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27 INGREDIENTS I HYALURONIC ACID

The Benefits of HA inOphthalmic DeliveryA Q&A with Novozymes’ Khadija Schwach-Abdellaoui, PhD

30 TOOLS OF THE TRADEX-RAY DIFFRACTION SOURCES

Uses of X-Ray Powder Diffractionin the Pharmaceutical IndustryBy Igor Ivanisevic, Richard B. McClurg,and Paul J. Schields

Contents

AUGUST | SEPTEMBER 2011pharmaquality.com

Pharmaceutical Formulation & Quality® (ISSN 1092-7522) is published 6 times a year in Feb/Mar, Apr/May, June/July, Aug/Sept, Oct/Nov, Dec/Jan by Wiley Subscription Services, Inc., a Wiley Company,111 River St., Hoboken, NJ 07030-5774. Periodical postage paid at Hoboken, NJ, and additional mailing offices. Subscription for U.S. is $126 per year. International subscription is $160.

EDDIE and ASBPE award winner for editorial and graphics excellence

POSTMASTER: Returns and address changes to PFQ magazine, PO Box 9051, Maple Shade, NJ 08052-9651

August/September 2011 > Pharmaceutical Formulation & Quality 3

InThis Issue34 JPS UPDATE36 PHARMASCAN/WIRES UPDATE37 HELP DESK38 PRODUCT SPOTLIGHT40 INDUSTRY EVENTS40 ADVERTISER DIRECTORY

A 70-person PerkinElmer OneSourceon-site team takes complete responsibilityfor maintaining and qualifying more than50,000 Merck Research Laboratoriesassets in six facilities. See Page 24.

Departments10 GREEN CHEMISTRY I WASTE REDUCTION

A Green SweepBig pharma is drafted by ethical and fiscalresponsibilities to collaborate on wastereduction efforts By Neil Canavan

14 DELIVERY I CYCLOSPORINE

TBI’s Miracle DrugAn accidental discovery about 20 years agohas led to a cyclosporine pharmaceutical onthe threshold of approval By Steve Campbell

22 FORMULATION I NANOPARTICLES

Strides for Small Cancer FightersNanoparticles used to formulate and deliverdrugs to cells and tumors show increasingpromise By James Netterwald, PhD

24 IN THE LAB I OUTSOURCING

Perfect Partners Merck Research Laboratories reducesequipment maintenance costs and improvesproductivity with PerkinElmer OneSourceteam By Maurizio Sollazzo, Paul Luchino,and Ted Gresik

Cover Story6New Gums fromAncient LandsIndian plants studied as bindingagents in tablet formulationsBY MAYBELLE COWAN-LINCOLN

4 Pharmaceutical Formulation & Quality > August/September 2011

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Printed in the United States by Dartmouth Printing, Hanover, NH.Copyright 2011 Wiley Periodicals, Inc., a Wiley Company. All rights reserved. No

part of this publication may be reproduced in any form or by any means, except aspermitted under Sections 107 or 108 of the 1976 United States Copyright Act, withouteither the prior written permission of the publisher, or authorization through theCopyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923: (978) 750-8400:fax (978) 750-4470. All materials published, including but not limited to original research, clinical notes,

editorials, reviews, reports, letters, and book reviews represent the opinions and viewsof the authors and do not reflect any official policy or medical opinion of the institu-tions with which the authors are affiliated or of the publisher unless this is clearly spec-ified. Materials published herein are intended to further general scientific research,understanding, and discussion only and are not intended and should not be reliedupon as recommending or promoting a specific method, diagnosis or treatment byphysicians for any particular patient.While the editors and publisher believe that the specifications and usage of equip-

ment and devices as set forth herein are in accord with current recommendations andpractice at the time of publication, they accept no legal responsibility for any errorsor omissions, and make no warranty, express or implied, with respect to materialcontained herein. Publication of an advertisement or other discussions of productsin this publication should not be construed as an endorsement of the products or themanufacturers’ claims. Readers are encouraged to contact the manufacturers withany questions about the features or limitations of the products mentioned.

Mansoor M. Amiji, RPh, PhDProfessor and Acting Chair

Department of Pharmaceutical SciencesSchool of Pharmacy, Co-Director of Nanomed-icine Education and Research Consortium(NERC), Northeastern University, Boston, MA

Robin H. Bogner, PhDUniversity of Connecticut School of Pharmacy

Storrs, Conn.Rosario LoBrutto, PhD

Group Head, Pharmaceutical andAnalytical Development

Novartis Pharmaceuticals Corp.East Hanover, NJ

Daniel L. Norwood, PhDDirector of Physical and ChemicalAnalysis, Boehringer Ingelheim

Pharmaceuticals Inc.Ridgefield, Conn.

Brian K. Nunnally, PhD Head of Process Validation

PfizerSanford, NC

Ron Ortiz, PhDSolubility Specialist

Upsher-Smith Laboratories, Inc.Maple Grove, MN

Doug Raynie, PhDResearch Associate ProfessorDepartment of Chemistry

and Biochemistry,South Dakota State University

Brookings, SD Colleen E. Ruegger, PhD, RPh

Specialist inOral Delivery/OralFormulationNovartis Pharmaceutical Corp.

