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AUGUST | SEPTEMBER 2011
pharmaquality.com
Contents
Cover Story
6
New Gums from
Ancient Lands
Indian plants studied as binding
agents in tablet formulations
BY MAYBELLE COWAN-LINCOLN
Departments
10 GREEN CHEMISTRY I WASTE REDUCTION
A Green Sweep
Big pharma is drafted by ethical and fiscal
responsibilities to collaborate on waste
reduction efforts By Neil Canavan
14 DELIVERY I CYCLOSPORINE
TBI’s Miracle Drug
An accidental discovery about 20 years ago
has led to a cyclosporine pharmaceutical on
the threshold of approval By Steve Campbell
22 FORMULATION I NANOPARTICLES
Strides for Small Cancer Fighters
Nanoparticles used to formulate and deliver
drugs to cells and tumors show increasing
promise By James Netterwald, PhD
24 IN THE LAB I OUTSOURCING
A 70-person PerkinElmer OneSource
on-site team takes complete responsibility
for maintaining and qualifying more than
50,000 Merck Research Laboratories
assets in six facilities. See Page 24.
27 INGREDIENTS I HYALURONIC ACID
The Benefits of HA in
Ophthalmic Delivery
InThis Issue
A Q&A with Novozymes’ Khadija SchwachAbdellaoui, PhD
34
36
37
38
40
40
30 TOOLS OF THE TRADE
Perfect Partners
Merck Research Laboratories reduces
equipment maintenance costs and improves
productivity with PerkinElmer OneSource
team By Maurizio Sollazzo, Paul Luchino,
and Ted Gresik
X-RAY DIFFRACTION SOURCES
Uses of X-Ray Powder Diffraction
in the Pharmaceutical Industry
By Igor Ivanisevic, Richard B. McClurg,
and Paul J. Schields
JPS UPDATE
PHARMASCAN/WIRES UPDATE
HELP DESK
PRODUCT SPOTLIGHT
INDUSTRY EVENTS
ADVERTISER DIRECTORY
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August/September 2011 > Pharmaceutical Formulation & Quality 3
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Professor and Acting Chair
Department of Pharmaceutical Sciences
School of Pharmacy, Co-Director of Nanomedicine Education and Research Consortium
(NERC), Northeastern University, Boston, MA
Robin H. Bogner, PhD
University of Connecticut School of Pharmacy
Storrs, Conn.
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4 Pharmaceutical Formulation & Quality > August/September 2011
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Upsher-Smith Laboratories, Inc.
Maple Grove, MN
Rosario LoBrutto, PhD
Group Head, Pharmaceutical and
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East Hanover, NJ
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Research Associate Professor
Department of Chemistry
and Biochemistry,
South Dakota State University
Brookings, SD
Daniel L. Norwood, PhD
Director of Physical and Chemical
Analysis, Boehringer Ingelheim
Pharmaceuticals Inc.
Ridgefield, Conn.
Colleen E. Ruegger, PhD, RPh
Specialist in
Oral Delivery/OralFormulation
Novartis Pharmaceutical Corp.
East Hanover, NJ
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WHERE DO THE
KEY PLAYERS IN PHARMA,
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COME TOGETHER?
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COVER STORY
CAPSULE
Studies continue to evaluate plant gums found throughout the world for their usefulness as binding agents. Plant gums are a readily available,
renewable resource that can be substituted for more expensive synthetic materials. They not only lower the cost of manufacturing tablets or topical
formulations but also bolster the economies of the areas in which they are found.
© ISTOCKPHOTO,COM
NEW
GUMS
FROM
ANCIENT
LANDS
Indian plants studied as binding
agents in tablet formulations
> BY MAYBELLE COWAN-LINCOLN
T
ablets are a popular medication
delivery system. They allow powders and granules to be packaged
in a compact and accurate dosing
form that can be efficiently and inexpensively produced. The secret to the tablet’s
success is the binding agent.1-2
Binding agents are excipients that provide cohesiveness and structural strength
to powdered material during the manufacture of tablets. Binders allow tablets to remain intact after the compression process.
Numerous compounds have been used
as binding agents. Maize, potato starches,
gelatin, and natural gums, as well as modified natural and synthetic polymers, have
historically performed well as binders.3
Gums are often chosen as binders for
tablets because of their physiochemical profile and the fact that they are relatively inert.4
Gums are polysaccharides made from sugar
and uronic acid units. These translucent,
amorphous substances, byproducts of plant
metabolic processes, are often produced to
protect the plant after injury. Though insoluble in alcohol, gums will either dissolve or
swell in water.5
There are many benefits to using natural,
plant-based gums in tablet manufacture.
They are inexpensive and do not cause side
effects. They are a locally available, renewable resource that can be processed in an
environmentally friendly manner. In addition, they improve the economy of their
country of origin by using local materials.
These benefits have provided the impetus for numerous recent endeavors to
evaluate the efficacy of plant-based gums
and mucilages grown in various regions of
India. There are several factors to consider
when choosing and evaluating a binder.
The type and concentration of the binding
agent affect the strength, friability (ease of
crumbling), and times for disintegration
and dissolution. An additional consideration is the compatibility of the binder with
the other substances in the tablet, particularly the active ingredient.
Several of these efforts to identify new
sources of inexpensive binding agents
have yielded promising results.
TAMARIND SEED POLYSACCHARIDE
Tamarind seed polysaccharide (TSP), obtained from the seeds of the native Indian
plant Tamarindus indica, produces a viscous, mucoadhesive mucilage with a broad
pH tolerance and no carcinogenicity. A
6 Pharmaceutical Formulation & Quality > August/September 2011
study conducted in Vishakhapatan, India
at Andhara University evaluated this mucilage as a natural polymer to be used in
pharmaceutical formulations.
To determine if the mucilage had the
properties necessary to perform as an efficient binding agent, it was tested for several properties, including swelling index,
solubility, microbial count, and thermal
stability. Investigators reported that TSP
hydrates quickly and swells up to 1,700%.
It dissolves rapidly in warm water, sparingly in cold water, and not at all in alcohol.
Microbial growth was not supported. Additionally, TSP is stable at temperatures
up to 210 degrees C in solid form and 145
degrees C in liquid form, indicating that
it can be used in both liquid and solid formulations. Upon hydration, TSP forms a
thick, viscous surrounding layer. This
coating retards drug release.
Tamarind seed polysaccharide forms a
thick coating upon hydration that retards
drug release.
Binding agents have a significant impact on the flow properties of powdered
tablet ingredients, an important property
for an excipient. Flow properties can be
determined by measuring the angle of repose, a calculation based on the radius of
the base of the conical pile produced by
pouring the powder through a funnel. An
angle of repose of less than 30 degrees
indicates a free-flowing powder. The TSP
angle of repose was determined to be 29.50
degrees, indicating good flow properties.
In view of these results, including high
swelling index, thermal stability, good flow
properties, and unfriendly environment for
pathogens, investigators concluded that
TSP would make a useful excipient, particularly for sustained-release tablets.
PHARMAQUALITY.COM
CASSIA ROXBURGHII SEED GUM
IN PARACETAMOL TABLETS
Cassia roxburghii is a large Indian tree with
seeds that consist of 50% endosperm,
which yields a water-soluble gum. The
binding properties of the gum, including
stability and viscosity, were evaluated in a
study conducted by the KMCH College of
Pharmacy in Coimbatore, India, and compared to the properties of two standard
binders, sodium carboxymethyl cellulose
(sodium CMC) and gelatin.6
Three batches of C. roxburghii gum solution, containing 1%, 1.5%, and 2% C. roxburghii seed gum, were prepared, along with
solutions made with sodium CMC and gelatin. A comparative study revealed that C.
roxburghii seed gum showed higher viscosity than solutions containing the standard
binders. The samples were retested after 16
days, and the C. roxburghii seed gum solution
displayed the least decrease in viscosity.
Paracetamol tablets were also prepared
using these solutions as binding agents.
Research shows that Cassia seed gum is a
useful binder when high mechanical strength
and slower drug release are desired.
Three batches of tablets using C. roxburghii
seed gum were manufactured, containing
2%, 4%, and 6% binder. All tablets were
evaluated for hardness, friability, disintegration time, and dissolution rate. The results were encouraging: Tablets made with
2% C. roxburghii seed gum showed higher
hardness and longer disintegration time
than those made with sodium CMC or gelatin. Of the three formulations, C. roxburghii
seed gum showed the lowest friability.
As the C. roxburghii seed gum concentration increased, binding characteristics
such as hardness and disintegration time
also increased, while friability decreased.
These results demonstrate that the binding capacity of the tablet is in proportion to
the C. roxburghii seed gum concentration.
Not surprisingly, as this concentration increases, the drug release rate decreases.
These results suggest that C. roxburghii
seed gum is a useful binder when high mechanical strength and slower drug release
are desired.
MORINGA OLEIFERA GUM
Moringa oleifera is a fast-growing tree
found throughout India. The plant extrudes a white gum that darkens to reddish
brown or brownish black on exposure. The
gum is sparingly soluble in water, producing a highly viscous solution. Victoria
College of Pharmacy in Andhrapradesh,
India, recently studied the binding proper(Continued on p. 8)
CASE STUDY
Grewia Gum Shows Promise
P
harmaceutical excipients are usually imported into
sub-Saharan Africa from the developed world, adding
to the cost of medicine and reducing the number of
patients who can afford to take it. According to Martins Emeje,
PhD, research fellow at the National Institute for Pharmaceutical
Research and Development (NIPRD) in Nigeria, finding locally
grown materials to substitute for imported excipients achieves
several objectives:
• Lowers manufacturing costs;
• Creates jobs in multiple areas, including planting, harvesting, and crop storage; and
• Increases national pride.
In 2007, a study on the use of locally grown grewia gum
as a binding agent was published by NIPRD. Grewia gum is
used for a wide variety of domestic purposes in Nigeria—from
mixing the materials used to build hut walls to serving as a
vegetable. These uses led Dr. Emeje to form the hypothesis
that grewia gum could serve as an effective binder.1
According to Dr. Emeje, the first important property of this
plant is that it is edible and, therefore, suitable for tablet preparations. In addition, because it can hold sand together to make
a cement-like preparation for walls, there must be significant
potential for grewia gum to be a successful binding agent.
To investigate its binding properties, dried, powdered
mucilage from the plant was mixed with paracetamol granules. The formulation was evaluated for compressibility and
packing and then pressed into tablet form for further study.
The results demonstrated that grewia gum performs well as
a binder. In fact, the paracetamol tablets made with powdered
grewia gum mucilage outperformed the current standard
binder, polyvinylpyrollidone (PVP), by showing a slower
onset of plastic deformation.
After this successful trial, grewia gum has continued to
achieve positive results in research studies. Dr. Emeje’s work
with this mucilage was recognized with a 2010 grant award to
further study the gum’s potential. He expects to see a finished,
commercialized grewia gum binder formulation for the pharmaceutical, food, and cosmetic industries within the next
10 to 15 years.2 ■
REFERENCES
1. Emeje M, Isimi C, Olobayo K. Effect of grewia gum on the mechanical
properties of paracetamol tablet formulations. African J Pharmacy
Pharmacol. 2008;2(1):1-6.
2. Ogaji IJ, Hoag SW. Effect of grewia gum as a suspending agent on
ibuprofen pediatric formulation. AAPS PharmSciTech.
2011;12(2):507-513.
August/September 2011 > Pharmaceutical Formulation & Quality 7
COVER STORY | NEW GUMS FROM ANCIENT LANDS
(Continued from p. 7)
PHARMAQUALITY.COM
REFERENCES
ties of the gum by evaluating paracetamol
tablets made with Moringa oleifera gum
for properties such as angle of repose,
hardness, disintegration time, dissolution
rate, and friability. Three concentrations
of Moringa oleifera were tested—8%, 10%,
and 12%—and compared to equivalent
concentrations of gelatin.
1. Arul Kumaran KSG, Palanisamy S,
Rajasekaran A, et al. Evaluation of Cassia
roxburghii seed gum as binder in tablet formulations of selected drugs. Int J Pharm Sci
Nanotechnol. 2010;2(4):726-732.
