieder and Y. Finkelstein, Pharmacoepidemiology
artificial sweetener used in a number of CDER- and Drug Safety, 20(12): 12461252 (2011).
9. S. Winnick, et al, Pediatrics, 115(6), e718-e724
approved oral drug products but requires a warn- (2005).
ing on the label, because it is a source of phenylala- 10. E. Schirm, et al, Acta Padeiatr. 92(12), 1486-1489
nine and a possible concern for phenylketoneurics. (2003).
11. Committee for Medicinal Products for Human Use:
Thus its use should be carefully assessed in the Reflection Paper: Formulations of Choice for the
product development and should be avoided where Pediatric Population. EMEA/CHMP/
PEG/194810/2005.
possible to mitigate this risk to a sub-set of the 12. A. Cram, et al, Int. J. Pharm. 365 (1-2), 13 (2009).
general population (5557). 13. T.L. Reiland and J.M. Lipari, Flavors and Flavor
Bitter or unpleasant taste of pharmaceuticals Modifiers in Encyclopedia of Pharmaceutical Tech-
nology, James Swarbrick Ed. (informa healthcare,
is one of the causes of non-compliance and often 3rd ed., 2006), pp. 1763-1772.
leads to failure of the treatment in a variety of pa- 14. G. P. McNally, and A. M. Railkar, Formulation
chemistry and Manufacturing Controls, in Pediat-
tient populations. Because of this crucial patient
ric Drug Development: Concepts and Applications, An- 33. T. Ishikawa, et al, Chem. Pharm. Bull. 47(10), 14511454
drew E. Mulberg, Dianne Murphy, Julia Dunne, and (1999).
Lisa L. Mathis, Eds. (John Wiley & Sons. 2nd ed., 2013), 34. J.W. Mauger, and D.H. Robinson, The Board of Re-
pp. 565-575. gents of the University of Nebraska, Coating tech-
15. S. Niazi, and A. Shamesh, Chewing gum containing a nology for taste-masking orally administered bitter
medicament and taste maskers, US Patent 04639368, drugs, US patent 5728403 A, Oct. 1994.
Jan. 1987. 35. A. Vaziri, and B. Warburton, J. Microencapsul. 11(6),
16. Y. Katsuragi, et al, Pharm. Res. 12 (5), 658-662 (1995). 641-648 (1994).
17. C.M. Blase, and M.N. Shah, Taste masked pharmaceu- 36. M. Stojanov et al, J. Pharm. Sci. 100(8), 3177-3185
tical suspensions for pharmaceutical actives, Eur. Pat. (2011).
Appl. EP0556057, August 1993. 37. N. Ono, et al, J. Pharm. Sci. 100(5), 1935 1943
18. A.T.P. Skraanga, and R.E. Tully/ Akzo Nobel, N.V., (2011).
Oral liquid antidepressant solution, U.S. Patent 38. P. P. Shah and R. C. Mashru, AAPS PharmSciTech,
6,040,301, March 2000. 9(3), 1025-1030 (2008).
19. Y. Fu, S. Yang, et al., Therapeutic Drug Carrier Sys- DOI: 10.1208/s12249-008-9137-6
tem,21(6), 433-475 (2004). 39. G. M. Roy, Pharm. Tech. 18, 84-99 (1994).
20. R.K. Chang, et al, Pharm. Technol. N. Am. 24(6), 5258 40. W. Samprasit, et al, Pharm. Dev. and Tech. 17(3) 315-
(2000). 320 (2012).