East Hanover, NJ

WHERE DO THE KEY PLAYERS IN PHARMA, BIOTECH AND MANUFACTURING COME TOGETHER?

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COVER STORY

Tablets are a popular medicationdelivery system. They allow pow-ders and granules to be packagedin a compact and accurate dosing

form that can be efficiently and inexpen-sively produced. The secret to the tablet’ssuccess is the binding agent.1-2

Binding agents are excipients that pro-vide cohesiveness and structural strengthto powdered material during the manufac-ture of tablets. Binders allow tablets to re-main intact after the compression process.

Numerous compounds have been usedas binding agents. Maize, potato starches,gelatin, and natural gums, as well as mod-ified natural and synthetic polymers, havehistorically performed well as binders.3

Gums are often chosen as binders fortablets because of their physiochemical pro-file and the fact that they are relatively inert.4Gums are polysaccharides made from sugarand uronic acid units. These translucent,amorphous substances, byproducts of plantmetabolic processes, are often produced toprotect the plant after injury. Though insol-uble in alcohol, gums will either dissolve orswell in water.5

There are many benefits to using natural,plant-based gums in tablet manufacture.

They are inexpensive and do not cause sideeffects. They are a locally available, renew-able resource that can be processed in anenvironmentally friendly manner. In addi-tion, they improve the economy of theircountry of origin by using local materials.

These benefits have provided the im-petus for numerous recent endeavors toevaluate the efficacy of plant-based gumsand mucilages grown in various regions ofIndia. There are several factors to considerwhen choosing and evaluating a binder.The type and concentration of the bindingagent affect the strength, friability (ease ofcrumbling), and times for disintegrationand dissolution. An additional considera-tion is the compatibility of the binder withthe other substances in the tablet, particu-larly the active ingredient.

Several of these efforts to identify newsources of inexpensive binding agentshave yielded promising results.

TAMARIND SEED POLYSACCHARIDE Tamarind seed polysaccharide (TSP), ob-tained from the seeds of the native Indianplant Tamarindus indica, produces a vis-cous, mucoadhesive mucilage with a broadpH tolerance and no carcinogenicity. A

study conducted in Vishakhapatan, Indiaat Andhara University evaluated this mu-cilage as a natural polymer to be used inpharmaceutical formulations.

To determine if the mucilage had theproperties necessary to perform as an effi-cient binding agent, it was tested for sev-eral properties, including swelling index,solubility, microbial count, and thermalstability. Investigators reported that TSPhydrates quickly and swells up to 1,700%.It dissolves rapidly in warm water, spar-ingly in cold water, and not at all in alcohol.Microbial growth was not supported. Ad-ditionally, TSP is stable at temperaturesup to 210 degrees C in solid form and 145degrees C in liquid form, indicating thatit can be used in both liquid and solid for-mulations. Upon hydration, TSP forms athick, viscous surrounding layer. Thiscoating retards drug release.

Binding agents have a significant im-pact on the flow properties of powderedtablet ingredients, an important propertyfor an excipient. Flow properties can bedetermined by measuring the angle of re-pose, a calculation based on the radius ofthe base of the conical pile produced bypouring the powder through a funnel. Anangle of repose of less than 30 degreesindicates a free-flowing powder. The TSPangle of repose was determined to be 29.50degrees, indicating good flow properties.

In view of these results, including highswelling index, thermal stability, good flowproperties, and unfriendly environment forpathogens, investigators concluded thatTSP would make a useful excipient, partic-ularly for sustained-release tablets.


CAPSULEStudies 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 topicalformulations but also bolster the economies of the areas in which they are found.

NEWGUMSFROMANCIENTLANDSIndian plants studied as bindingagents in tablet formulations> BY MAYBELLE COWAN-LINCOLN

Tamarind seed polysaccharide forms a thick coating upon hydration that retardsdrug release.

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CASSIA ROXBURGHII SEED GUM IN PARACETAMOL TABLETSCassia roxburghii is a large Indian tree withseeds that consist of 50% endosperm,which yields a water-soluble gum. Thebinding properties of the gum, includingstability and viscosity, were evaluated in astudy conducted by the KMCH College ofPharmacy in Coimbatore, India, and com-pared to the properties of two standardbinders, sodium carboxymethyl cellulose(sodium CMC) and gelatin.6

Three batches of C. roxburghii gum so-lution, containing 1%, 1.5%, and 2% C. rox-burghii seed gum, were prepared, along withsolutions made with sodium CMC and gela-tin. A comparative study revealed that C.roxburghii seed gum showed higher viscos-ity than solutions containing the standardbinders. The samples were retested after 16days, and the C. roxburghii seed gum solutiondisplayed the least decrease in viscosity.

Paracetamol tablets were also preparedusing these solutions as binding agents.