2. Shivalingam MR, Kumaran KSGA, Kishore
Reddy YV, et al. Evaluation of binding properties of Moringa oleifera gum in the formulation
of paracetamol tablets. Drug Invention Today.
2010;2(1):69-71.
Sesbania gum binds gel formulations well.
Moringa gum is sparingly soluble in water.
The study demonstrated that tablet
hardness and disintegration time increased
with the concentration of binding agent.
Friability decreased, as did the percentage
of drug released. In view of these results,
the investigators concluded that Moringa
oleifera can be used as a binder, particularly for sustained-release tablets, which
require higher mechanical strength.
SESBANIA SEED GUM
In addition to tablets, binding agents are
also used in topical delivery systems. When
plant mucilages are mixed with water, a
soothing, protective application is formed.
Sesbania seed gum, derived from the endosperms of Sesbania grandiflora seeds,
was evaluated as a gelling agent in a study
at the Kalol Institute of Pharmacy in Gujarat, India.7
Six batches of diclofenac diethylammonium gel were prepared using various
concentrations of sesbania seed gum: 2%,
2.25%, 2.5%, 2.75%, 3%, and 3.5%. The gel
was evaluated for drug content, extrudability, and viscosity.
All the prepared gels were clear and
smooth as well as homogenous and pliable. However, the batch containing 2.5%
sesbania seed gum had the best pH profile
and spreadability. Interestingly, this batch
also showed the best drug release results,
extruding 80% of the diclofenac diethylammonium over eight hours. The results
led investigators to conclude that sesbania
seed gum, particularly in a 2.5% concentration, does make a suitable binder for gel
formulations. ■
3. Patil BS, Soodam SR, Kulkarni U, et al.
Evaluation of Moringa oleifera gum as a
binder in tablet formulation. Int J Res
Ayurveda Pharmacy. 2010;1(2):590-596.
4. Adeleye AO, Odeniyi MA, Jaiyeoba KT. The
influence of cissus gum on the mechanical
and release properties of paracetamol
tablets—a factorial analysis. Rev Ciênc Farm
Básica Apl. 2010;31(2):131-136.
5. Phani KGK, Gangaroa B, Kotha NS, et al.
Isolation and evaluation of tamarind seed
polysaccharide being used as a polymer in
pharmaceutical dosage forms. Res J Pharm
Biol Chem Sci. 2011;2(2):274-290.
6. Girhepunje K, Arulkumaran, Pal R, et al. A
novel binding agent for pharmaceutical formulation from Cassia roxburghii seeds. Int J
Pharmacy Pharm Sci. 2009;1(Suppl. 1):1-5.
7. Patel GC, Patel MM. Preliminary evaluation of
sesbania seed gum mucilage as gelling agent.
Int J PharmTech Res. 2009;1(3):840-843.
Maybelle Cowan-Lincoln is a pharmaceutical writer based in New Jersey.
She specializes in articles for patients
and professionals; her writing has been featured
in numerous scientific publications.
Editor’s Choice
1. Shivalingam MR, Arul Kumaran KSG, Jeslin D, et al. Cassia roxburghii seed galactomannan–a potential binding agent in the
tablet formulation. J Biomed Sci Res. 2010;2(1):18-22.
2. Bamiro OA, Sinha VR, Kumar R, et al. Characterization and evaluation of Terminalia randii gum as a binder in carvedilol tablet
formulation. Acta Pharmaceutica Sciencia. 2010;52:254-262.
3. Deshmukh VN, Singh SP, Sakarkar DM. Formulation and evaluation of sustained release metoprolol succinate tablet using
hydrophilic gums as release modifiers. Int J PharmTech Res. 2009;1(2):159-163.
4. Emeje M, Nwabunike P, Isimi C, et al. Isolation, characterization and formulation properties of a new plant gum obtained from
Cissus refescence. Int J Green Pharmacy. 2009;3(1):16-23.
5. Panda DS, Choudhury NS, Yedukondalu M, et al. Evaluation of gum of Moringa oleifera as a binder and release retardant in
tablet formulation. Indian J Pharm Sci. 2008;70(5):614-618.
8 Pharmaceutical Formulation & Quality > August/September 2011
GREEN CHEMISTRY
CAPSULE
Enabled by advances in biotechnology and chemical engineering and driven by the need to go green, fiercely competitive big pharma companies have come together to solve the many vexing challenges of producing chemical and biological compounds without the concurrent
creation of waste.
WASTE REDUCTION
A Green Sweep
T
he EPA defines green chemistry
as “the design of chemical products and processes that reduce
or eliminate the use or generation of hazardous substances.” This definition is taken to include the entire life cycle
of the product from bench to bedside.
While such endpoints are easily expressed, even the experts find it a bit much
to comprehend in practical terms. Thus the
formation of the American Chemical Soci-
ety’s Green Chemistry Institute (ACS GCI)
and within that—and more to the medicinal point—the collaborative working group
known as the ACS GCI Pharmaceutical
Roundtable (GCIPR).
Green Team
It could almost be said that that big
pharma’s awareness of green chemistry
and the roundtable’s creation in 2005 were
prompted by a growing embarrassment.
10 Pharmaceutical Formulation & Quality > August/September 2011
“A paper came out by Roger Sheldon that
looked at a metric called e-factor,” explained
Julie Manley, senior industrial coordinator
with the ACS GCI and the GCIPR. “E-factor
generally referred to the amount of waste
generated per kilo of product produced, and
he showed that, on that basis, pharma generated the most waste” as compared with
other chemical-based industries.1
Because the waste comprises chemicals,
it is rarely benign. Corporate reputations are
© IMAGES.COM/CORBIS
Big pharma is drafted by ethical and fiscal responsibilities to collaborate on
waste reduction efforts > By Neil Canavan
PHARMAQUALITY.COM
at risk, liabilities accrue, and waste in this
or any context can be measured in terms
of resources squandered. “The roundtable
looks to combine the ethical and fiscal
objectives,” Manley explained. “This not
only helps the bottom line of the company,
but improves its environmental health and
safety standards as well.”
But why and how do pharmaceutical
companies collaborate on what should be
a competitive issue? “There are, in fact,
common challenges across the industry,”
said Manley, “and while each company
has a focus on their unique molecule, in
general, much of the chemistry is very similar. Everyone uses certain solvents, certain
reactants… .”
One company looking for green alternatives on its own cannot match the creativity
of 16 companies—the current number of
roundtable members—working together.
“The key is to interact in a noncompetitive
way, and that is how the roundtable is set
up,” Manley said. Shared data sets are
blinded to retain corporate privacy, and cocompany authored papers are legally vetted
by all contributors.
Further, the roundtable is able to encourage, and hopefully share in, green
chemistry innovation beyond its membership by using a portion of membership
dues, ranging from $10,000 to $25,000 a
year, to fund research grants that have
totaled more than $950,000.
“Right now the program is limited to
academics,” said Manley. Part of the reason
for this restriction is to focus on spreading
the word, to influence academic curricula.
“If people are doing the research, then
green chemistry is being communicated
internally within that institution.”
Available to non-GCIPR members are
analytic tools that can be accessed through
the ACS green chemistry website.2 For
example, there is a tool for calculating the
so-called process mass intensity (PMI),
defined as the kilos of mass of all materials
that go into producing an active pharmaceutical ingredient (API), normalized by
the mass of the end product; this is taken
as a measure of the “greenness” of a given
process.3 “The benchmark of PMI has been
a very useful tool so that companies can
compare apples to apples,” of particular
use when considering the greenness of
third-party manufacturers that may be a
part of your supply chain. (Continued on p. 12)
CASE STUDY
Green Means
T
he 15th annual Green Chemistry and Engineering
Conference—the premier green chemistry event—saw
BioAmber Inc., win the Presidential Green Chemistry
Challenge Award, bestowed by the Environmental Protection
Agency and the American Chemical Society in Washington,
D.C., in June.
BioAmber, a renewable chemistry company, received the
honor for their innovation in the biosynthesis of succinic acid,
which is normally produced with petrochemicals. BioAmber’s
proprietary platform uses microbes that have been optimized
for succinic acid production.
Last year’s co-winners, Merck and Codexis, were honored
for their green chemistry approach in retooling the synthesis
steps for making the diabetes drug sitagliptin. Along with
numerous green optimizations, the critical alteration was finding an alternative to the catalytic use of rhodium, a rare metal
that became prohibitively expensive during the scale-up of
manufacture for sitagliptin; for this, scientists were able to
substitute a transaminase enzyme for a rhodium-based
hydrogenation catalyst.1
Another example of biocatalysis in green pharmaceutical
chemistry is seen in the production of the neuroactive agent
pregabalin. In this case, the initially developed API synthesis
was highly wasteful, producing 86 kg of waste per one kilogram of product. In addressing this issue, the manufacturer,
Pfizer, performed an enzymatic screen for a problematic
cyanodiester. The resulting hit was a lipase derived from
Thermomyces lanuginosus, resulting in a marked reduction of
useless byproduct.2
A final example of green pharmaco-chemistry comes from
the familiar class of drugs known as statins—specifically, rouvastatin. In this instance, an initially wasteful chemical reaction
was replaced with an enzymatic step that uses deoxyribose
phosphate aldolase (DERA) an innovation pioneered in an academic lab. Once the efficacy of this approach was established,
a nagging problem remained involving the irreversible deactivation of the enzyme by a chloroacetaldehyde. This was solved
with DERA 2.0, if you will, which was created using the biotech
method of directed mutagenic evolution.3
For a review of these and other green chemistry options
see: Dunn PJ. The importance of green chemistry in process
research and development [published online ahead of print
May 12, 2011]. Chem Soc Rev. ■
REFERENCES
1. Grate J, Huisman G. A greener biocatalytic manufacturing route to
sitagliptin. Paper presented at: 13th Annual Green Chemistry and
Engineering Conference; June 23, 2009; College Park, Md.
2. Martinez CA, Hu S, Dumond Y, et al. Development of a chemoenzymatic
manufacturing process for pregabalin. Org Process Res Dev. March 18,
2008. Available at: http://pubs.acs.org/doi/abs/10.1021/ op7002248.
Accessed August 1, 2011.
3. Jennewein S, Schürmann M, Wolberg M, et al. Directed evolution of
an industrial biocatalyst: 2-deoxy-D-ribose 5-phosphate aldolase.
Biotechnol J. 2006;1(5):537-548.
August/September 2011 > Pharmaceutical Formulation & Quality 11
GREEN CHEMISTRY | WASTE REDUCTION
(Continued from p. 11)
Green Team Player
“I hope we’re reaching a tipping point of
awareness for green chemistry,” said Concepción Jiménez-González, PhD, director
and team leader of operational sustainability at GlaxoSmithKline (GSK), a GCIPR
member. “That’s part of what we wanted to
do with the roundtable.”
An engineer by training who has published on the subject, Dr. Jiménez-González
is concerned with the production issues
beyond the flask: “There are very common
techniques outside of pharma that are not
really as practiced within pharma, like life
cycle assessment, process identification, or
the use of continuous processes. We need to
move away from emulating what happens
in the lab when considering scale up.” 4
For example, GSK has recently finalized
a carbon footprint analysis for its global operations. “We wanted to identify the main
contributors to the footprint—what we call
‘hotspots,’ ” Dr. Jiménez-González said. The
chief suspect of un-greenness she identified
overall is GSK’s use of solvents. “We did
some case studies going from cradle to
gate in manufacture, from the moment you
extract raw materials to the moment you
finish the API, and we found out that the
impact of solvents is, on average, around
70% to 75% of all the overall environmental impact of the process.”5
So what to do? Recycling is one possibility, and it can be done is such a way that
it does not affect good manufacturing
practices. For instance, you can use recy-
This process mass intensity calculator is one of several analytic tools available at the ACS Green
Chemistry Institute website: http://bit.ly/qb5buA
cled solvent to serve the same step in a
synthesis. “The other option, when you are
looking at the process from the life cycle
standpoint, is [that] it really doesn’t matter
if you recycle through the same process or
you down-cycle, say, to a paint manufacturer,” Dr. Jiménez-González noted.