21. R.K. Khankari, et al., Cima Labs. Inc., Rapidly dissolv- 41. S. Patra, et al, Pharm. Dev. and Tech. 15(5), 511517
ing tablet dosage form, US Patent 6,221,392, April (2010).
2001. 42. R.B. Shah, et al, Drug Dev. Ind. Pharm. 35(12), 1409
22. T. Mizumoto, Y. Masuda, and M. Fukui, Yamanouchi 1418 (2009).
Pharmaceutical Co., Ltd., Intrabuccally dissolving 43. E.P. Taylor, J. Pharm. Pharmacol. 5(1), 254256 (1953).
compressed moldings and production process thereof, 44. A.A. Sinkula, and S.H. Yalkowsky, J. Pharm. Sci. 64,
200203 (1975).
US Patent 5,576,014, November 1996.
45. M.A. Hussain, et al, Pharm Res. 5(9), 615-618 (1988).
23. F. Cilurzo, et al, Drug Dev. Ind. Pharm. 37(3), 252259
46. D. Yu and E. Roche, Taste masked pharmaceutical
(2011).
liquid formulations US Patent 6586012, Jul. 2003.
24. R. Mishra, and A. Amin, Pharm. Tech. 33(2), 48-56
47. R. Cohen, et al, Eur. J. Pediatr. 168, 851857 (2009).
(2009).
48. A. Legin, et al, Electronic tongues: new analytical
25. J.C. McElnay and C.M. Hughes, Drug Delivery: Buc-
perspective for chemical sensors, In Integrated Ana-
cal Route, in Encyclopedia of Pharmaceutical Technol-
lytical Systems, S. Alegret, Ed. (Elsevier, Amsterdam,
ogy, J. Swarbrick, Ed. (Marcel Dekker Inc., New York,
Vol. 39, 2003), pp. 437-486.
NY, 3rd ed., 2006), pp. 1071-1081.
49. L.M. Schmidtke, et al., J. Agric. Food Chem., 58 (8),
26. Y.D. Yan et al., Biol. Pharm. Bull. 33 (8), 1364-1370
50265033 (2010).
(2010). 50. O. Rachid, et al, AAPS PharmSciTech, 11 (2), 550-557
27. J. Xu, L. Bovet, and K. Zhao, Int. J. Pharm. 359 (1-2), (2010). DOI:10.1208/S12249-010-9402-3
6369 (2008). 51. K. Woertz, et al, Int. J. Pharm. 400 (1-2):114-23 (2010).
28. D.A. Chiappetta, et al., AAPS PharmSciTech, 10 (1), 1-6 52. Z. Rahman, et al, Int. J. Pharm. 422 (1-2), 91-100
(2009). (2012).
29. S. Khan, P. Kataria, P. Nakhat, and P. Yeole, AAPS 53. L. Li, V. Naini, et al, J. Pharm. Sci. 96 (10), 27232734
PharmSciTech, 8(2), E127-E133 (2007). (2007).
30. D.S. Jones, Chitosan in Handbook of Pharmaceutical 54. M. Maniruzzaman, et al, Eur. J. Pharm. Biopharm.
Excipients, R.C. Rowe, P.J. Sheskey, and M.E. Quinn 80(2), 433-442 (2012).
Eds. (Pharmaceutical Press and the American Pharma- 55. Title 21 CFR 201.21
cists Association, Washington DC., 6th ed. 2009), pp. 56. FDA, Drugs, FDA.org, www.fda.gov/Drugs/Informa-
159-161. tionOnDrugs/ucm113978.htm
31. D. Bora, et al, AAPS PharmSciTech, 9(4), 1159 1164 57. FDA, Guidance for Industry, Orally Disintegrating
(2008). Tablets (CDER, December 2008), www.fda.gov/down-
32. Y. Paul, S. Tyagi, and B. Singh, Int. J. Pharma and Bio loads/Drugs/GuidanceComplianceRegulatoryInfor-
Sciences, 2 (2), 20-30 (2011). mation/Guidances/UCM070578.pdf. PT
Oral Dosage Formulation
Using Polymers for