Three batches of tablets using C. roxburghiiseed gum were manufactured, containing2%, 4%, and 6% binder. All tablets wereevaluated for hardness, friability, disinte-gration time, and dissolution rate. The re-sults were encouraging: Tablets made with2% C. roxburghii seed gum showed higherhardness and longer disintegration timethan those made with sodium CMC or gela-tin. Of the three formulations, C. roxburghiiseed gum showed the lowest friability.

As the C. roxburghii seed gum concen-tration increased, binding characteristicssuch as hardness and disintegration timealso increased, while friability decreased.These results demonstrate that the bind-ing capacity of the tablet is in proportion tothe C. roxburghii seed gum concentration.Not surprisingly, as this concentration in-creases, the drug release rate decreases.These results suggest that C. roxburghiiseed gum is a useful binder when high me-chanical strength and slower drug releaseare desired.

MORINGA OLEIFERA GUMMoringa oleifera is a fast-growing treefound throughout India. The plant ex-trudes a white gum that darkens to reddishbrown or brownish black on exposure. Thegum is sparingly soluble in water, produc-ing a highly viscous solution. VictoriaCollege of Pharmacy in Andhrapradesh,India, recently studied the binding proper-

(Continued on p. 8)

PHARMAQUALITY.COM

CASE STUDY

Grewia GumShows Promiseharmaceutical excipients are usually imported intosub-Saharan Africa from the developed world, addingto 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 PharmaceuticalResearch and Development (NIPRD) in Nigeria, finding locallygrown materials to substitute for imported excipients achievesseveral objectives:• Lowers manufacturing costs;• Creates jobs in multiple areas, including planting, harvest-ing, 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 isused for a wide variety of domestic purposes in Nigeria—frommixing the materials used to build hut walls to serving as avegetable. These uses led Dr. Emeje to form the hypothesisthat grewia gum could serve as an effective binder.1

According to Dr. Emeje, the first important property of thisplant is that it is edible and, therefore, suitable for tablet prepa-rations. In addition, because it can hold sand together to makea cement-like preparation for walls, there must be significantpotential for grewia gum to be a successful binding agent.

To investigate its binding properties, dried, powderedmucilage from the plant was mixed with paracetamol gran-ules. The formulation was evaluated for compressibility andpacking and then pressed into tablet form for further study.The results demonstrated that grewia gum performs well asa binder. In fact, the paracetamol tablets made with powderedgrewia gum mucilage outperformed the current standardbinder, polyvinylpyrollidone (PVP), by showing a sloweronset of plastic deformation.

After this successful trial, grewia gum has continued toachieve positive results in research studies. Dr. Emeje’s workwith this mucilage was recognized with a 2010 grant award tofurther study the gum’s potential. He expects to see a finished,commercialized grewia gum binder formulation for the phar-maceutical, food, and cosmetic industries within the next10 to 15 years.2 �

REFERENCES

1. Emeje M, Isimi C, Olobayo K. Effect of grewia gum on the mechanicalproperties of paracetamol tablet formulations. African J PharmacyPharmacol. 2008;2(1):1-6.

2. Ogaji IJ, Hoag SW. Effect of grewia gum as a suspending agent onibuprofen pediatric formulation. AAPS PharmSciTech.2011;12(2):507-513.

P

Research shows that Cassia seed gum is auseful binder when high mechanical strengthand slower drug release are desired.


ties of the gum by evaluating paracetamoltablets made with Moringa oleifera gumfor properties such as angle of repose,hardness, disintegration time, dissolutionrate, and friability. Three concentrationsof Moringa oleifera were tested—8%, 10%,and 12%—and compared to equivalentconcentrations of gelatin.

The study demonstrated that tablethardness and disintegration time increasedwith the concentration of binding agent.Friability decreased, as did the percentageof drug released. In view of these results,the investigators concluded that Moringaoleifera can be used as a binder, particu-larly for sustained-release tablets, whichrequire higher mechanical strength.

SESBANIA SEED GUMIn addition to tablets, binding agents arealso used in topical delivery systems. Whenplant mucilages are mixed with water, a

soothing, protective application is formed.Sesbania seed gum, derived from the en-dosperms of Sesbania grandiflora seeds,was evaluated as a gelling agent in a studyat the Kalol Institute of Pharmacy in Gu-jarat, India.7

Six batches of diclofenac diethylam-monium gel were prepared using variousconcentrations of sesbania seed gum: 2%,2.25%, 2.5%, 2.75%, 3%, and 3.5%. The gelwas evaluated for drug content, extrud-ability, and viscosity.

All the prepared gels were clear andsmooth as well as homogenous and pli-able. However, the batch containing 2.5%sesbania seed gum had the best pH profileand spreadability. Interestingly, this batchalso showed the best drug release results,extruding 80% of the diclofenac diethy-lammonium over eight hours. The resultsled investigators to conclude that sesbaniaseed gum, particularly in a 2.5% concen-tration, does make a suitable binder for gelformulations. �

REFERENCES

1. Arul Kumaran KSG, Palanisamy S,Rajasekaran A, et al. Evaluation of Cassiaroxburghii seed gum as binder in tablet for-mulations of selected drugs. Int J Pharm SciNanotechnol. 2010;2(4):726-732.