Or, you could simply use a more benign
solvent. Though chemists may be loath to
make changes to a set process, there are
now references available to guide them in
selecting alternative solvents; resources
include advice from GSK, Pfizer, and the
GCIPR.6-8
“In general, it makes life easier for us
if we include those types of changes prior
to filing the IND [investigational new drug
application],” Dr. Jiménez-González said.
Beyond that, a retooling of the process
could cost you valuable patent expiration
time.
Green Think
Retooling, or even thinking de novo, can often be a challenge for creatures of habit. If
you’re stuck in a circle of self-referencing
ideas, you may want to bring someone in
from outside—someone like John Warner,
Editor’s Choice
1. Komura K, Nakano Y, Koketsu M. Mesoporous silica MCM-41 as a highly active, recoverable and reusable catalyst for direct
amidation of fatty acids and long-chain amines. Green Chem. 2011;13:828-831.
2. Lu J, Toy PH. Tandem one-pot Wittig/reductive aldol reactions in which the waste from one process catalyzes a subsequent
reaction. Chem Asian J. July 6, 2011. Available at: http://onlinelibrary.wiley.com/doi/10.1002/asia.201100296/abstract.
Accessed August 1, 2011.
3. Conte V, Floris B. Vanadium and molybdenum peroxides: synthesis and catalytic activity in oxidation reactions. Dalton Trans.
2011;40(7):1419-1436.
4. Emer E, Sinisi R, Capdevila MG, et al. Direct nucleophilic SN1-type reactions of alcohols. Eur J Org Chem. 2011;4:647-666.
12 Pharmaceutical Formulation & Quality > August/September 2011
PHARMAQUALITY.COM
“The most amazing, most shocking thing is that a chemist can
go through six years of higher education and never have a single
course in toxicology. Never have a course in environmental
mechanisms, never a course in anything at all to prepare them
for understanding the regulatory consequences of chemistry.”
—John Warner, PhD, president and chief technology officer of the Warner Babcock Institute for Green Chemistry
PhD, president and chief technology officer of the Warner Babcock Institute for
Green Chemistry in Wilmington, Mass.
“It happens all the time: a company
has enormous resources working on a
problem, they’re poring over the literature, the textbooks, people are scouring
this material, pushing to get that incremental change to do something new, and
they come up against a brick wall,” Dr.
Warner explained. The problem is the
starting point of having an outdated chemical methods perspective.
To start fresh in green chemistry, you
might want to first check out the bible of the
field, Dr. Warner’s Green Chemistry: Theory
and Practice, cowritten with Paul Anastos,
PhD, of the Environmental Protection
Agency.9 In it you will find the 12 guiding
principles of practicing green chemistry,
which are, though initially intended for use
by the chemical industry, easily applied
to medicinal chemistry. Not so surprising,
given the fact that Dr. Warner’s career
started by contributing to the synthesis of
the anticancer agent Alimpta.
In Dr. Warner’s opinion, the impediments to green chemistry adoption are
not merely intellectual but institutional
as well. “There is a love-hate relationship
between discovery and process,” he asserted. “The people in discovery are always very grumpy that the people in
process don’t take their pearls of wisdom
and bring them to amazing fruition, and
the people downstream look at the discovery people and say, Why do you keep sending us stuff that can’t be scaled up? Why
these solvents, and these toxic reagents?
Green chemistry is the language they
should both be speaking. If you think
about it, the least changes that are made in
a process from the bench to the bottle, the
more profitable the company will be.”
Dr. Warner acknowledged that progress
is being made. Great strides, for instance,
have been made in biocatalysis (see case
study). And he sees the possibility of one
day attaining the holy grail of pharma
manufacture: continuous-flow reactions,
which would make for a much smaller
footprint at greater cost savings. But he remains concerned about the generation of
toxic byproducts.
Of particular note is the book’s green
principle No. 4: Chemical products should
be designed to preserve efficacy of function while reducing toxicity. “The most
amazing, most shocking thing is that a
chemist can go through six years of higher
education and never have a single course
in toxicology,” said Dr. Warner. “Never
have a course in environmental mechanisms, never a course in anything at all to
prepare them for understanding the regulatory consequences of chemistry.”
He is also concerned about competition: “India is mandating that all chemists
in training take a yearlong course in green
chemistry. China has opened up 15 national research centers dedicated to green
chemistry.” These developing economies
are going to become far more competitive
and innovative because they are putting
green chemistry into the front end of innovation and creativity, “and we are still
scratching our heads about whether we
should do it.” ■
REFERENCES
1. Sheldon RA. Catalysis: the key to waste
minimization. J Chem Technol Biotechnol.
1997;68(4):381-388.
2. American Chemistry Society. ACS GCI
Pharmaceutical Roundtable. American
Chemistry Society website. Available at:
http://portal.acs.org/portal/acs/corg/content?_nfpb=true&_pageLabel=PP_TRANSITIONMAIN&node_id=1407&use_sec=false
&sec_url_var=region1&__uuid=a628a938-
683c-4c0d-8cac-2aba9f3f06ab. Accessed
August 1, 2011.
3. American Chemistry Society. PMI worksheet.
Available at: http://portal.acs.org:80/portal/
PublicWebSite/greenchemistry/industriainnovation/roundtable/CNBP_026644.
Accessed August 1, 2011.
4. Jiménez-González C, Poechlauer P, Broxterman QB, et al. Key green engineering
research areas for sustainable manufacturing:
a perspective from pharmaceutical and fine
chemicals manufacturers. Org Process Res
Dev. February 22, 2011. Available at:
http://pubs.acs.org/doi/abs/10.1021/op1003
27d. Accessed August 1, 2011.
5. Constable DJC, Jiménez-González C, Henderson RK. Perspective on solvent use in the
pharmaceutical industry. Org Process Res
Dev. December 14, 2006. Available at:
http://pubs.acs.org/doi/abs/10.1021/op0601
70h. Accessed August 1, 2011.
6. Jiménez-González C, Curzons AD, Constable
DJC, et al. Expanding GSK’s Solvent Selection
Guide—application of life cycle assessment
to enhance solvent selections. Clean Technol
Environ Policy. April 8, 2004. Available at:
www.springerlink.com/content/bk59v8me1l6
pv85q/. Accessed August 1, 2011.
7. Alfonsi K, Colberg J, Dunn PJ, et al. Green
chemistry tools to influence a medicinal
chemistry and research chemistry based
organisation. Green Chem. November 16,
2007. Available at: http://pubs.rsc.org/en/
content/articlelanding/2008/gc/b711717e.
Accessed August 1, 2011.
8. Hargreaves CR. Collaboration to deliver a
solvent selection guide for the pharmaceutical industry. Paper presented at: American
Institute of Chemical Engineers Annual
Meeting; November 17, 2008; Philadelphia.
9. Anastas PT, Warner JC. Green Chemistry:
Theory and Practice. New York: Oxford
University Press; 1998.
Neil Canavan, a science/medical
writer based in Brooklyn, N.Y., holds a
master’s degree in molecular biology.
In addition to press coverage of medical meetings, he and has been writing about pharmaceutical science for more than 10 years.
August/September 2011 > Pharmaceutical Formulation & Quality 13
DELIVERY
CAPSULE
Historically, doctors have been helpless to prevent secondary cell death after a traumatic brain injury. But unintended results during a series
of experiments in the early 1990s showed cyclosporine can mitigate cellular damage once the pharmaceutical crosses the blood-brain barrier.
First discovered by
Sandoz (now Novartis)
scientists in Norway
in 1969, cyclosporine
is isolated from the
fungus Tolypocladium
inflatum.
CYCLOSPORINE
TBI’s Miracle Drug
O
ften called the silent epidemic,
traumatic brain injury (TBI) afflicts approximately 1.7 million
Americans annually. More than
52,000 are killed, and 275,000 are hospitalized.1 Most are left in various states of
disability—from almost full recovery to
mild symptoms but able to function with
some or moderate disability to severe disability requiring around-the-clock intensive care and support. The annual costs of
TBI, both direct and indirect, including
such factors as lost work time or reduced
productivity, have been estimated at more
than $60 billion, and there may be more
than six million TBI survivors in society.
Over the past decade, TBI has come to
the fore as tens of thousands of wounded
soldiers return home from the Middle East
suffering both hidden and visible TBIs and
trauma caused by blast injuries from improvised roadside explosions.2
What is called post-traumatic stress
disorder may actually be the long-term effects of TBI.
Due to the economic and social costs of
14 Pharmaceutical Formulation & Quality > August/September 2011
TBI, a significant ongoing effort is being
made to develop and apply emerging new
clinical and pre-clinical pharmaceuticals
with the potential to mitigate the cascading additional brain damage that occurs
during the critical secondary phase in TBI.
Among these is an interesting pharmaceutical compound called cyclosporine (also
known as cyclosporin-A, or CsA), which
has been found to have significant neuroprotective capabilities and the ability to
moderate the resulting damage and longterm disability in TBI.3-6
IMAGE COURTESY OF NEUROVIVE
An accidental discovery about 20 years ago has led to a cyclosporine
pharmaceutical on the threshold of approval > By Steve Campbell
PHARMAQUALITY.COM
• Cyclosporine Mitigates Heart Attacks
itochondria are present and produce effective energy in almost all
cells in the body. It turns out that mitochondrial collapse may be
associated with a variety of acute injuries, such as myocardial infarctions and chronic diseases like amyotrophic lateral sclerosis, multiple sclerosis, and other neurological disorders. In myocardial infarctions, reperfusion
of the blocked artery can cause reperfusion injury and extra damage and
disability to the heart muscle, as well as increased mortality. Mitochondrial
protection in heart muscle tissue is one answer to moderating the long-term
impact of heart attacks on health and lifestyle.
Every year, an estimated 500,000 people in the United States suffer a
myocardial infarction. Infarct size is a major determinant of mortality. During
myocardial reperfusion, the abruptness of the reperfusion can cause additional damage—a phenomenon called myocardial reperfusion injury. Studies
indicate that this form of injury can account for up to 50% of the final size
of the infarct.1 Focusing on reducing the additional infarct resulting from
reperfusion would protect heart muscle and allow the patient to live longer
and in better health after the initial attack.
Interestingly, a number of proposed interventions, such as ischemic
postconditioning, have been claimed to mediate cardioprotective actions by
acting on the opening of the mitochondrial permeability transition pore
(MPT), which is directly inhibited by cyclosporine. CsA has been studied for
its cardioprotective capabilities and found to be a potentially significant
pharmaceutical for ameliorating long-term damage from heart attacks.
A small proof-of-concept clinical study by Christophe Piot, MD, PhD, and
his colleagues, published in The New England Journal of Medicine in 2008,
found that the administration of CsA with the aim of inhibiting the induction
of the MPT was associated with a 40% reduction in infarct size.2 An editorial
in the journal called for large, multi-center studies to determine if this new
treatment option can positively influence clinical outcomes. In addition,
targeting the MPT “may also offer protection in other clinical contexts, such
as stroke, cardiac surgery, and organ transplantation.”
Following that lead, in April, a European investigator-initiated multi-center
phase III study of NeuroVive’s cyclosporine-based cardioprotection pharmaceutical CicloMulsion in myocardial infarctions enrolled the first of 1,000
patients.3 —SC
Cyclosporine is a cyclic peptide of 11 amino
acids and contains a single D-amino acid,
rarely encountered in nature. Cyclosporine
protects mitochondria in TBI, myocardial
infarction and other acute injury applications.
Pre-clinical mouse model studies
show an 80% reduction in neural damage
after the application of this pharmaceutical.7-8 More than 17 years in development
for neuroprotection, CsA is working its
way toward approval as a treatment that
can greatly ameliorate the effects of TBI
in humans.
Two Stages
TBI has two stages. The first stage occurs
at the time of injury, whether it is caused
by a gunshot, blast, fall, or hit. This initial
stage could be either a closed-head or
open wound, and medical emergency
personnel focus on treating the wound
or injury and stabilizing the patient’s
vital signs.
The secondary stage of damage to
the brain takes place after the initial insult, as the injury continues to ripen and
worsen in the hours and days after the
(Continued on p. 16)
initial trauma.