More Efficient Hot-Melt
Extrusion and Spray Drying
Kevin P. ODonnell, William W. Porter III, and True L. Rogers
O
New cellulosic polymers ral drug delivery is the preferred route of administration
have been shown to because it is convenient, relatively painless, and ame-
improve solubility in these nable to patients varying in age and cultural background
key amorphous solid
dispersion processes. (1). However, a challenge in formulating oral dosage
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 (24).
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 drugs 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 GAult/OJO ImAGeS/Getty ImAGeS
platform has gained popularity. An ASD is a metastable system that

enables supersaturated dissolution of the API above its equilibrium
Kevin ODonnell is associate solubility, making more of the delivered dose available for systemic
research scientist, R&D; William
Trey Porter III is associate absorption. Cellulose derivatives have emerged as leading polymeric
research scientist, R&D; and True
Rogers is technologies leader,
excipients in ASD formulations, because they provide a matrix into
R&D, all at Dow Pharma and which the amorphous API is dispersed and stabilized. They also in-
Food Solutions.
hibit precipitation, maintaining the API at a supersaturated concen-
tration once dissolved, which is referred to as the Spray-dried dispersions are produced by dissolv-
spring-and-parachute phenomenon (5). In addi- ing the API and cellulose derivative in an organic
tion, cellulose derivatives are sustainable polymers solvent or co-solvent mixture, then atomizing the
derived from wood and cotton linters, and most solution into fine droplets in a drying chamber.
are generally regarded as safe (GRAS) for human The drying medium, typically heated nitrogen
consumption. gas, evaporates the organic solvent, leaving the dry
ASD to be collected in the cyclone.
Spray drying, like Due to rapid solvent evaporation, spray-dried
dispersions achieve intimate mixing of API and
hot-melt extrusion, offers
polymer, ideally delivering a molecular dispersion.
benefits in the formation These dispersions are also flowable and compress-
of solid dispersions. ible for downstream processing, for example, com-
pression to tablets.
Hot-melt extrusion and spray drying have
emerged as the leading ASD technologies. For HME, Spray-dried dispersions
the polymer must be brought to a softened or mol-
ten state, so that the API can be dispersed within
achieve intimate mixing of API
the polymer matrix while the combination of heat and polymer, ideally delivering
and shear render it amorphous. a 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 can available to a growing global population, ASD
be pelletized, milled, calendared, or left as a strand manufacturing processes must be robust and sus-
or film. tainable. Hydroxypropyl methylcellulose (HPMC)
In addition to softening or melting, the polymer and hydroxypropyl methyl cellulose acetate suc-
used in hot-melt extrusion must be able to with- cinate (HPMCAS) polymers developed to work in
stand high shear and elevated temperature environ- hot-melt extrusion, spray drying, and other ASD
ments. Once softened or molten, the polymer must processes are examined in this article.
also provide sufficient melt viscosity to create work-
ability and some of the structural resistance neces- Hot-melt extrusion
sary to knead and traverse the mass through the The scale of hot-melt extrusion technology allows
extruder and to mold the final form. The polymer for rapid throughput at production level, with a
should also allow the API to supersaturate in aque- small manufacturing footprint. The number of
ous media. Few polymers are available that are melt available excipients for hot-melt extrusion is lim-
processable, stable during extrusion, stabilize the ited, however, due to the aforementioned high tem-
amorphous API, and enable API supersaturation. perature and shear exposure during the process.
HPMC has historically been Figure 1: Dissolution of Griseofulvin from milled extrudate (low-viscosity HPMC HME) polymers.
disadvantaged in hot-melt
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.
A f f i nisol HPMC (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
t hroughput. 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 flexibility and control of the dissolution ing the 100 cP, 4M, and experimental high viscos-
All FIGuReS ARe cOuRteSy OF the AuthORS.
profile, as well as significant nucleation inhibition ity grade were pelletized. All extrudates were vis-
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 extru-
drug load of 10%. date provided immediate release and supersatura-
Figure 3: Processing drive load on a Leistritz Nano 16 extruded of formulations with 25%
HPMC to produce solid dis-
Itraconazole in AFFINISOLTM HPMC HME polymers of various viscosity grades. persions. Although the litera-
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 3, drive load was low for
Figure 4: Dissolution release rate of Itraconazole solid dispersions in acidic media.
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 was attained with
tion of the poorly soluble API and that the polymer all milled extrudates regardless of the viscosity
successfully held the drug in solution for six hours. grade of polymer used.
Figure 2 shows how viscosity grade selection impacts Itraconazole solubility is pH-dependent, and
the supersaturated dissolution profile, from immedi- maintaining the drug in solution upon transition
ate- to sustained-release. In all cases, the polymer not from simulated gastric to intestinal media is criti-
only controlled GRIS release but also maintained the cal for bioavailability improvement (10). Therefore,
dissolved drug in solution for up to 24 hours. a pH change dissolution study was performed on
Itraconazole (ITZ), another poorly soluble BSC ITZ formulated with relevant grades of Affinisol
Class II compound, has been melt extruded with polymers and compared to an equivalent dose of
100%
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Figure 5: Dissolution of Itraconazole following a pH transition dissolution method. Buffer viscosities to enable success-
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
morpholog y, 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 HPMC process the powder into the
can achieve significant increase in dissolved solids content at the same viscosity.
desired dosage form.
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 the
were first exposed to acidic media for two hours 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 sol-
and maintained that supersaturation following the ubility of the pharmacopeial substitution grades.
pH transition. Low viscosity HPMC 2910 is typically utilized to
These case studies demonstrate Affinisol prevent viscosity associated atomization issues.
HPMCs ability to be extruded over a range of Affinisol HP polymers were developed 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 dr yer, 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 MCT 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-
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 normalized to HPMCAS with Affinisol HP
the standard HPMCAS for each drug to account for variation in drug loading for each API. HPMCAS will impact atomi-
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).
6. O.A. Abu-Diak, D.S. Jones, and G.P. Andrews, Molecular Phar-
conazole, and ketoconazole as model APIs, with all maceutics 8(4) 1362-1371 (2011).
7. K.A. Coppens, et al., Pharm Tech, January, 62-70 (2006).
spray solutions made at 2% solids with 25% (w/w)
8. K. P. ODonnell and W.H.H. Woodward, Drug Dev Ind Pharm.
API loading. May 20:1-10 (2014).
9. K. Six, et al., Pharmaceutical Research 20(7) 1047-1054 (2003).
The spray-dried dispersions were analyzed by 10. D.A. Miller, et al., Drug Dev Ind Pharm. 34, 890-902 (2008).
MCT dissolution testing, and the AUC90 values 11. D.T. Friesen, et al., Mol. Pharm. 5 (6) 1003-1019 (2008). PT
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Analytical Techniques
Analytical Techniques for