2. Shivalingam MR, Kumaran KSGA, KishoreReddy YV, et al. Evaluation of binding proper-ties of Moringa oleifera gum in the formulationof paracetamol tablets. Drug Invention Today.2010;2(1):69-71.

3. Patil BS, Soodam SR, Kulkarni U, et al.Evaluation of Moringa oleifera gum as abinder in tablet formulation. Int J ResAyurveda Pharmacy. 2010;1(2):590-596.

4. Adeleye AO, Odeniyi MA, Jaiyeoba KT. Theinfluence of cissus gum on the mechanicaland release properties of paracetamoltablets—a factorial analysis. Rev Ciênc FarmBásica Apl. 2010;31(2):131-136.

5. Phani KGK, Gangaroa B, Kotha NS, et al.Isolation and evaluation of tamarind seedpolysaccharide being used as a polymer inpharmaceutical dosage forms. Res J PharmBiol Chem Sci. 2011;2(2):274-290.

6. Girhepunje K, Arulkumaran, Pal R, et al. Anovel binding agent for pharmaceutical for-mulation from Cassia roxburghii seeds. Int JPharmacy Pharm Sci. 2009;1(Suppl. 1):1-5.

7. Patel GC, Patel MM. Preliminary evaluation ofsesbania seed gum mucilage as gelling agent.Int J PharmTech Res. 2009;1(3):840-843.

COVER STORY | NEW GUMS FROM ANCIENT LANDS PHARMAQUALITY.COM

(Continued from p. 7)

Editor’s Choice1. Shivalingam MR, Arul Kumaran KSG, Jeslin D, et al. Cassia roxburghii seed galactomannan–a potential binding agent in thetablet 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 tabletformulation. Acta Pharmaceutica Sciencia. 2010;52:254-262.

3. Deshmukh VN, Singh SP, Sakarkar DM. Formulation and evaluation of sustained release metoprolol succinate tablet usinghydrophilic 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 fromCissus 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 intablet formulation. Indian J Pharm Sci. 2008;70(5):614-618.

Maybelle Cowan-Lincoln is a phar-maceutical writer based in New Jersey.She specializes in articles for patients

and professionals; her writing has been featuredin numerous scientific publications.

Moringa gum is sparingly soluble in water.

Sesbania gum binds gel formulations well.

GREEN CHEMISTRY

The EPA defines green chemistryas “the design of chemical prod-ucts and processes that reduceor eliminate the use or genera-

tion of hazardous substances.” This defini-tion is taken to include the entire life cycleof the product from bench to bedside.

While such endpoints are easily ex-pressed, even the experts find it a bit muchto comprehend in practical terms. Thus theformation of the American Chemical Soci-

ety’s Green Chemistry Institute (ACS GCI)and within that—and more to the medici-nal point—the collaborative working groupknown as the ACS GCI PharmaceuticalRoundtable (GCIPR).

Green TeamIt could almost be said that that bigpharma’s awareness of green chemistryand the roundtable’s creation in 2005 wereprompted by a growing embarrassment.

“A paper came out by Roger Sheldon thatlooked at a metric called e-factor,” explainedJulie Manley, senior industrial coordinatorwith the ACS GCI and the GCIPR. “E-factorgenerally referred to the amount of wastegenerated per kilo of product produced, andhe showed that, on that basis, pharma gen-erated the most waste” as compared withother chemical-based industries.1

Because the waste comprises chemicals,it is rarely benign. Corporate reputations are


CAPSULEEnabled by advances in biotechnology and chemical engineering and driven by the need to go green, fiercely competitive big pharma compa-nies have come together to solve the many vexing challenges of producing chemical and biological compounds without the concurrentcreation of waste.

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A Green SweepBig pharma is drafted by ethical and fiscal responsibilities to collaborate onwaste reduction efforts > By Neil Canavan

WASTE REDUCTION


at risk, liabilities accrue, and waste in thisor any context can be measured in termsof resources squandered. “The roundtablelooks to combine the ethical and fiscalobjectives,” Manley explained. “This notonly helps the bottom line of the company,but improves its environmental health andsafety standards as well.”

But why and how do pharmaceuticalcompanies collaborate on what should bea competitive issue? “There are, in fact,common challenges across the industry,”said Manley, “and while each companyhas a focus on their unique molecule, ingeneral, much of the chemistry is very simi-lar. Everyone uses certain solvents, certainreactants… .”

One company looking for green alterna-tives on its own cannot match the creativity

of 16 companies—the current number ofroundtable members—working together.“The key is to interact in a noncompetitiveway, and that is how the roundtable is setup,” Manley said. Shared data sets areblinded to retain corporate privacy, and co-company authored papers are legally vettedby all contributors.

Further, the roundtable is able to en-courage, and hopefully share in, greenchemistry innovation beyond its member-ship by using a portion of membershipdues, ranging from $10,000 to $25,000 ayear, to fund research grants that havetotaled more than $950,000.

“Right now the program is limited toacademics,” said Manley. Part of the reasonfor this restriction is to focus on spreadingthe word, to influence academic curricula.