REFERENCES
© DREAMSTIME.COM
1. Hausenloy DJ, Yellon DM. Time to take myocardial perfusion injury seriously. N Engl J
Med. 2008;359(5):518-520.
2. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute
myocardial infarction. N Engl J Med. 2008; 359(5):473-481.
3. AktieTorget. NeuroVive: first heart attack patient treated in European cardioprotection
phase III trial with NeuroVive’s Ciclomulsion. AktieTorget website. Available at:
www.aktietorget.se/NewsItem.aspx?ID=58252. Accessed Aug. 12, 2011.
Stick model of cyclosporine, as found in the
P 212121 crystalline form, demonstrates the
complexity of this peptide.
August/September 2011 > Pharmaceutical Formulation & Quality 15
DELIVERY | CYCLOSPORINE
This is when the doctor says, “Now we
just wait and see,” because there’s nothing more that medicine can do. In this
secondary stage, the trauma to the brain
triggers a series of cascading intra-cellular biochemical reactions that cause severe demise of brain cells, brain damage,
and expanded disability. If this secondary stage can be mitigated, the potential
damage and disability can be reduced
significantly, enabling the victim to get
closer to full recovery.
Some of the secondary-stage mechanisms believed by researchers to be involved in brain-cell death after TBI include
uncontrolled release of signalling molecules (neurotransmitters), cellular calcium
overload, inflammation, energy failure,
oxidative damage, and the overactivation
of enzymes such as calpains and caspases.9
All of these are believed to create the
intra- and extra-cellular conditions that
lead to the destruction of millions of additional brain cells, along with the damage
(Continued on p. 18)
IMAGE COURTESY OF NEUROVIVE
(Continued from p. 15)
Cyclosporine protects brain cells by preventing the cascading biochemical imbalances of the
TBI from causing the mitochondria to collapse and stop powering the brain cells, exacerbating
brain damage and leading to disability.
Pharmaceutical Approaches to TBI
here are a number of TBI pharmaceuticals in a variety of stages of development. The most promising of
these approaches are “multipotential,” targeting at
least two secondary-stage injury mechanisms, including
excitotoxicity, apoptosis, inflammation, edema, blood–
brain barrier disruption, oxidative stress, mitochondrial
disruption, calpain activation, and cathepsin activation.1
The value of multipotential agents is their potential to
modulate one or more of these multiple secondary injury
factors, greatly increasing the chance of achieving clinical
value. Previously, more than 30 phase III clinical studies
for single-factor targeted TBI pharmaceuticals failed to
find significance. Multipotential agents may have a better
chance of delivering a successful therapeutic result for TBI
patients and, ultimately, recouping the costs of development and trials.
Promising pharmacological multipotential agents fall
into two categories: those that have been studied clinically
and those that constitute emerging pre-clinical strategies.
16 Pharmaceutical Formulation & Quality > August/September 2011
Clinically studied pharmaceuticals include the statins
(targeting excitotoxicity, apoptosis, inflammation,
edema), progesterone (excitotoxicity, apoptosis, inflammation, edema, oxidative stress), and cyclosporine
(mitochondrial disruption, calpain activation, apoptosis,
oxidative stress).
Emerging multipotential neuroprotective agents
showing promise in pre-clinical studies include diketopiperazines (apoptosis, calpain activation, cathepsin
activation, inflammation), substance P antagonists
(inflammation, blood–brain barrier, edema), SUR1-regulated NC channel inhibitors (apoptosis, edema, secondary hemorrhage, inflammation), cell cycle inhibitors
(apoptosis, inflammation), and PARP inhibitors (apoptosis, inflammation). —SC
REFERENCE
1. Loane DJ, Faden AI. Neuroprotection for traumatic brain injury:
translational challenges and emerging therapeutic strategies.
Trends Pharmacol Sci. 2010;31(12):596–604.
PHARMAQUALITY.COM
© DREAMSTIME.COM
• What is TBI?
CRUSHED
After the initial brain injury,
excessive calcium imbalances
during the all-important secondary
damage phase cause brain cell
mitochondria to swell and burst,
releasing calcium that creates a
cascading avalanche of further
mitochondrial collapse, cellular
energy depletion, and subsequent
brain cell death. By protecting
mitochondria, cyclosporine limits
overall brain damage and eventual
disability.
BRUISED
Limiting the secondary stage
brain damage that occurs after
the initial injury is a key strategy
in treating TBIs. Cyclosporine
does this by protecting the brain
cell mitochondria from collapse
during the secondary stage,
enabling non-injured brain cells
to continue energy production
and operation while recovery
from the initial injury occurs.
IMAGES COURTESY OF NEUROVIVE
traumatic brain injury is
defined as a blow or jolt to the
head or a penetrating head
injury that disrupts the function of the
brain. Not all blows to the head result
in a TBI. The severity of a TBI may range
from “mild,” involving a brief change in
consciousness, to “severe,” featuring
an extended period of amnesia or
unconsciousness. A TBI can result in
problems with independent function,
either short- or long-term.
Millions of Americans have a longterm need for help in performing their
daily activities as a result of suffering a
TBI. By one estimate, there are up to
6 million survivors of TBI. Statistics on
the full extent of TBI are not known,
however, because the number of people with TBI who were not seen in an
emergency department and/or who
have received no formal care cannot
be determined.
The leading causes of TBI include
falls, car crashes, hitting or being hit
in sports, and physical assault. In war
zones, blasts from roadside improvised explosive devices (IEDs) and
other explosions are a leading cause
of TBI for soldiers. Males are 1.5 times
as likely as females to suffer a TBI, and
the two age groups at highest risk are
children aged 0–4 years and teenagers
aged 15–19. African Americans have
the highest death rates from TBI, and
it is the fourth-leading cause of death
for males under age 45.1
More recently, the Iraq and
Afghanistan wars have brought the
issue to the attention of the public and
Congress, as advances in combat
protection and helmets have allowed
soldiers to survive blasts that would
previously have killed them.
Post injury, there is little that can be done for soldiers returning home with
TBI. It’s been estimated that some 200,000 returning soldiers have varying
degrees of TBI, ranging from mild to severe. Symptoms include depression, an
inability to concentrate, moodiness, and frustration as the TBI sufferer struggles to complete formerly routine tasks. Moreover, much anti-social behavior
exhibited in society may be related to diagnosed and undiagnosed traumatic
brain injuries sustained in battle, on sports fields, on the streets, or around
the home. —SC
REFERENCE
1. U.S. Centers for Disease Control and Prevention (CDC). National Center for Injury Prevention and Control. Injury prevention and control: traumatic brain injury. CDC website.
Available at: www.cdc.gov/traumaticbraininjury/statistics.html. Accessed Aug. 12, 2011.
August/September 2011 > Pharmaceutical Formulation & Quality 17
DELIVERY | CYCLOSPORINE
(Continued from p. 16)
and disability that result. Many of these
are being targeted by a variety of pharmaceutical compounds and medical treatments that are in various stages of clinical
development—including forcing oxygen
into the brain through the use of hyperbaric chambers. Because it targets the protection of mitochondria inside brain cells,
cyclosporine is perhaps the most promising of these.
initial mechanism that leads to neuronal
cell death.10
How does this affect brain cells? Increases in calcium lead to its rapid uptake
into the mitochondria, which act as cellular
sinks for calcium. However, the excessive
transport and uptake of calcium negatively
impacts mitochondrial energy production,
because the driving force for both ATP production and calcium transport relies on
the “proton motive force” (the proton gra-
Research confirms that mitochondria, the
cellular energy producers inside the brain
cells, play a pivotal role in neuronal cell
death or survival, and that mitochondrial
dysfunction in brain injuries is an early
event that causes neuronal cell death.
Role of Mitochondria
Research confirms that mitochondria, the
cellular energy (adenosine triphosphate,
or ATP) producers inside the brain cells,
play a pivotal role in neuronal cell death or
survival, and that mitochondrial dysfunction in brain injuries is considered an early
event that causes neuronal cell death. The
uncontrolled release of signalling molecules with resulting overstimulation/stress
of brain cells and accumulation of high
levels of intracellular calcium may be the
dient created over the mitochondrial inner
membrane by the respiratory chain). Further, excessive calcium uptake by mitochondria, in combination with energy
failure, leads to the formation of protein
channels (pores) in the inner membrane—
the induction of the so-called mitochondrial permeability transition (MPT).
The increased permeability of the inner
membrane caused by the MPT pores immediately collapses mitochondrial function
and structure, because when the pores are
18 Pharmaceutical Formulation & Quality > August/September 2011
opened, the osmotically active inner compartment (matrix) of the mitochondria attracts water, and the mitochondria swell
and pop like balloons. In addition to causing the cessation of energy production,
upon induction of the MPT, the stored calcium and harmful proteins are then released from mitochondria, resulting in an
avalanche of further mitochondrial collapse, cellular energy depletion, and subsequent cell death. When brain cell death
is repeated millions of times during the
cascading biochemical imbalances that
characterize the secondary phase, the extent of brain damage and eventual disability are greatly increased.
Protecting the mitochondria by targeting the MPT is a viable neuroprotective
approach that has emerged in the last
decade. Published research has found
that the protein cyclophilin D is an essential component to opening the MPT pores
and that cyclosporine binds to cyclophilin
D and inhibits the induction of MPT.11,12
The result is that mitochondria can absorb
much more calcium without collapsing, allowing them to survive. As mitochondria
survive to produce energy for brain cells,
fewer brain cells die during the secondary
stage. This is the core battleground in the
war against TBI.
Cyclosporine Protects
Cyclosporine was discovered in 1969 when
it was first isolated from the fungus Tolyp-
IMAGE COURTESY OF NEUROVIVE
Cyclosporine acts to
protect the brain cell’s
mitochondria from the
cascading biochemical
imbalances that cause
these cellular power
sources to collapse and
stop powering millions
of brain cells. This
reduces the additional
brain damage and
disability that occurs
during the secondary
damage phase of TBI.
PHARMAQUALITY.COM
German Boy
Recovers After
Severe Head Injury
IMAGE COURTESY OF NEUROVIVE
Cyclosporine is isolated from the fungus Tolypocladium inflatum. In the early 1990s, NeuroVive’s
chief scientific officer Eskil Elmér and his Japanese colleague Hiroyuki Uchino discovered
cyclosporine was strongly neuroprotective when it crossed the blood–brain barrier.
cladium inflatum in Norway by researchers
working for Sandoz (now Novartis). Its
impressive immunosuppressive properties
led to its use as a pharmaceutical to prevent
tissue rejection in organ transplant recipients. It has been in use for immunosuppressive applications since the early 1980s
as a commercially successful Novartis
product called Sandimmune.13
CsA’s ability to protect the mitochondria in the brain by binding to cyclophilin
D and preventing the induction of the MPT
was discovered in 1993–1994, a period during which medical researcher Eskil Elmér,
MD, PhD, and his Japanese colleague Hiroyuki Uchino, MD, PhD, were conducting
experiments in cell transplantation. An
unintended finding was that CsA was
strongly neuroprotective when it crossed
the blood–brain barrier.14 This startling
discovery became the starting point for
basic research and patent applications in a
promising new avenue of neuroprotection.
Basic research mapping out CsA’s extensive neuroprotective capabilities has
been running continuously since 1993,
and many international and independent
research teams have since conducted and
published numerous studies confirming
that CsA is a powerful nerve-cell protector
in TBI, stroke, and brain damage associated with cardiac arrest. Advanced studies
also show that CsA is useful in protecting
mitochondria in heart tissue facing reperfusion injury during heart attacks (see
(Continued on p. 20)
sidebar).15
ometime in the 1990s, an
anonymous 14-year-old
liver transplant patient from
Germany—taking cyclosporine to
prevent tissue rejection—was hit
by a car and suffered head
injuries. By chance, an anaesthesiologist was at the scene when
the accident occurred. He immediately examined the boy and
suspected severe brain damage, a
suspicion later confirmed by an
early Glasgow Coma Scale (GCS)
score of three.
Although doctors feared the
worst—children under 14 with a
GCS below eight have a 28%
mortality rate or suffer significant
brain disability if they do survive—the patient not only survived but proceeded to make an
amazing recovery. He was discharged from the hospital five
weeks later and was able to return
to school after two months. He is
now an adult with a young son.