Oral Solid Dosage Formulation
Paul Kippax and Deborah Huck-Jones
T
Analytical technologies he workflows associated with the development of an oral
must accurately identify solid dosage (OSD) product, whether innovator or generic,
and measure the critical focus on detailed characterization of the API and excipi-
material attributes of APIs
ents, both individually and then in combination, within the
and excipients, separately
blended formulation. Processing steps such as blending can alter the
and when combined during
oral solid dosage formulation characteristics of an API, thereby affecting the efficiency of a drugs
and development. 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
Jonathan KItchen/PhotodIsc/Getty IMaGes
needed to ensure success, which include:

Definition of the quality target product profile (QTPP)
Identification of the critical quality attributes (CQAs)
of the product
Paul Kippax is product group
Determination of the CQAs of the drug substance
manager and Deborah Huck- and excipients
Jones is product manager, ana-
lytical imaging, both with Malvern Selection of an appropriate manufacturing process
Instruments.
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 appropri-
cacy, quality, and safety, and involves the consid- ate manufacturing process. Putting in place the
eration of such issues as drug strength, bioavail- monitoring and control strategies needed to ensure
ability, and the rate of drug delivery. The CQAs of consistent manufacture marks the endpoint of the
the product are the product variables that have a 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 disintegra- (QbD) is evident from the language used to define
tion rate, dose uniformity, and hardness. this workflow. However, there is no regulatory re-
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 material ciples, as set forth in FDAs question-based review
attributes of the API and approach, are required. Applying QbD does not
the excipients separately change the underlying formulation workflow, but
it does influence the rigor with which each stage is
prior to processing, and also implemented.
within a multicomponent A QbD approach to investigating the CQAs of
blend, is essential. the API, for example, might extend to develop-
ing functional relationships between these CQAs
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 spacean operating window
to determine which of their properties is linked in which success is assuredrather 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-
all fIGures are courtesy of the authors.
might be its disintegration characteristics, while an formation gathering and intensifies the need for
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 very
excipient has been investigated, there is a require- much on the API and how its therapeutic effect can
ment to assess whether the individual components be most efficiently delivered to the patient. ICH
are changed as the blend is formulated and pro- Q6A, Specifications: Test Procedures and Accep-
Assessing the impact of these properties helps
Figure 1: Particle images captured for two different API 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 B essential to verify that the correct polymorphic
(red line) show clear differences between 11201300 cm . -1
form is used in the formulation and is delivered
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
identify the majority of in- Figure 3: Molecular weight distributions reported using a size-exclusion chromatography triple-
dividual particles in a blend 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 11201300 cm-1 region; focusing analysis here therefore essential.
allows the classification of particles as being ei- For example, the particle size of a bulk excipient
ther one polymorph or the other. This approach can influence the flow properties of the blend and
can be used to validate the data generated with its propensity to segregate. Neither property di-
automated imaging and to provide additional rectly affects the QTPP; however, both can be asso-
information about the crystal structure of the ciated with poor content uniformity and/or poorly
polymorphs, which supports the elucidation and controlled mechanical properties in the finished
control of formation mechanisms. tablet, in which case effective control measures are
needed. Laser diffraction particle sizing covers the
Optimizing excipient properties size range of interest and provides sufficient reso-
The simplest use of an excipient is as a bulking lution to accurately quantify both fine and coarse
agent to make tableting of a high-potency API that material within a blend, thereby supporting a com-
is administered in very small quantities a practical prehensive assessment of the grades available (3).
proposition. Blending with an excipient also helps In more sophisticated controlled-release formu-
enhance the bulk properties of a fine micronized lations, excipients control the rate at which the
APIproperties such as flow behavior, bulk den- API is released in vivo; their properties are more
sity, or compressibilityto improve the efficiency readily identified as CQAs. For example, proper-
of manufacturing. Though the properties of such ties of a polymeric controlled-release agent, such
ingredients may be expected to have little impact as its molecular weight (MW), have a direct im-
on the QTPP, they can, in some instances, be de- pact on the rate of drug delivery, itself a CQA of
fined as CQAs. Systematic investigation of the po- the product.
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 (Rg(w) and Rh(w)) and intrinsic viscosity (w).
Triple Detector Array (TDA) Conventional Results
Sample
Mw (Da) Rg(w) (nm) Rh(w) (nm) (w) (dL/g) Mw (Da)
hPMc 88,100 18.54 14.24 2.493 98,100
hPMcas-lf 162,300 13.49 10.36 0.87 83,400
hPMcas-Mf 167,500 13.5 10.36 0.882 74700
hPMcas-hf 360,900 15.95 12.25 0.792 72500
ple-detector array (Viscotek