“If people are doing the research, thengreen chemistry is being communicatedinternally within that institution.”

Available to non-GCIPR members areanalytic tools that can be accessed throughthe ACS green chemistry website.2 Forexample, there is a tool for calculating theso-called process mass intensity (PMI),defined as the kilos of mass of all materialsthat go into producing an active pharma-ceutical ingredient (API), normalized bythe mass of the end product; this is takenas a measure of the “greenness” of a givenprocess.3 “The benchmark of PMI has beena very useful tool so that companies cancompare apples to apples,” of particularuse when considering the greenness ofthird-party manufacturers that may be apart of your supply chain. (Continued on p. 12)

PHARMAQUALITY.COM

CASE STUDY

Green Meanshe 15th annual Green Chemistry and EngineeringConference—the premier green chemistry event—sawBioAmber Inc., win the Presidential Green Chemistry

Challenge Award, bestowed by the Environmental ProtectionAgency 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’sproprietary platform uses microbes that have been optimizedfor succinic acid production. Last year’s co-winners, Merck and Codexis, were honored

for their green chemistry approach in retooling the synthesissteps for making the diabetes drug sitagliptin. Along withnumerous green optimizations, the critical alteration was find-ing an alternative to the catalytic use of rhodium, a rare metalthat became prohibitively expensive during the scale-up ofmanufacture for sitagliptin; for this, scientists were able tosubstitute a transaminase enzyme for a rhodium-basedhydrogenation catalyst.1

Another example of biocatalysis in green pharmaceuticalchemistry is seen in the production of the neuroactive agentpregabalin. In this case, the initially developed API synthesiswas highly wasteful, producing 86 kg of waste per one kilo-gram of product. In addressing this issue, the manufacturer,Pfizer, performed an enzymatic screen for a problematiccyanodiester. The resulting hit was a lipase derived from

Thermomyces lanuginosus, resulting in a marked reduction ofuseless byproduct.2

A final example of green pharmaco-chemistry comes fromthe familiar class of drugs known as statins—specifically, rou-vastatin. In this instance, an initially wasteful chemical reactionwas replaced with an enzymatic step that uses deoxyribosephosphate aldolase (DERA) an innovation pioneered in an aca-demic lab. Once the efficacy of this approach was established,a nagging problem remained involving the irreversible deacti-vation of the enzyme by a chloroacetaldehyde. This was solvedwith DERA 2.0, if you will, which was created using the biotechmethod of directed mutagenic evolution.3

For a review of these and other green chemistry optionssee: Dunn PJ. The importance of green chemistry in processresearch and development [published online ahead of printMay 12, 2011]. Chem Soc Rev. �

REFERENCES

1. Grate J, Huisman G. A greener biocatalytic manufacturing route tositagliptin. Paper presented at: 13th Annual Green Chemistry andEngineering Conference; June 23, 2009; College Park, Md.

2. Martinez CA, Hu S, Dumond Y, et al. Development of a chemoenzymaticmanufacturing 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 ofan industrial biocatalyst: 2-deoxy-D-ribose 5-phosphate aldolase.Biotechnol J. 2006;1(5):537-548.

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Green Team Player“I hope we’re reaching a tipping point ofawareness for green chemistry,” said Con-cepción Jiménez-González, PhD, directorand team leader of operational sustain-ability at GlaxoSmithKline (GSK), a GCIPRmember. “That’s part of what we wanted todo with the roundtable.”

An engineer by training who has pub-lished on the subject, Dr. Jiménez-Gonzálezis concerned with the production issuesbeyond the flask: “There are very commontechniques outside of pharma that are notreally as practiced within pharma, like lifecycle assessment, process identification, orthe use of continuous processes. We need tomove away from emulating what happensin the lab when considering scale up.”4

For example, GSK has recently finalizeda carbon footprint analysis for its global op-erations. “We wanted to identify the maincontributors to the footprint—what we call‘hotspots,’ ” Dr. Jiménez-González said. Thechief suspect of un-greenness she identifiedoverall is GSK’s use of solvents. “We didsome case studies going from cradle togate in manufacture, from the moment youextract raw materials to the moment youfinish the API, and we found out that theimpact of solvents is, on average, around70% to 75% of all the overall environmen-tal impact of the process.”5

So what to do? Recycling is one possi-bility, and it can be done is such a way thatit does not affect good manufacturingpractices. For instance, you can use recy-

cled solvent to serve the same step in asynthesis. “The other option, when you arelooking at the process from the life cyclestandpoint, is [that] it really doesn’t matterif you recycle through the same process oryou down-cycle, say, to a paint manufac-turer,” Dr. Jiménez-González noted.

Or, you could simply use a more benignsolvent. Though chemists may be loath tomake changes to a set process, there arenow references available to guide them inselecting alternative solvents; resourcesinclude advice from GSK, Pfizer, and theGCIPR.6-8

“In general, it makes life easier for usif we include those types of changes priorto filing the IND [investigational new drugapplication],” Dr. Jiménez-González said.Beyond that, a retooling of the processcould cost you valuable patent expirationtime.