The neuroprotective properties of
cyclosporine were suspected in
the recovery, and the case was
reported in a detailed case study
published in the Journal of Neurosurgical Anesthesiology in 1998.1
The study authors stated,
“We conclude that neuroprotective properties of cyclosporine A
may have been involved in the
good recovery after severe brain
injury in this 14-year-old
patient.”—SC
REFERENCE
1. Gogarten W, Van Aken H, Moskopp
D, et al. A case of severe cerebral
trauma in a patient under chronic
treatment with cyclosporine A. J
Neurosurg Anesthesiol.
1998;10(2):101-105.
August/September 2011 > Pharmaceutical Formulation & Quality 19
PHARMAQUALITY.COM
6. Cook AM, Whitlow J, Hatton J, Young B.
Cyclosporine A for neuroprotection: establishing dosing guidelines for safe and effective use. Expert Opinion on Drug Safety.
2009 Jul;8(4):411-419.
7. Sullivan PG, Sebastian AH, Hall ED. Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic
brain injury. J Neurotrauma. 2011;
28(2):311-318.
• Crossing the Blood–Brain Barrier
lthough it is difficult for many drugs, including cyclosporine, to cross
the blood–brain barrier, traumatic brain injury often causes the barrier
to open and permit cyclosporine to reach those areas of the brain in
which the need is greatest.1 In other conditions, such as stroke, however, the
barrier does not open in the same way as in TBI. NeuroVive is conducting
research to identify variants of cyclosporine that can penetrate the
blood–brain barrier, with a view to providing the brain with neuronal protection under conditions other than TBI. NeuroVive is also evaluating the possibility of administering cyclosporine directly to the brain fluid (e.g., through
lumbar puncture).
In pre-clinical pilot
studies, NeuroVive’s
researchers demonstrated, in collaboration
with scientists in the
Army, that cyclosporine
crosses the blood–brain
barrier in prolonged
seizures due to hyperactivity in the brain. In
cases of stroke, scheduled cardiac surgery, and
cardiac arrest, the brain
cannot yet be reached
satisfactorily through
intravenous therapy,
because a method of
increasing the passage
A network of capillaries supplies brain cells with nutriof cyclosporine through
ents. Tight seals in their walls keep blood toxins–and
the blood–brain barrier
many beneficial drugs–out of the brain.
in these conditions has
not yet been found. To this effect, in 2010, NeuroVive and the Dutch brain drug
delivery company to-BBB entered into a joint program to develop therapies for
stroke and other acute neurodegenerative diseases.
According to its CSO, Eskil Elmér, MD, PhD, NeuroVive is also conducting
research to develop advanced cyclosporins, formulations, new chemical
compounds, or small molecules that allow improved or free passage across
the blood–brain barrier. The company is also researching and developing
cyclosporine analogue molecules without immunosuppressive effects that
can be combined with new formulations and technologies. —SC
8. Sullivan PG, Thompson M, Scheff SW. Continuous infusion of cyclosporin A post injury
significantly ameliorates cortical damage
following traumatic brain injury. Exp Neurol.
2000;161(2):631-637.
9. Loane DJ, Faden AI. Neuroprotection for
traumatic brain injury: translational challenges and emerging therapeutic strategies.
Trends Pharmacol Sci. 2010;31(12):596604.
10. Mazzeo AT, Beat A, Singh A, Bullock MR.
The role of mitochondrial transition pore,
and its modulation, in traumatic brain injury
and delayed neurodegeneration after TBI.
Exp Neurol. Review. 2009 Aug; 218(2):3637370. Epub 2009 May 27.
11. Schinzel AC, Takeuchi O, Huang Z, et al.
Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral
ischemia. Proc Natl Acad Sci U S A.
2005;102(34):12005-12010.
12. Waldmeier PC, Zimmermann K, Qian T, Tintelnot-Blomley M, Lemasters, J., Cyclophilin
D as a drug target. Current Medicinal
Chemistry. 2003;10:(16):1485-1506.
13. Novartis Pharmaceuticals Corp. Sandimmune information booklet. Available at:
www.pharma.us.novartis.com/product/
pi/pdf/sandimmune.pdf. Accessed
Aug. 12, 2011.
14. Uchino H, Elmér E, Uchino K, Lindvall O,
Siesjo BK. Cyclosporin A dramatically ameliorates CA1 hippocampal damage following
transient forebrain ischaemia in the rat. Acta
Physiologica Scandinavica. 1995
Dec;155(4):469-471.
16. Neurovive Pharmaceutical AB. Project
overview: cyclophilin-D-inhibiting
cyclosporine-based drugs. Neurovive website. Available at: www.neurovive.com/
en/Research—Development/Projectoverview/. Accessed Aug. 12, 2011.
Steve Campbell is a writer and
communications consultant in
Vancouver, B.C., who writes for and
about pharmaceutical and scientific research,
products, and companies. He can be reached
at [email protected].
© DREAMSTIME.COM
15. Piot C, Croisille P, Staat P, et al. Effect of
cyclosporine on reperfusion injury in acute
myocardial infarction. New Engl J Med.
2008;359(5):473-481.
REFERENCES
1. Osherovich L. Beating the brain’s bouncer. Science-Business eXchange. May 14, 2009.
Available at: www.nature.com/scibx/journal/v2/n19/full/scibx.2009.773.html.
Accessed Aug. 12, 2011.
August/September 2011 > Pharmaceutical Formulation & Quality 21
FORMULATION
CAPSULE
Circa 1980, one of the earliest papers on the use of circulating nanoparticles was published. Since then, there has been sort of revolution in the
world of nanotechnology. The use of nanoparticles to formulate and deliver cancer drugs is affecting the treatment of the disease significantly.
NANOPARTICLES
Strides for Small Cancer Fighters
Nanoparticles used to formulate and deliver drugs
to cells and tumors show increasing promise
> By James Netterwald, PhD
N
anometer-sized particles, typically made of iron oxide, are
beginning to transform the
world of medicine. In particular,
nanomedicine’s impact has been defined
by the potential use of nanoparticles in the
formulation and delivery of cancer drugs.
When a nanoparticle-based drug is developed, some thought must be put into
how biodistribution, targeting, and postdelivery mechanism of action will be incorporated into its design.
“The research we are doing is really
based on the premise that altering the temperature of the tumor can dramatically
change its response to things like radiation
therapy or chemotherapy,” said Theodore
DeWeese, MD, professor and chairman of
radiation oncology and molecular radiation sciences at The Johns Hopkins University in Baltimore, Md. Doing that in a
reproducible way has been a challenge.
That was until about four to five years
ago when cancer biologists decided to employ nanoparticles to do the heating “using
so-called iron oxide particles, which, in the
right configuration and when placed in
an alternating magnetic field, will actually heat to a very high temperature and
lead to the sensitization of cancer cells to
chemotherapy and radiation therapy,” said
Dr. DeWeese. Just heating the tumor by
three degrees nearly doubles its sensitivity
to therapy.
One of the major challenges in the path
to building a nanoparticle delivery system
for cancer therapy has been targeting, the
process by which the nanoparticles are
coated with either antibodies, RNA molecules, or small proteins so that they are
targeted to a certain cancer cell type. Dr. DeWeese and his colleagues coat their particles with dextran as well as polyethylene
glycol, which aid in biodistribution of the
drug when it is administered either intratumorally or intravenously.
However, these iron particles, which
range from 80 to 100 nanometers in diameter, do not specifically carry a drug. In fact,
the iron itself is what is delivered to the tumor cell. “When the iron reaches the cell
and when that cell is placed in an alternating magnetic field, substantial heating of
the targeted cell results,” said Dr. DeWeese.
“Even in the untargeted state, these particles are taken up by pinocytosis. Cancer
cells like to take up these particles, but noncancer cells take up the particles as well.
So, nonspecific targeting is also possible.”
“So you have a particle filled with the
chemotherapy medication decorated with
a targeting entity on the outside of the
nanoparticles,” said Dr. Soule. “When you
introduce these things systemically to the
patient, the theory is that these particles
will go into circulation and, based on their
specificity, they will find the tumor.” He explained that the tumor would take up the
particle, degrade it, and then release the
drug inside the tumor cell, thereby sparing
bystander (normal) cells.
“Targeting is really a complex issue,”
he explained. “These are virus-sized particles that distribute in ways that chemicals
don’t. However, there are still questions
and challenges about the potential of nanotherapies for cancer.” For instance, how
specific will a given particle be for a tumor,
and how much of the tumor-targeting
specificity is due to the vascular leakiness
of the tumor, which is a property of metastatic malignancies?
“We just don’t know the answers to
these questions yet,” he said.
Targeting a Challenge Although heating the nanoparticle to destroy a target cancer cell is one possible
mechanism of action, it is somewhat nonspecific.
“The holy grail is
to take a highly toxic
substance and target it
within a nanoparticle
to a specific tissue—and
in the case of prostate
cancer, that would be
Howard Soule, PhD
the metastatic tumor,”
said Howard Soule, PhD, executive vice
president and chief science officer of the
Prostate Cancer Foundation in Santa
Monica, Calif.
The toxic substance referred to is a
chemotherapeutic agent for cancer. Just as
they are being developed for solid tumors,
nanoparticles are also being crafted to target
prostate cancer cells. The targeting is made
possible by labeling the particles with ligands that selectively bind to prostate-specific membrane antigen (PSMA), a clinical
biomarker that is highly expressed on the
surface of metastatic prostate cancer cells
and many solid-tumor blood vessels.
22 Pharmaceutical Formulation & Quality > August/September 2011
Nanoparticles to Nanomedicine
Omid Farokhzad, MD, an associate professor at Harvard Medical School and director
of the Laboratory of Nanomedicine and
Biomaterials at Brigham and Women’s
Hospital in Boston, Mass., has made some
seminal discoveries in the world of nanomedicine. His academic pursuits have led
to the development of a platform that enables one to target nanoparticles for a
number of therapeutic applications.
That success ended the academic challenges and opened a new set of issues:
commercial scale-up and development.
The solution was start a company to license
the technology from the university so that it
could be further developed and eventually
marketed. The company, BIND Biosciences,
was co-founded in 2007 by Dr. Farokhzad
and Robert Langer, ScD, David H. Koch
Institute Professor at the Massachusetts
Institute of Technology (MIT).
“The company eventually made a
modification to the formulation to make
the particles much more stable and much
more appropriate from a drug development standpoint … BIND started human
PHARMAQUALITY.COM
trials of BIND-014, a targeted nanoparticle
therapeutic for treatment of solid tumors,
in January 2011,” explained Dr. Farokhzad.
“The technology is composed of very long
circulating, controlled release, polymeric
nanoparticles that are targeted to specific
receptors on the surface of disease cells for
targeted and controlled release of drugs.”
BIND’s platform enables the company
to engineer nanoparticles with the appropriate sizes and surface properties, targeting the ligand density, circulation times,
and drug release profiles that would be required for optimizing a drug’s performance
for various therapies.
“Based on the research of MIT nanoparticle guru Dr. Robert Langer, BIND’s
nanoparticles provide the unique opportunity to control the drug load and release
profile while actively targeting diseased
cells with ligand-directed receptor-mediated binding,” said Jeff Hrkach, PhD, senior
vice president of pharmaceutical sciences
for BIND. The particle’s surface is coated
with polyethylene glycol, which enables it
to reach its drug target by evading recognition by the immune system. Ligands can
also be attached to the surface of the particles, allowing them to bind directly to the
desired cells or tissues to be treated. BIND’s
nanoparticles were developed in collaboration with Drs. Langer and Farokhzad.
“BIND has spent the last four years
translating that academic bench work into
more robust processes for development
and clinical translation,” said Dr. Hrkach.
BIND’s lead program is a targeted
nanoparticle loaded with docetaxel, the
active ingredient in Taxotere—a well-known
and successful Sanofi-Aventis cancer drug
that has recently gone off patent. The product, BIND-014, which is in Phase 1 clinical
trials for a number of solid-tumor indications, targets PSMA.