Figure 4: Particle elongation distributions reported for API particles before and after blending
with different excipients. Blending causes a reduction in elongation, suggesting the API TDAMax).
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 properties a relevant standard to deliver acceptable accuracy.
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 calibration.
for controlled drug release While the single detector suggests that the sam-
Figure 3 shows molecular weight distribution data ples have closely similar MW, the triple-detector
for four samples of polymers routinely used for con- system reveals that two of the derivatives have a
trolled drug release: hypromellose (hydroxypropyl weight-averaged MW approximately double that
methylcellulose, HPMC) and three different forms of the HPMC, and that the MW of the other de-
of hypromellose acetate succinate (HPMCAS). The rivative is approximately four times higher. These
MW data were generated using a GPC/SEC system differences would lead to different controlled drug-
with a single RI detector, and separately with a tri- release performance.
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 processing, of QbD, calls for detailed and systematic study of
in this case blending (5). the properties of APIs and excipients, and of these
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
blending. The shape parameter used is elongation, 1. ICH, Q8(R2) Pharmaceutical Development, Step 4
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, 470,
larly shaped as a result of blending but the ef- 77-87 (2014). PT

Process Analytical Technology
Simplify Formulation With PAT

Emil W. Ciurczak
T
PAT has aided formulation, he term PAT (process analytical technology) was introduced
both pre-and post-filing, by by FDA in 2002 (with final guidance published two years later)
reducing costs and time
to encourage pharmaceutical producers to better understand
frames. Contrary to popular
beliefs, it doesnt require big and control their production of solid and other dosage forms.
investments. 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 physical nuance (e.g., particle size, polymorphic form,
Snap DeCiSion/photoDiSC/Getty imaGeS
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 wasnt
changing grades, or material particle sizes. As the supply chain expanded
Emil Ciurczak is principal of
Doramaxx Consulting, emil.ciurczak@ from local, US-based suppliers to overseas suppliers, these extras became
gmail.com.
ever more important. With large pharma companies resorting more and
more to outsourcing packaging, production, and even cessity for a finished product and can shave time off
R&D, it became increasingly obvious that PAT and the process, it is also quite good for development work.
quality-by-design (QbD) controls were becoming cru- While formulating for initial clinical trials, blend
cial, and not just a cost-saving approach. uniformity is essential. However, since, at that point,
The tools for PAT need not merely be part of an the drug company is dealing with both a new drug
integrated system; as the NIR qualification showed, and a new formulation, it does not yet have a validated
several new techniques/instruments may be used for assay method with which to assure blend uniformity.
individual quality checks. The wireless NIR spec- Using light-induced fluorescence (LIF) for low con-
trometer was developed (primarily) for blend unifor- centration formulations (less than 1-2% w/w) or NIR
mity (in real time). It is an excellent example of how to show completeness of blending is an extremely fast
just one tool may be used for both production and approach instead of waiting for a day (if lucky) or a
development. While blend uniformity is, indeed, a ne- week for analytical results. This speed allows several
IFPAC 2015 ShowCASES PAT SoluTIoNS