Green ThinkRetooling, or even thinking de novo, can of-ten be a challenge for creatures of habit. Ifyou’re stuck in a circle of self-referencingideas, you may want to bring someone infrom outside—someone like John Warner,

GREEN CHEMISTRY | WASTE REDUCTION


Editor’s Choice1. Komura K, Nakano Y, Koketsu M. Mesoporous silica MCM-41 as a highly active, recoverable and reusable catalyst for directamidation 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 subsequentreaction. 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.

This process mass intensity calculator is one of several analytic tools available at the ACS GreenChemistry Institute website: http://bit.ly/qb5buA


PhD, president and chief technology offi-cer of the Warner Babcock Institute forGreen Chemistry in Wilmington, Mass.

“It happens all the time: a companyhas enormous resources working on aproblem, they’re poring over the litera-ture, the textbooks, people are scouringthis material, pushing to get that incre-mental change to do something new, andthey come up against a brick wall,” Dr.Warner explained. The problem is thestarting point of having an outdated chem-ical methods perspective.

To start fresh in green chemistry, youmight want to first check out the bible of thefield, Dr. Warner’s Green Chemistry: Theoryand Practice, cowritten with Paul Anastos,PhD, of the Environmental ProtectionAgency.9 In it you will find the 12 guidingprinciples of practicing green chemistry,which are, though initially intended for useby the chemical industry, easily appliedto medicinal chemistry. Not so surprising,given the fact that Dr. Warner’s careerstarted by contributing to the synthesis ofthe anticancer agent Alimpta.

In Dr. Warner’s opinion, the impedi-ments to green chemistry adoption arenot merely intellectual but institutionalas well. “There is a love-hate relationshipbetween discovery and process,” he as-serted. “The people in discovery are al-ways very grumpy that the people inprocess don’t take their pearls of wisdomand bring them to amazing fruition, andthe people downstream look at the discov-ery people and say, Why do you keep send-ing us stuff that can’t be scaled up? Whythese solvents, and these toxic reagents?Green chemistry is the language theyshould both be speaking. If you thinkabout it, the least changes that are made ina process from the bench to the bottle, themore profitable the company will be.”

Dr. Warner acknowledged that progressis being made. Great strides, for instance,have been made in biocatalysis (see casestudy). And he sees the possibility of oneday attaining the holy grail of pharmamanufacture: continuous-flow reactions,which would make for a much smallerfootprint at greater cost savings. But he re-mains concerned about the generation oftoxic byproducts.

Of particular note is the book’s greenprinciple No. 4: Chemical products shouldbe designed to preserve efficacy of func-tion while reducing toxicity. “The mostamazing, most shocking thing is that achemist can go through six years of highereducation and never have a single coursein toxicology,” said Dr. Warner. “Neverhave a course in environmental mecha-nisms, never a course in anything at all toprepare them for understanding the regu-latory consequences of chemistry.”

He is also concerned about competi-tion: “India is mandating that all chemistsin training take a yearlong course in greenchemistry. China has opened up 15 na-tional research centers dedicated to greenchemistry.” These developing economiesare going to become far more competitiveand innovative because they are puttinggreen chemistry into the front end of in-novation and creativity, “and we are stillscratching our heads about whether weshould do it.” �

REFERENCES1. Sheldon RA. Catalysis: the key to waste

minimization. J Chem Technol Biotechnol.1997;68(4):381-388.

2. American Chemistry Society. ACS GCIPharmaceutical Roundtable. AmericanChemistry Society website. Available at:http://portal.acs.org/portal/acs/corg/con-tent?_nfpb=true&_pageLabel=PP_TRANSI-TIONMAIN&node_id=1407&use_sec=false&sec_url_var=region1&__uuid=a628a938-

683c-4c0d-8cac-2aba9f3f06ab. AccessedAugust 1, 2011.

3. American Chemistry Society. PMI worksheet.Available at: http://portal.acs.org:80/portal/PublicWebSite/greenchemistry/industriain-novation/roundtable/CNBP_026644.Accessed August 1, 2011.

4. Jiménez-González C, Poechlauer P, Broxter-man QB, et al. Key green engineeringresearch areas for sustainable manufacturing:a perspective from pharmaceutical and finechemicals manufacturers. Org Process ResDev. February 22, 2011. Available at:http://pubs.acs.org/doi/abs/10.1021/op100327d. Accessed August 1, 2011.

5. Constable DJC, Jiménez-González C, Hen-derson RK. Perspective on solvent use in thepharmaceutical industry. Org Process ResDev. December 14, 2006. Available at:http://pubs.acs.org/doi/abs/10.1021/op060170h. Accessed August 1, 2011.

6. Jiménez-González C, Curzons AD, ConstableDJC, et al. Expanding GSK’s Solvent SelectionGuide—application of life cycle assessmentto enhance solvent selections. Clean TechnolEnviron Policy. April 8, 2004. Available at:www.springerlink.com/content/bk59v8me1l6pv85q/. Accessed August 1, 2011.