“We are working with partners who
have existing approved drugs or candidates
in their pipeline and are looking for opportunities to improve them or expand their existing indications,” said Dr. Hrkach. “Some
of these products are currently in clinical
development and show signs of promise
but have limitations related to their therapeutic index. Our technology can increase
a drug’s efficacy and reduce its toxicity by
keeping the drug sequestered in our longcirculating nanoparticles until they reach
and actively bind to their specific target
cells for maximal concentration at the site
of action and minimal systemic exposure.”
The Prostate Cancer Foundation funds
both the work done by Dr. Langer at MIT
and that of Dr. Farokhzad at Harvard.
Predictions
Targeting is half the challenge in nanopar-
ticle-based cancer drugs. Nanotechnology is opening new roads for delivery,
however.
“I think that nanotechnology offers a
huge advantage in delivering nucleic acidbased drugs,” Dr. Soule said. “For example,
in prostate cancer, a major driving force
is the androgen receptor, a transcription
factor that is also currently a non-druggable target. There is promise in the use of
nanoparticles on targets like that, which
can be targeted by using a silencing gene
against it. By blocking the expression of
androgen receptor, this would be groundbreaking treatment for castration-resistant
prostate cancer.”
Dr. DeWeese predicts nanotechnology
will be one of the ways cancer is treated,
especially metastatic cancer. However,
there are still many obstacles to overcome—the most challenging of which is
the toxicity of the treatment. “One of the
critical hurdles to overcome in the field is
that the nanoparticles can accumulate in
organs where we would rather they not
distribute, such as the liver,” he noted. “If
the particles amass in the non-targeted organs to a large degree, this could result in
unwanted side effects.” ■
Dr. James Netterwald is a biomedical writer based in New Jersey who writes articles
and blogs on all things related to the pharmaceutical and biotechnology industry.
He started Biopharmacomm LLC in 2009; his clients include medical education companies, medical advertising companies, science publishing companies, pharma-biotech companies,
and public relations companies. More information on his writing can be found on
www.nasw.org/users/netterjr.
Editor’s Choice
1. De Jong WH, Borm PJA. Drug delivery and nanoparticles: applications and hazards. Int J Nanomedicine. 2008;3(2):133-149.
2. Ishihara T, Goto M, Kanazawa H, et al. Efficient entrapment of poorly water-soluble pharmaceuticals in hybrid nanoparticles.
J Pharm Sci. 2009;98(7):2357-2363.
3. Puri A, Loomis K, Smith B, et al. Lipid-based nanoparticles as pharmaceutical drug carriers: from concepts to clinic. Crit Rev
Ther Drug Carrier Syst. 2009;26(6):523-580.
4. Hall JB, Dobrovolskaia MA, Patri AK, et al. Characterization of nanoparticles for therapeutics. Nanomedicine (Lond.).
2007;2(6):789-803.
5. Pissuwan D, Niidome T, Cortie MB. The forthcoming applications of gold nanoparticles in drug and gene delivery systems.
J Control Release. 2011;149(1):65-71.
August/September 2011 > Pharmaceutical Formulation & Quality 23
IN THE LAB
A 70-person
PerkinElmer
OneSource on-site
team takes complete responsibility
for maintaining and
qualifying more
than 50,000 Merck
Research Laboratories assets in six
facilities.
OUTSOURCING
Perfect Partners
Merck Research Laboratories reduces equipment maintenance costs
and improves productivity with PerkinElmer OneSource team
> By Maurizio Sollazzo, Paul Luchino, and Ted Gresik
M
aintaining laboratory instruments is critical to the
productivity of pharmaceutical researchers at Merck
Research Laboratories (MRL). In the past,
individual MRL departments were responsible for arranging their own instrument
maintenance using original equipment
manufacturers (OEMs). With the broad
array of instrumentation in their labs, this
meant administration of 120 maintenance
contracts, often by multiple people at multiple sites within the organization.
To curb inefficiencies, MRL initiated a
program that centralized responsibility for
the maintenance of more than 35,000 assets in three facilities with a single service
provider—PerkinElmer OneSource. Using
a combination of asset management models (providing the ideal level of insurance
and service for each instrument), on-site
service engineers, and third-party parts,
the consolidated approach delivers substantial cost savings while enhancing the
quality and timeliness of service.
Based on the success of the program,
MRL is implementing the model across the
organization, shifting all maintenance responsibilities and contracts to PerkinElmer.
A 70-person PerkinElmer OneSource on-site
team maintains and qualifies more than
50,000 assets in six facilities. Assets in
the “maintain” category are serviced by
PerkinElmer directly, while those in the
24 Pharmaceutical Formulation & Quality > August/September 2011
“manage” category are maintained by
service partners under the management of
PerkinElmer OneSource. With a single point
of contact, MRL only has to make one call to
manage the entire program.
The bottom line? Response times have
typically been reduced from a day or two to
an hour or two, on-time preventive maintenance exceeds 90%, and the cost of asset
management has been reduced by 20%
since the program’s inception.
Consolidated Approach
When MRL was dealing with myriad
OEMs, each department spent a considerable amount of time negotiating and administering multiple contracts and found
IN THE LAB | OUTSOURCING
PHARMAQUALITY.COM
(Continued from p. 25)
return on invested capital. PerkinElmer
OneSource is proving to be that vendor.
Upon selection, a team of 22
PerkinElmer OneSource certified service
personnel was assigned to provide on-site
support at the three MRL facilities at the
start of the program. The program was administered by a PerkinElmer OneSource
management team that provided a single
point of contact for all of the services. The
services were defined by an SLA that was
developed jointly by MRL and PerkinElmer
and included metrics on all maintenance
and qualification details, including response time, instrument downtime, and
completion rate.
All assets among the three facilities
were managed from installation and warranty to disposition by PerkinElmer OneSource. Asset management software tracks
each piece of equipment and each critical
event in the life of these assets. Standardized operational performance data is delivered through a comprehensive asset
management program.
The Benefits
The improved reporting provided by
PerkinElmer OneSource helps MRL’s managers maintain better control over the assets in their facilities. Managers now have
access to reports that show what equip-
PerkinElmer OneSource personnel
service equipment
from most top
manufacturers.
justify redeploying an underutilized asset
to another branch or laboratory to distribute workload.
Recently, MRL decided to rationalize
its clinical areas globally. This change
necessitated moving approximately 800
pieces of equipment among MRL locations around the world. PerkinElmer OneSource experts handled the move from
start to finish, relocating and recommis-
Recently, MRL needed to move approximately
800 pieces of equipment among its locations
around the world. PerkinElmer OneSource
experts handled the move from start to finish.
ment they have, where it is, its service history, response time, downtime, total cost of
ownership, and other key data. Utilization
information for each instrument, regardless of technology or manufacturer, coupled with operational service and financial
metrics, improves decision-making capabilities. With this type of information, the
lab manager can justify capital requests
using quantifiable data about instrument
utilization. The lab manager can pinpoint
the time when assets become too costly to
maintain and need to be decommissioned
or auctioned. He or she has information to
sioning all instrumentation to minimize
downtime and ensure continued regulatory compliance.
As part of the agreement, PerkinElmer
OneSource demonstrated that every piece
of equipment was working in its new location. Whenever equipment did not perform exactly as expected, PerkinElmer
OneSource personnel responded and repaired the items. PerkinElmer OneSource
also provided reporting to track the location and status of every asset throughout
the move.
By streamlining the entire vendor management process, significantly reducing the
daily administration burden on scientists
and allowing them to focus on research instead of managing multiple vendors, the
consolidated maintenance program delivers significant cost savings. At the same
time, improvements in record keeping and
service tracking are enabling significant
improvements in purchasing decisions.
In light of these results, MRL is expanding the partnership, assigning to
PerkinElmer OneSource the vendor management of all its OEM service contracts
as well as responsibility for the procurement and storage of parts. This approach
provides endless possibilities, all based
on the fundamental approach of letting
specialized experts do what they do best
so that the laboratory can focus on being a
laboratory and generating science. ■
Maurizio Sollazzo is executive director for Merck; reach him at
[email protected]. Paul Luchino is a regional manager for PerkinElmer;
reach him at [email protected]. Ted Gresik is the Northeast general
manager within Analytical Sciences and Laboratory Services at PerkinElmer; reach him at
[email protected].
26 Pharmaceutical Formulation & Quality > August/September 2011
INGREDIENTS
CAPSULE
Owing to its exceptional water-binding, viscoelastic, and biological properties, hyaluronic acid (HA) provides new benefits for the delivery of
ophthalmic drugs. Khadija Schwach-Abdellaoui, PhD, director of biopharmaceutical application development at Novozymes Biopharma,
discusses the use of HA in ophthalmology applications.
HYALURONIC ACID
The Benefits of HA in Ophthalmic Delivery
A Q&A with Novozymes’ Khadija Schwach-Abdellaoui, PhD
Dr. SchwachAbdellaoui is
director of biopharmaceutical
application
development
at Novozymes
Biopharma.
She earned her
pharmaceutical degree in Lyon, France,
and her doctorate in controlled-release
systems in Montpellier, France. She has
written more than 46 articles and more
than 60 abstracts for presentations,
and has obtained 15 issued and
pending patents.
Q. What are the benefits of using
HA in ophthalmic drug delivery?
A. Whether it is to enhance the hydration
and lubrication of corneal surfaces, promote physiological wound healing, or extend
the residence time of topically applied drugs
in the eye, the benefits of incorporating
hyaluronic acid (HA) in ophthalmic formulations are well documented. As an excipient, HA offers a range of benefits, delivering
new and improved attributes to existing formulations. Due to its exceptional water-binding, viscoelastic and biological properties,
this product is compatible with a variety of
ophthalmic drugs such as ciprofloxacin,
diclofenac, and dexamethasone.
The use of HA as an efficient carrier
for ophthalmic drugs is characterized by
a unique set of advantages, including sustained and targeted drug release, an excellent safety and purity profile, and
unmatched moisturization properties.
Formulation using HA decreases filtration
time, allowing for streamlined manufacturing processes, and provides optimal
profiles for convenient applications and
Novozymes says its
bacillus-derived HA
dissolves up to 35%
faster than original
HA formulations,
reducing time and
production costs.
increased patient comfort and compliance.
HA in ophthalmic drug delivery also increases drug retention in the tear fluid,
along with drug contact time with the ocular surface, enhancing bioavailability.
Q. How does HA work in
ophthalmology?
A. HA is a naturally occurring polysaccharide that gives structure to tissues and
contributes to the optimal functioning of
a number of biological systems in the
human body. It works by entrapping the
drug in a viscoelastic matrix and slowly
releasing it while it is degraded by hylauronidases. In dermatology, HA forms a
film at the surface of the skin, protecting
the drug from degradation and forming a
reservoir that releases the drug topically.
In ophthalmology, HA can interact
with the drug physically in the viscoelastic
polymeric matrix but can also interact
chemically with positively charged drugs.
The ionic compound formed will enable
(Continued on p. 28)
August/September 2011 > Pharmaceutical Formulation & Quality 27
PHARMAQUALITY.COM
This reduces time and costs in production. Pharmaceutical companies are under
ever-increasing pressure to take new products to market faster; working with raw
materials that are already Q7 cGMP compliant will accelerate regulatory processes
and significantly reduce testing time, making HA economically efficient.
with multi-angle laser light scattering has
shown that Novozymes’ HA remains remarkably stable during the heat sterilization of ophthalmic solutions. A recent
study demonstrated that after treatment
at 121 degrees C for 16 minutes, the HA retained 82% of its initial molecular weight
against 60% for a Streptococcus-derived
HA of the same starting chain length. This
enhanced stability upon heating is most
likely due to the lower content in heavy
metals, including copper and iron, of
Novozymes’ HA. HA-containing formulations can therefore be heat-sterilized under
standard conditions without compromising final product viscosity. ■
Q. How do these developments
increase patient comfort in
ophthalmic treatments?
A. The performance of eye drops and artificial tears is dependent on their rheological
properties and primarily relies on the nature, molecular weight, and concentration
of the viscosifying agents employed. HA
contributes to the uniform distribution of
ophthalmic solutions on the surface of
the eye while decreasing the drainage rate.