There were some interesting trends at the International Fourier-Transform Molecular Rotational Resonance (FTMRR)
Foundation for Process Analytical Chemistry (IFPAC) meeting spectroscopy, introduced by Brightspec. It imposes a
held in Alexandria, VA from Jan. 2528, 2015. frequency in the microwave-to-teraHerz (THz) range,
For one thing, several sessions were dedicated to generic- measuring the degree that it is rotated by a single molecule
drug producers, and generic industry issues were addressed in or mixture of molecules. It is used for both trace gases and
greater depth than in previous meetings: major components, with the only requirement being that
Lawrence Yu, deputy director of FDAs Office of Product they be in vapor phase.
Quality called on the generic-drug industry to be held to the TimeGate Instruments described a time-resolved Raman
same standards as innovator companies as far as instrument, using a visible (532-nm) laser for maximum
submitting risk assessments and so forth. Because his office Raman signal, applying a 100-ps time-gate, to capture
now includes oversight of both new drug and abbreviated the Raman spectrum while shutting out the interfering
new drug applications (NDAs and ANDAs), reviews will fluorescence signal. The software allows for 2-D graphics to
become more similar (and comprehensive) than ever. determine optimum gating times v. Raman shift or 3-D
An entire session was devoted to risk management, and all graphics to optimize gating time v. Raman shift v.
the speakers were either FDA officials or representatives maximum detection wavelengths.
from generic-drug companies. A number of detailed risk- EMA guideline
management programs were presented by professionals The European Medicines Agency (EMA) near-infrared guideline
from generic drug companies, and were indistinguishable was presented by Sean Jones, pharma assessor at the UKs
from others presented by speakers from Big Pharma Medicines and Healthcare products Regulatory Agency
companies. (MRHA; London). An entire evening session was devoted to it,
Continuous manufacturing (CM) was addressed as a cost- and some repeating themes were evident:
saving and quality management tool for contract It was encouraging that the 2004 guideline has finally been
manufacturing organizations (CMOs) and generics, and was updated and codified.
no longer discussed as a large innovator tool. There were some obvious difficulties, however, because it is
NIR and Raman instruments largely based on International Conference on
There were a huge number of near-infrared (NIR) and Raman Harmonization (ICH) Q2 (R1), which is a blueprint for
instrument booths at the show. Some of the more interesting chromatographic analyses, rather than spectroscopic
were: methods. Some updates are needed.
JDSUs new wireless NIR, based on its linear variable filter Sample selection (e.g., synthetic vs. production samples)
(LVF) technology should be more reflective of the RM guidances (e.g., ICH Q9)
Brimroses smaller, Acousto-Optic Tuneable Filter (AOTF)- and not be fixed for all levels of API and type of drug (e.g.,
based, wireless device for blend uniformity. high vs. low toxicity).