7. Alfonsi K, Colberg J, Dunn PJ, et al. Greenchemistry tools to influence a medicinalchemistry and research chemistry basedorganisation. 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 asolvent selection guide for the pharmaceuti-cal industry. Paper presented at: AmericanInstitute of Chemical Engineers AnnualMeeting; November 17, 2008; Philadelphia.

9. Anastas PT, Warner JC. Green Chemistry:Theory and Practice. New York: OxfordUniversity Press; 1998.

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Neil Canavan, a science/medicalwriter based in Brooklyn, N.Y., holds amaster’s degree in molecular biology.

In addition to press coverage of medical meet-ings, he and has been writing about pharma-ceutical science for more than 10 years.

“The most amazing, most shocking thing is that a chemist cango through six years of higher education and never have a singlecourse in toxicology. Never have a course in environmentalmechanisms, never a course in anything at all to prepare themfor understanding the regulatory consequences of chemistry.”—John Warner, PhD, president and chief technology officer of the Warner Babcock Institute for Green Chemistry

DELIVERY

Often called the silent epidemic,traumatic brain injury (TBI) af-flicts approximately 1.7 millionAmericans annually. More than

52,000 are killed, and 275,000 are hospi-talized.1 Most are left in various states ofdisability—from almost full recovery tomild symptoms but able to function withsome or moderate disability to severe dis-ability requiring around-the-clock inten-sive care and support. The annual costs ofTBI, both direct and indirect, includingsuch factors as lost work time or reduced

productivity, have been estimated at morethan $60 billion, and there may be morethan six million TBI survivors in society.

Over the past decade, TBI has come tothe fore as tens of thousands of woundedsoldiers return home from the Middle Eastsuffering both hidden and visible TBIs andtrauma caused by blast injuries from im-provised roadside explosions.2

What is called post-traumatic stressdisorder may actually be the long-term ef-fects of TBI.

Due to the economic and social costs of

TBI, a significant ongoing effort is beingmade to develop and apply emerging newclinical and pre-clinical pharmaceuticalswith the potential to mitigate the cascad-ing additional brain damage that occursduring the critical secondary phase in TBI.Among these is an interesting pharmaceu-tical compound called cyclosporine (alsoknown as cyclosporin-A, or CsA), whichhas been found to have significant neuro-protective capabilities and the ability tomoderate the resulting damage and long-term disability in TBI.3-6


CAPSULEHistorically, doctors have been helpless to prevent secondary cell death after a traumatic brain injury. But unintended results during a seriesof experiments in the early 1990s showed cyclosporine can mitigate cellular damage once the pharmaceutical crosses the blood-brain barrier.

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TBI’s Miracle DrugAn accidental discovery about 20 years ago has led to a cyclosporinepharmaceutical on the threshold of approval > By Steve Campbell

CYCLOSPORINE

First discovered bySandoz (now Novartis)scientists in Norwayin 1969, cyclosporineis isolated from thefungus Tolypocladiuminflatum.


Pre-clinical mouse model studiesshow an 80% reduction in neural damageafter the application of this pharmaceuti-cal.7-8 More than 17 years in developmentfor neuroprotection, CsA is working itsway toward approval as a treatment thatcan greatly ameliorate the effects of TBIin humans.

Two StagesTBI has two stages. The first stage occursat the time of injury, whether it is causedby a gunshot, blast, fall, or hit. This initialstage could be either a closed-head oropen wound, and medical emergencypersonnel focus on treating the woundor injury and stabilizing the patient’svital signs.

The secondary stage of damage tothe brain takes place after the initial in-sult, as the injury continues to ripen andworsen in the hours and days after theinitial trauma. (Continued on p. 16)

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Stick model of cyclosporine, as found in theP212121 crystalline form, demonstrates thecomplexity of this peptide.

Cyclosporine is a cyclic peptide of 11 aminoacids and contains a single D-amino acid,rarely encountered in nature. Cyclosporineprotects mitochondria in TBI, myocardialinfarction and other acute injury applications.

• Cyclosporine Mitigates Heart Attacks

itochondria are present and produce effective energy in almost allcells in the body. It turns out that mitochondrial collapse may beassociated with a variety of acute injuries, such as myocardial infarc-

tions and chronic diseases like amyotrophic lateral sclerosis, multiple sclero-sis, and other neurological disorders. In myocardial infarctions, reperfusionof the blocked artery can cause reperfusion injury and extra damage anddisability to the heart muscle, as well as increased mortality. Mitochondrialprotection in heart muscle tissue is one answer to moderating the long-termimpact of heart attacks on health and lifestyle.

Every year, an estimated 500,000 people in the United States suffer amyocardial infarction. Infarct size is a major determinant of mortality. Duringmyocardial reperfusion, the abruptness of the reperfusion can cause addi-tional damage—a phenomenon called myocardial reperfusion injury. Studiesindicate that this form of injury can account for up to 50% of the final sizeof the infarct.1 Focusing on reducing the additional infarct resulting fromreperfusion would protect heart muscle and allow the patient to live longerand in better health after the initial attack.