This results in increased lubrication and
function, enhancing comfort for the patient. However, despite these advantages,
highly viscous HA preparations can lead
to increased blinking frequency, blurry
vision, and ocular discomfort. Novozymes
has developed its HA with enhanced rheological properties and optimal viscosity profiles, overcoming these issues to
provide improved patient comfort and
compliance.
Q. Can manufacturers be sure of
the corneal tolerance of HA?
A. The corneal tolerance of HAs of different origins and molecular weights has
been evaluated by Novozymes. The study
involved estimating the level of corneal
lesions (epithelial cell loss) following repeated applications of HA-containing formulations onto the cornea of rabbit eyes
(see Figure 1). All HA samples, irrespective of their source, molecular weight, or
concentration, included a percentage of
corneal lesions lower than 10%. This
demonstrates good corneal tolerance and
the biocompatibility of HA for ophthalmology applications.
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August/September 2011 > Pharmaceutical Formulation & Quality 29
TOOLS OF THE TRADE
CAPSULE
X-ray diffraction (XRD) has a broad range of applications in various stages of drug development and manufacturing, such as characterization
and identification of active pharmaceutical ingredients (APIs). API characterization is more commonly applied during drug development,
while API identification is directed more toward manufacturing, regulatory aspects, and intellectual property. The article from which this excerpt
is taken focuses on basic principles and experimental procedures of XRD and its application in API characterization and identification.
X-RAY DIFFRACTION
Uses of X-Ray Powder Diffraction
in the Pharmaceutical Industry
> By Igor Ivanisevic, Richard B. McClurg, and Paul J. Schields
Bruker says the
“push-plug technology” on its D8
Focus allows the
exchange of optics,
sampleholders or
detectors without
realignment.
EDITOR’S NOTE
This is an excerpt of a chapter from the book Pharmaceutical Sciences Encyclopedia: Drug
Discovery, Development, and Manufacturing, published in 2010 by John Wiley & Sons Inc.
Read the complete chapter at www.pharmaquality.com.
A
mong the many experimental
techniques available for the
identification of solid forms,
including polymorphs, solvates,
salts, co-crystals, and amorphous forms, Xray powder diffraction (XRPD) stands out as
a generally accepted “gold standard.”
While this does not mean that XRPD
should be used to the exclusion of other
experimental techniques when studying
solid forms, X-ray diffraction (XRD) has
applications throughout the drug development and manufacturing process, ranging
from discovery studies to lot release. The
utility of XRD becomes evident when one
considers the direct relationship between
the measured XRD pattern and the structural order and/or disorder of the solid.
XRPD provides information about the
structure of the underlying material,
whether it exhibits long-range order as in
crystalline materials or short-range order
as in glassy or amorphous materials. This
information is unique to each structure—
whether crystalline or amorphous—and is
encoded in the uniqueness of the XRPD
pattern collected on a well-prepared sample of the material being analyzed.
30 Pharmaceutical Formulation & Quality > August/September 2011
One must draw a distinction between
crystalline materials, which give rise to
XRPD patterns with numerous well-defined sharp diffraction peaks, and glassy
or amorphous materials, whose XRPD patterns contain typically three or fewer broad
maxima (X-ray amorphous halos). In practice, when using XRPD, one can usually
measure a sequence of crystalline materials that are progressively more disordered,
ultimately resulting in glass. A classification system has been proposed by Wunderlich (Table 1) to describe the type of
structural order and molecular packing
present in molecular organic solid forms
using three order parameter classes: translation, orientation, and conformation.1
XRPD can be used to identify and characterize solid forms of a given molecule
exhibiting long-range crystalline order (e.g.,
polymorphs, solvates, co-crystals, and salts)
by their unique combination of order parameters. Amorphous solid forms do not
exhibit any long-range order but are identifiable and characterized by their unique
local molecular order, apparent in the Xray amorphous diffraction pattern.2
Given XRPD’s sensitivity to structural
order, some of its typical applications in
the analysis of solid-state properties of a
drug substance or product include:
• Identification of existing forms of the
API;
• Characterization of the type of order
present in the API (crystalline and/or
amorphous);
• Determination of physical and chemical stability;
• Identification of the solid form of the
API in the drug product;
• Identification of excipients present in a
drug product;
• Monitoring for solid-form conversion
upon manufacturing;
• Detection of impurities in a drug product; and
• Quantitative analysis of a drug product.
Where appropriate data are available,
XRPD analysis can determine the solidform structure and crystal-packing relationship among individual molecules in
PHARMAQUALITY.COM
the solid. This information is essential to
the understanding of solid-state chemistry
of drugs and important from the regulatory
perspective.
Applications in Drug Development
XRD has a broad range of applications in
various stages of drug development and
manufacturing. This section will address
many of the common XRPD uses from a
practical standpoint. In the broadest terms,
these applications can be divided between
API characterization and identification.
While there is some overlap in both categories, the former is more commonly applied during drug development (before the
drug is on the market), while the latter is directed more toward manufacturing, regulatory aspects, and intellectual property.
crystal XRD and XRPD.4 Other techniques
like thermal or spectroscopic methods can
be helpful in further characterizing drug
products, but only X-ray provides the necessary structural information to uniquely
identify different polymorphs. Therefore,
in early drug development, XRPD is often
used as a primary experimental technique
and a means of differentiating among
experimentally generated materials. Fully
characterizing any material requires the
use of complementary techniques (thermal or spectroscopic) but X-ray is typically
done first because it is fast, is nondestructive, requires little material, and provides
the necessary structural information.
Databases of known XRPD patterns for
various pharmaceutical materials are published annually by the International Centre
for Diffraction Data and the Cambridge Crystallographic Data Centre, which publishes
the Cambridge Structural Database.
API Characterization
Guidelines from regulatory authorities regarding the need for characterization of a
drug substance under development have
been clearly stated. Below is an example
relating to the issue of polymorphism:
“Polymorphic forms of a drug substance
can have different chemical and physical
properties, including melting point,
chemical reactivity, apparent solubility,
dissolution rate, optical and mechanical
properties, vapor pressure, and density.
These properties can have a direct effect on
the ability to process and/or manufacture
the drug substance and the drug product,
as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and
efficacy of the drug product.” 3
While there are a number of methods
to characterize polymorphs of a drug substance, the two broadly accepted methods
for providing unequivocal proof of polymorphism that are recognized by the U.S.
Food and Drug Administration are single-
Table 1.
phase identification was recognized early
and remains the most common application of XRPD to pharmaceuticals.7 This socalled qualitative analysis typically refers
either to the initial characterization of material not previously analyzed by XRPD or
to the identification of a phase or phases
in a sample of material by comparison to
reference patterns. Reference patterns are
previously collected XRPD patterns of the
same material.
Where available, XRPD patterns calculated from, for example, single-crystal
structures can be substituted, but one
should remember that the temperature at
which the pattern is calculated can have a
Synchrotron XRD has frequently
been used to characterize pharmaceutical materials in applications that require
additional sensitivity not provided by
laboratory X-ray diffractometers (e.g.,
crystallization monitoring).5-6 The tradeoff is the greater expense and time investment typically associated with such
measurements. Because such applications tend to be specialized, this section
will focus primarily on laboratory XRPD
methods.
Qualitative Analysis of Materials
(Phase Identification)
Because every structurally different crystalline material exhibits a unique XRPD
pattern upon analysis, the use of XRPD for
significant effect on the calculated XRPD
profile. When dealing with mixtures of
phases, qualitative analysis can provide
an estimate of the relative proportions of
different phases in the sample, usually
based on the comparison of peak intensities for characteristic peaks of the different
phases.
Due to sample artifacts such as preferred orientation and poor particle statistics, this type of analysis should never be
confused with quantitative analysis of
mixtures. Databases of known XRPD patterns for various pharmaceutical materials
are published annually by the International Centre for Diffraction Data and the
Cambridge Crystallographic Data Centre,
(Continued on p. 32)
Types of Solid Forms Described by the Wunderlich Classification System
SOLID FORM
TRANSLATION
ORIENTATION
CONFORMATION
CRYSTAL
CONDIS CRYSTAL (GLASS)
PLASTIC CRYSTAL (GLASS)
LIQUID CRYSTAL (GLASS)
AMORPHOUS (GLASS)
LONG RANGE
LONG RANGE
LONG RANGE
SHORT RANGE
SHORT RANGE
LONG RANGE
LONG RANGE
SHORT RANGE
LONG RANGE
SHORT RANGE
LONG RANGE
SHORT RANGE
SHORT RANGE
SHORT RANGE
SHORT RANGE
August/September 2011 > Pharmaceutical Formulation & Quality 31
PHARMAQUALITY.COM
characterization using thermal methods
(TGA, DSC), for example, would confirm
that these materials are not solvates or
mixtures but actual polymorphs and
would aid in determining the thermodynamically stable polymorph. XRPD provides information about the structure of
materials, not thermodynamics, although
variable-temperature XRPD has been used
to study changes in structure at different
temperatures.
One can envision a large number of different crystallization experiments (using
different solvents or conditions) performed
on the API, some possibly in automated
fashion, with the resulting material characterized initially by XRPD. This is in fact a
common approach to polymorphism, salt,
and co-crystal screening and is perhaps
the most common application of XRPD in
the drug development process. The latter
two screens are usually performed when
the polymorphs of the drug candidate itself are not sufficiently bioavailable, in
an effort to produce a formulation that
addresses the bioavailability problem. An
XRPD pattern is taken—of the API, the
guest material (e.g., acid), and the mixture
of the two. If a salt or co-crystal forms, the
XRPD pattern of the mixture should be
more than just a sum of the reference patterns of the API and the guest.
Therefore, the first application for
XRPD during drug development is typically to identify the materials generated
using different experimental methodologies, often in automated, high throughput
screening environments.9-11 To simplify
this pattern recognition problem, which
often involves hundreds or thousands of
experimental data sets per screen, people
have developed various computational
approaches to recognize, sort, and classify
unknown XRPD patterns, either through
comparison to a known database of materials or simply within the experimental set
of unknown patterns.12-15 The latter often
uses an approach called hierarchical clustering.16-17
XRPD data are often cataloged in databases using the so-called Hanawalt system.18-19 In this system, the data are stored
as d versus I/Imax pairs. The use of d-space
eliminates the need to specify the radiation source wavelength and allows com-
ing of solution crystallization using energy
dispersive X-ray diffraction. Cryst Growth
Des. 2002;3(2):197-201.
7. Jenkins R, Snyder RL. Introduction to X-ray
powder diffractometry. In: Winefordner JD,
editor. Chemical analysis. Vol. 138. New
York: John Wiley & Sons; 1996.
8. United States Pharmacopeial Convention.
General chapter 941: X-ray diffraction. In:
USP 31-NF 26. Rockville, Md.: United
States Pharmacopeial Convention;
2008:374.
9. Hertzberg RP, Pope AJ. High-throughput
screening: new technology for the 21st
century. Curr Opin Chem Biol. 2000;4(4):
445-451.
PANalytical’s Empyrean X-ray diffractometer is
a 2011 winner of an R&D 100 award in the
‘winning technology’ category.
parison between laboratories using different instrumentation.
A similar system is often used for intellectual property filings. However, there is
considerable structural information available in a typical XRPD pattern that can be
used to characterize the material. Making
use of this information usually requires
high quality laboratory data and the use of
advanced computational methods. ■
REFERENCES
10. Barberis A. Cell-based high-throughput
screens for drug discovery. Eur Biopharm
Rev website. Winter 2002. Available at:
www.samedanltd.com/magazine/12/issue/43
/article/1231. Accessed August 3, 2011.
11. Johnston PA, Johnston PA. Cellular platforms for HTS: three case studies. Drug
Discov Today. 2002;7(6):353-363.
12. Ivanisevic I, Bugay DE, Bates S. On pattern
matching of X-ray powder diffraction data.
J Phys Chem B. 2005;109(16):7781-7787.
13. Marquart RG, Katsnelson I, Milne GWA, et
al. A search-match system for X-ray powder
diffraction data. J Appl Cryst. 1979;12(6):
629-634.