Process Analytical Technology
formulations to be made in short order, so that tablets with the indigenous raw materials, then scale up to
or capsules can be made for quality control or clinical production levels. But, the time involved (and time
purposes, and in vivo-in vitro (IVIVC) testing in less means longer time to market and cost overruns) can
time than it took with previous cGMP-based methods. make the project come close to losing money.
In addition, the final formulation chosen would now One answer to these problems is continuous manu-
have a process signature, divined from the initial facturing (CM). In CM, there is a series of material
blending work. dispensers for the various ingredients (API and excipi-
Within a company, the scale-up of a new product ents) where the materials are dispensed (into a mixing
from pilot batches to production-sized lots can be ex- chamber) by weight (or volume) in the proper stoi-
pensive and take up to 18 months. The ability to gauge, chiometric ratios. The mixer, usually a screw-driven
in real time, the uniformity of larger sized batches, blender, brings the powders to a well-blended mixture.
speeds up the process. Tech transfer (e.g., of an entire The powder blend can be granulated, compressed to a
production line) from one location (even domestically) ribbon, or used as is in direct compression. Another
to a second site can sometimes take as long as the screw unit is used to lubricate the blend and it is then
first scale-up procedure. Using PAT-based monitor- compressed into tablets or filled in capsules.
ing tools, this time can be reduced substantially (the
concept of design space enters here). This time lag Advantages of CM
occurs, even though the company is using the same At each step of the process, there are controlling
Master Manufacturing Formula (MMF), operational monitors: weight/volume dispensers, NIR/Raman,
standard operating procedures, and (essentially) the LIF, and so forth. These monitors assure the staff
exact same sources of raw materials and, on the sur- that every step of the process is under control.
face, often the same models of production equipment. The amounts of each ingredient is controlled
Just imagine the difficulty of transferring a method to at all times, assuring the proper materials are
a subsidiary or a contract manufacturing organization being added to the blender (weight, solenoids).
(CMO) in a developing country. There will be differ- The mixture is shown to be well-blended and
ent equipment, different API and excipient suppliers have the correct material ratios (NIR,
(it would not be economically feasible to import aspi- Raman).
rin, lactose, or talc, for example, and most countries The granulation or ribbon is shown to have
wouldnt allow it, anyway), and different training and the proper moisture and particle sizes (gran-
language of the staff. ulation) or proper mix and physical proper-
Despite oversight from members of the develop- ties (ribbon) (NIR, Raman).
ment staff, different materials and equipment make The tablets and/or capsules are monitored for
for potentially long (and expensive) delays before full weight and/or API and some physical proper-
production is achieved. Quite often, a series of test ties (prediction of dissolution profile), usually
batches must be run before the quality of the finished up to 100% (NIR, Raman).
product is good enough for sales. As with the initial Coating levels may be controlled and moni-
formulation, the CMO could run a series of pilot runs tored, in real time (NIR, Raman).
The two most important advantages of CM have Miscellaneous applications
to do with waste of materials. In a production set- Several other applications of the same PAT tools used
ting, at any given time, only a few kilograms of for production may be applied to other parts of the
material are being processed. That means, should system:
there be an event that causes an out of speci- Clinical packaging. Currently, the double-
fication (OOS) incident, manufacturing can be blind nature of a clinical study can frustrate
stopped (remember, it is continuously monitored any attempt at true control. The patient cards
for product quality) and, at the worst case, only a are made up and several are sacrificed to the
few kilos of material are lost. These OOS materials QC lab for analyses. If the QC results match
may be discarded and the process restarted. up with the coded identities for those cards,
Because there is no actual batch size stated, the the batch is considered validated. In the
lost materials may be made up by simply running real world, mistakes can be made, and all that
the unit longer, with raw materials being added to the QC tests prove is that the cards that were
the hoppers at the beginning of the run, as needed. sacrificed were or were not properly made.
Indeed, when a campaign is run, i.e., a long run of Using NIR or Raman or chemical imaging,
a product, either for product introduction or stock the packaging line may check the identity of
shortages, there are no limits on the size of a batch. every blister in the packaging line, assuring a
In fixed batch sizes, there may be a need for mul- proper trial.
tiple discrete lots to be run with the required clean- Packaging materials. The polymeric materials
ing and cleaning validation between each lot. That used in packaging do not lend themselves to
means more hardware used, tying up production easy compendial spot tests or, for that matter, to
units away from other products. The end result is simple lab tests. Assuring the packaging facility
higher overhead. that they are using the correct bottles (i.e.,
Because the unit uses much smaller quantities HDPE of MDPE or LDPE), that the blister pack-
of materials, a design of experiment (DoE) may aging polymer is correct wound on the roll (one
be run to optimize the product for the local raw side melts in multi-layer polymer covering), or
materials, using far less material. There would not that the line is actually packaging the drug that
be a need to run production-sized lots, because is shown on the label (a cause for recalls), are
the formulation, pilot, and production lots are all some of the benefits of a simple NIR unit on the
the same size. shop floor.
Another obvious advantage is, when you have In short, a company can utilize any or all the
an expensive (or even moderately priced) API, a tools available for PAT/QbD. Despite what some
DoE in a CM unit takes far less material, and a people may claim, you do not have to spend mil-
typical series may be run in days, not weeks, with lions, all at once, to achieve cost savings with PAT.
results immediately available. The reduction in The task of formulating dosage forms can be made
costs could be as much as 7580% over conven- simpler by adopting some or all of the tools avail-
tional means. able for PAT in the production arena. PT
Lipid Formulations
Boosting Solubility in
Lipid-Based Formulations
Higher API loading can mean smaller daily doses.
Agnes Shanley
I
Ionic liquid technologies n January, Capsugel (Morristown, NJ) acquired proprietary ionic
offer a new way to improve liquids technology from Australias Monash Institute of Phar-
bioavailability and maceutical Sciences. The technology uses lipid-like counter-ion
potentially shrink patients
daily dose requirements salts to improve the solubility of lipid-based liquid, semi-solid,
Keith Hutchison, PhD, senior and multiparticulate formulations.
vice-president of R&D for Ionic liquids offer formulators the potential to increase drug solu-
Capsugel, describes the bility, reduce absorption variability, decrease excipient levels, and
technology.
reduce pill burden, according to Capsugels 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
Mandy disher PhotograPhy/MoMent/getty iMages
formulas across several marketsnot 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 relatively
Agnes Shanley is senior editor of low drug loading, which can translate into a commercially unaccept-
pharmaceutical technology.
able daily dose requirement. Higher solubility with ILT will result in
Achieving
Faster Time to
First in Human
Xcelolab Powder Dispenser
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 100g, 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
processing speeds of up to 33,000 capsules per
hour. Designed for high-speed semi-automatic
filling applications, it introduces cost-effective
quality and performance.
Learn more at
To find out more about our R&D portfolio of products, New York City
April 21-23, 2015
services, and equipment, call 888-783-6361 or send
Booth #1453
an email to solutions@capsugel.com
2015 Capsugel Belgium NV All rights reserved.