14. Gurley K, Kijewski T, Kareem A. First- and
higher-order correlation detection using
wavelet transforms. J Eng Mech. 2003;
129(2):188-201.
1. Wunderlich B. A classification of molecules,
phases, and transitions as recognized by
thermal analysis. Thermochim Acta.
1999;340/341:37-52.
15. Gilmore CJ, Barr G, Paisley J. High-throughput powder diffraction. I. A new approach to
qualitative and quantitative powder diffraction
pattern analysis using full pattern profiles.
J Appl Cryst. 2010;37:231-242.
2. Yu L. Amorphous pharmaceutical solids:
preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48(1):27-42.
16. Johnson SC. Hierarchical clustering
schemes. Psychometrika. 1967;32(3):241254.
3. U.S. Food and Drug Administration. Center
for Drug Evaluation and Research. Guidance
for Industry: ANDAs: Pharmaceutical Solid
Polymorphism Chemistry, Manufacturing,
and Controls Information. FDA. Available at:
www.fda.gov/OHRMS/DOCKETS/98fr/2004d
-0524-gdl0001.doc. Accessed Aug. 3,
2011.
17. Borgatti SP. How to explain hierarchical
clustering. Connections. 1994;17(2):78-80.
4. Brittain HG. Polymorphism in Pharmaceutical Solids. New York: Marcel Dekker, Inc;
1999.
5. Varshney DB, Kumar S, Shalaev EY, et al.
Solute crystallization in frozen systems–use
of synchrotron radiation to improve sensitivity. Pharm Res. 2006;23(10):2368-2374.
6. Blagden N, Davey R, Song M, et al. A novel
batch cooling crystallizer for in situ monitor-
18. Hanawalt JD, Rinn HW, Frevel LK.
Chemical analysis by X-ray diffraction. Ind
Eng Chem Anal Ed. 1938;10(9):457-512.
19. Byrn SR, Pfeiffer RR, Stowell JG. Solid-State
Chemistry of Drugs. 2nd ed. West Lafayette,
Ind.: SSCI, Inc.; 1999.
Drs. Ivanisevic, McClurg, and
Schields are with Solid State Chemical Information, a division of Aptuit
Inc., in West Lafayette, Ind. SSCI offers cGMP
contract pharmaceutical development services, specializing in crystallization, stability,
and polymorphism.
August/September 2011 > Pharmaceutical Formulation & Quality 33
Development of polyethylene glycol-conjugated alendronate, a novel nitrogen-containing
bisphosphonate derivative: Evaluation of absorption, safety, and effects after intrapulmonary
administration in rats
Bisphosphonates are widely used for the treatment of bone
diseases, including hypercalcemia and osteoporosis. However, the bioavailability (BA) of orally administered bisphosphonates is low, at approximately 0.9%–1.8%. In addition,
the oral administration of bisphosphonates is associated
with mucosal damage, including gastritis, gastric ulcer, and
erosive esophagitis. To develop a new delivery system for
bisphosphonates that improves their BA and safety, we developed polyethylene glycol (PEG)-conjugated alendronate,
a novel nitrogen-containing bisphosphonate derivative. We
evaluated the absorption and safety of PEG-alendronate in
rats following intrapulmonary administration. The BA of
PEG-alendronate after intrapulmonary administration was
approximately 44 ± 10% in rats, similar to that of alendronate Effect of PEG–alendronate on the cell viability of osteoclast-like cells derived
(54 ± 3.9%). Alendronate significantly increased total protein from RAW264.7 cells. The number of osteoclast-like cells derived from
concentration and lactate dehydrogenase activity in bron- RAW264.7 cells is expressed as a percentage of the values in the no treatment
group. Results are expressed as the mean ± SE of four experiments
choalveolar lavage fluid, suggesting that pulmonary epithe- (**p < 0.01 compared with the no treatment group).
lium was locally damaged by intrapulmonary administration
of alendronate. In marked contrast, PEG-alendronate did not significantly increase the markers following intrapulmonary administration. In an osteoporosis model in rats, intrapulmonary administration of PEG-alendronate effectively inhibited decreases in the width of
the growth plate to a level similar to that achieved by intrapulmonary administration of alendronate. These results indicate that pulmonary delivery of PEG-alendronate is a promising approach for the treatment of bone diseases.
Katsumi H, Takashima M, Sano J, et al. Development of polyethylene glycol-conjugated alendronate, a novel nitrogen-containing
bisphosphonate derivative: Evaluation of absorption, safety, and effects after intrapulmonary administration in rats. J Pharm Sci.
2011;100(9):3783–3792. E-mail: Akira Yamamoto ([email protected]).
Comparison of drug permeabilities across the blood-retinal barrier, blood-aqueous
humor barrier, and blood-brain barrier
Drugs vary in their ability to permeate the blood-retinal barrier (BRB), blood-aqueous humor barrier (BAB), and blood-brain barrier
(BBB), and the factors affecting the drug permeation remain unclear. In this study, the permeability of various substances across the
BRB, BAB, and BBB in rats was determined using the brain uptake index (BUI), retinal uptake index (RUI), and aqueous humor uptake
index (AHUI) methods. Lipophilic substances showed high permeabilities across the BBB and BRB. The RUI values of these substances
were approximately four-fold higher than the BUI values. The AHUI versus lipophilicity curve had a parabolic shape with AHUImax
values at log D7.4 ranging from −1.0 to 0.0. On the basis of the difference in
Plot of log UI
lipophilicities, verapamil, quinidine, and digoxin showed lower permeabilversus log D7.4 for
the 13 compounds ity than predicted from those across BBB and BRB, whereas only digoxin
tested (passive
showed a lower permeability across BRB. These low permeabilities were sigdiffusion; Table 1). nificantly increased by P-glycoprotein inhibitors. Furthermore, anion transEach symbol repporter inhibition increased the absorption of digoxin to permeate into the
resents the mean
± SD of three to
retina and aqueous humor. In conclusion, this study suggests that efflux
four experiments.
transport systems play an important role in the ocular absorption of drugs
from the circulating blood after systemic administration.
Toda R, Kawazu K, Oyabu M, Miyazaki T, Kiuchi, Y. Comparison of drug
permeabilities across the blood-retinal barrier, blood-aqueous humor
barrier, and blood-brain barrier. J Pharm Sci. 2011;100(9):3904–3911.
E-mail: Kouichi Kawazu ([email protected]).
August/September 2011 > Pharmaceutical Formulation & Quality 35
PRODUCT SPOTLIGHT
Want to be featured in PFQ’s Product Spotlight section? Please e-mail a high-resolution jpeg (1mb max.) photo and a 100-word
description to: [email protected]
Bioneer ExiSpin
Wyatt Technology announces that its Möbius electrophoretic mobility instrument can measure
precise protein charges. The innovative optical design of the Möbius boosts the sensitivity of mobility measurements, enabling protein net charge characterization at much lower concentrations than
previously possible. This unique capability is illustrated in a new application note, titled “Möbius
Computation of Protein Net Charge from Electrophoretic Mobility,” and available for download at
www.wyatt.com/literature/application-notes/mobius.html. The note demonstrates how the Möbius
overcomes the limitations of traditional phase analysis light scattering (PALS) methods, eliminates
undesirable interactions, and facilitates protein charge measurements at low concentrations—all
without damaging the protein. The Möbius mobility instrument can carry out protein net charge
measurements with a moderate antibody concentration of 1.0 mg/mL, measurements that are not
possible with conventional PALS instruments.
Bioneer introduces the ExiSpin, a system
that combines the functions of a vortexer
and a centrifuge into a single product.
The ExiSpin can be programmed to function as a vortexer or a micro-centrifuge,
or it can be set to a sequential spin/vortex/spin (SVS) mode to resuspend samples
and mix enzyme reactions. The ExiSpin
comes with two rotors, a 12-place rotor
for micro-centrifuge tubes and a 32-place
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is backed by a comprehensive two-year
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www.wyatt.com
http://us.bioneer.com
Wyatt Möbius Electrophoretic Mobility Instrument
(805) 681-9009
(877) 264-4300
AdvantaPure Hose Identification
AdvantaPure offers several solutions for taking the guesswork out of
hose and manifold identification. The company gives users a choice of
viable identification strategies for critical process hoses used in the
pharmaceutical, biopharmaceutical, biomedical, chemical, and food
and beverage industries. Hose identification is crucial for safety, traceability, regulatory compliance, and identification of capabilities or
limitations. AdvantaPure’s options range from quick visual identifiers
such as color to laser-etched items to radio frequency identification
tags. They’re designed for tubing and reinforced hose manufactured of
platinum-cured silicone and for rubber-covered or overbraided hoses
of various materials. The identification methods can be used separately or in combination.
www.advantapure.com
38 Pharmaceutical Formulation & Quality > August/September 2011
(888) 755-4370
PHARMAQUALITY.COM
AES Semi-Gas Systems
SEMI-GAS Systems, a division of Applied
Energy Systems, Inc. and a manufacturer
of industry-leading ultra-high purity gas
source and distribution systems, offers
bulk specialty gas source systems to deliver hazardous specialty gases from large
vessels at high flow rates. The source
systems are designed to supply NH3, HCl,
SiH4, N2O, H2 and other hazardous specialty process gases at flow rates from 100
standard liters per minute (slpm) to 1,000
slpm. SEMI-GAS Systems’ bulk specialty
gas source systems consolidate many gas
cabinets into a single system for high-volume semiconductor production as well as
for high gas volume-consuming processes,
as found in LED and solar cell production
applications. With consideration to the
local climate, the source systems can be
installed indoors or outdoors. Source
vessel heating is incorporated into the
system to facilitate the liquid-to-gas
phase change and to sustain the high
gas flow rates.
www.semi-gas.com
(610) 647-8744
NewAge Industries Silcon Med-X
NewAge Industries manufactures silicone tubing that’s platinum cured for the highest degree of purity. Called Silcon Med-X, it’s one of the company’s medical grades of
silicone tubing and reinforced hose. Silcon MedX is particularly suited for applications in the
medical, biomedical, pharmaceutical, laboratory, surgical, food, beverage, and health and
beauty industries. NewAge produces peroxideand platinum-cured silicone tubing. The platinum-cured version offers the fewest number of
extractables—compounds that can be drawn
out of tubing and adversely affect the fluid flowing within. It also contains no plasticizers that
can leach out and cause flow contamination or
tube hardening. Using purer tubing in processing and transfer applications ensures a purer
end product as well. The elastomer used in Silcon Med-X meets United States
Pharmacopoeia Class VI requirements, and the tubing is produced in a controlled
environment. Silcon Med-X is soft and pliable, and it will not support bacteria growth.
Supplied in individual, heat-sealed polybags, the tubing may be reused after sterilization by autoclave or gamma radiation. Silcon Med-X is stocked in 17 sizes, ranging
from .030” through .625” (5/8”) inside diameter. Other sizes, durometers, and colored
Silcon Med-X are available through custom order. Barbed fittings, including those
made from FDA-approved polypropylene, are stocked, along with a variety of clamps.
www.newageindustries.com
Spinnovation Spedia-NMR
For new biologicals and biosimilars, the Spedia-NMR technology from Spinnovation Biologics provides an advantage for optimizing cell
cultures, monitoring, and standardizing manufacturing processes in preparation for larger
scale production. Within the past four months,
this claim has been validated by 37 companies
developing biologics or delivering services to
this industry. This premium nuclear magnetic
resonance (NMR) analysis service rapidly
identifies a wide selection of feed components,
metabolites, and toxic compounds in culture
media. By comparing media profiles from different cell culture batches, Spedia-NMR identifies how a cell consumes and metabolizes the
media along the culture process. This allows
the composition of the media to be fine tuned
to improve cell viability, reach highest yields of
biologic product, and perform rapid process
troubleshooting. Spedia-NMR has gained rapid
popularity in both the biotech research and
manufacturing communities because of its
speed—analysis in a matter of minutes/hours
and service delivery within five working days—
and the valuable information it provides in
assisting process development.
www.spinnovation-analytical.com
+31-24-240-3400
(800) 506-3924
August/September 2011 > Pharmaceutical Formulation & Quality 39
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