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 burden solubility.
for patients across a range of low solubility drugs. MIPS researchers took an alternative approach
for ILTutilizing 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 spray- self-emulsifying systems (SEDDS or SMEDDS)
dried formulations to help design the best prod- that are well known to improve oral bioavailabil-
ucts for brick dust low solubility drugsvery ity in vivo.
poorly water soluble compounds that are easily
wetted in water, but seem to be insoluble in almost ILT and existing technology
everything else. The ionic liquids technology from PharmTech: How does ILT complement or expand
Monash represents the first time that the solution existing technology?
is made available for a wide range of grease ball Hutchison: Solubility challenges are a major
lipophilic low solubility drugs, which show very problem for customers today. ILT broadens the
poor water solubility but are more easily wetted by range of solutions that can be used, including
oil. This means that patients might, for example, amorphous dispersions based on either spray dry-
only need to take one or two capsules formulated ing or hot-melt extrusion (HME), nanocrystal tech-
with ILT instead of 5 to 10 using conventional nology options, and a range of liquid, semi-solid,
technology. and multiparticulate lipid formulation approaches.
PharmTech: Can you explain the chemistry be- Proprietary ILT expands the potential use of
hind ILT? lipid formulation across a broader range of drugs
Hutchison: Salt-screening strategies are rou- and lipophilicity profiles. ILT can be utilized for
tinely utilized as an initial approach for address- ionizable compounds and enhances many lipid-
ing low solubility. In this approach, one combines based formulations (i.e., liquid, semi-solid or solid
a compound with a counter-ion to produce the lipid multiparticulate [LMP] technologies). As
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 addressing to choose one partner for the science of product
low solubility challenges? development, thereby reducing time to clinic, cost,
Hutchison: The most important step is to select and project complexity.
the right dosage form technology for each API. No
specific technology or finished dosage format can Technology collaboration
be utilized for all compounds, and it is critical to PharmTech: What is the nature of Capsugels on-
access a range of technologies, know-how, and going collaboration with Monash University?
track record across compound types and applica- Hutchison: Monash and Capsugel have a long
tions. To address a low bioavailability challenge, history of collaboration in LBF technology and
the physicochemical and/or biological obstacles its applications, including co-founding the Lipid
must be well understood in order to choose the Formulation Classification System (LFCS) Con-
right technology in meeting target product profile sortium to advance a common understanding of
and commercial objectives. lipid formulations in order to facilitate the technol-
Capsugel Dosage Form Solutions has developed ogys broad adoption. Capsugel has acquired all of
a proprietary technology selection methodology, MIPS intellectual property pertaining to ILT, and
based on modeling more than 1000 compounds the transfer of know-how. ILT-based LBF internal
across technologies, to rapidly select the optimal and lead user product development projects with
technology for a specific API and advance an ini- clients are currently being evaluated. PT
Call for papers on apis and exCipients

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

New Technology
Innovations in
Solid Dosage Equipment
Ashley Roberts
G
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
of issues that are top of mind for tablet producers.
complex manufacturing
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.
Romacos 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 Americas FE75 Tablet Press can be equipped
Romaco Group with up to 115 punch stations to produce more than 1.6 million tab-
lets per hour. The FE75 features four compression Figure 1: The PERFORMA Lite is GEAs compact tablet press,
rollers with a control system for direct com- capable of production rates up to 320,000 tablets per hour.
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: Natolis 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. GEAs 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-
IMAGES CouRTESY oF BoSCh, GEA, NATolI, AND PhARMA TEChNoloGY
ity, and greater product output. An exchange-

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 Natolis 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 Boschs 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
mit Europene-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
New Technology
Figure 3: Boschs TPR 500 is designed with separated production Laboratory and small-scale presses
and mechanical areas to reduce powder contamination. New small-scale equipment can be used in R&D. Na-
tolis 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-
Figure 4: Pharma Technology Inc. and Roeltgens FlexiTab
tablet press can operate with powder quantities up to 1 kg. 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 operating forces up to 100 kN. PT
Ad Index
COMPANY PAGE
Abitec Corp7
Capsugel, A Div Of Pfizer 45
CMIC CMO USA Corporation 11
Coating Place Inc 5
400,000 tablets per hour, and a True Flow tab-
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

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ebook series 2015

Solid Dosage and

PrOcess analyTical TechnOlOgy

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hPMc 88,100 18.54 14.24 2.493 98,100

hPMcas-lf 162,300 13.49 10.36 0.87 83,400

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hPMcas-hf 360,900 15.95 12.25 0.792 72500

ple-detector array (Viscotek

Pharmaceutical Technology Solid doSage & excipientS 2015 39

Simplify Formulation With PAT

crystallinity, and moisture) affected the spectrum of the material. Thus,

IFPAC 2015 ShowCASES PAT SoluTIoNS

Pharmaceutical Technology Solid doSage & excipientS 2015 41

Significance of ionic liquids technology

formulas across several marketsnot only for new chemical entities

Xcelodose S Precision Powder

CFS 1200 and the CFS 1500 C

Capsugel Ultra III

2015 Capsugel Belgium NV All rights reserved.

Call for papers on apis and exCipients

Pharmaceutical Technology Solid doSage & excipientS 2015 47

pression, enabling the machine to operate with

ity, and greater product output. An exchange-

output, especially with shaped or friable tab- Metrics Inc 33

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output, especially with shaped or friable tab- Metrics Inc 33