Interestingly, a number of proposed interventions, such as ischemicpostconditioning, have been claimed to mediate cardioprotective actions byacting on the opening of the mitochondrial permeability transition pore(MPT), which is directly inhibited by cyclosporine. CsA has been studied forits cardioprotective capabilities and found to be a potentially significantpharmaceutical for ameliorating long-term damage from heart attacks.

A small proof-of-concept clinical study by Christophe Piot, MD, PhD, andhis colleagues, published in The New England Journal of Medicine in 2008,found that the administration of CsA with the aim of inhibiting the inductionof the MPT was associated with a 40% reduction in infarct size.2 An editorialin the journal called for large, multi-center studies to determine if this newtreatment option can positively influence clinical outcomes. In addition,targeting the MPT “may also offer protection in other clinical contexts, suchas stroke, cardiac surgery, and organ transplantation.”

Following that lead, in April, a European investigator-initiated multi-centerphase III study of NeuroVive’s cyclosporine-based cardioprotection pharma-ceutical CicloMulsion in myocardial infarctions enrolled the first of 1,000patients.3 —SC

REFERENCES

1. Hausenloy DJ, Yellon DM. Time to take myocardial perfusion injury seriously. N Engl JMed. 2008;359(5):518-520.

2. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acutemyocardial infarction. N Engl J Med. 2008; 359(5):473-481.

3. AktieTorget. NeuroVive: first heart attack patient treated in European cardioprotectionphase III trial with NeuroVive’s Ciclomulsion. AktieTorget website. Available at:www.aktietorget.se/NewsItem.aspx?ID=58252. Accessed Aug. 12, 2011.

© DREAMSTIME.COM


This is when the doctor says, “Now wejust wait and see,” because there’s noth-ing more that medicine can do. In thissecondary stage, the trauma to the braintriggers a series of cascading intra-cellu-lar biochemical reactions that cause se-vere demise of brain cells, brain damage,and expanded disability. If this second-ary stage can be mitigated, the potentialdamage and disability can be reducedsignificantly, enabling the victim to getcloser to full recovery.

Some of the secondary-stage mecha-nisms believed by researchers to be in-volved in brain-cell death after TBI includeuncontrolled release of signalling mole-cules (neurotransmitters), cellular calciumoverload, inflammation, energy failure,oxidative damage, and the overactivationof enzymes such as calpains and cas-pases.9

All of these are believed to create theintra- and extra-cellular conditions thatlead to the destruction of millions of addi-tional brain cells, along with the damage

DELIVERY | CYCLOSPORINE


(Continued on p. 18)

Cyclosporine protects brain cells by preventing the cascading biochemical imbalances of theTBI from causing the mitochondria to collapse and stop powering the brain cells, exacerbatingbrain damage and leading to disability.

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Pharmaceutical Approaches to TBIhere are a number of TBI pharmaceuticals in a vari-ety of stages of development. The most promising ofthese approaches are “multipotential,” targeting at

least two secondary-stage injury mechanisms, includingexcitotoxicity, apoptosis, inflammation, edema, blood–brain barrier disruption, oxidative stress, mitochondrialdisruption, calpain activation, and cathepsin activation.1

The value of multipotential agents is their potential tomodulate one or more of these multiple secondary injuryfactors, greatly increasing the chance of achieving clinicalvalue. Previously, more than 30 phase III clinical studiesfor single-factor targeted TBI pharmaceuticals failed tofind significance. Multipotential agents may have a betterchance of delivering a successful therapeutic result for TBIpatients and, ultimately, recouping the costs of develop-ment and trials.

Promising pharmacological multipotential agents fallinto two categories: those that have been studied clinicallyand those that constitute emerging pre-clinical strategies.

Clinically studied pharmaceuticals include the statins(targeting excitotoxicity, apoptosis, inflammation,edema), progesterone (excitotoxicity, apoptosis, inflam-mation, edema, oxidative stress), and cyclosporine(mitochondrial disruption, calpain activation, apoptosis,oxidative stress).

Emerging multipotential neuroprotective agentsshowing promise in pre-clinical studies include dike-topiperazines (apoptosis, calpain activation, cathepsinactivation, inflammation), substance P antagonists(inflammation, blood–brain barrier, edema), SUR1-regu-lated NC channel inhibitors (apoptosis, edema, second-ary hemorrhage, inflammation), cell cycle inhibitors(apoptosis, inflammation), and PARP inhibitors (apopto-sis, 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.


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• What is TBI?

traumatic brain injury isdefined as a blow or jolt to thehead or a penetrating head

injury that disrupts the function of thebrain. Not all blows to the head resultin a TBI. The severity of a TBI may rangefrom “mild,” involving a brief change inconsciousness, to “severe,” featuringan extended period of amnesia orunconsciousness. A TBI can result inproblems with independent function,either short- or long-term.

Millions of Americans have a long-term need for help in performing theirdaily activities as a result of suffering aTBI. By one estimate, there are up to6 million survivors of TBI. Statistics onthe full extent of TBI are not known,however, because the number of peo-ple with TBI who were not seen in anemergency department and/or whohave received no formal care cannotbe determined.

The leading causes of TBI includefalls, car crashes, hitting or being hitin sports, and physical assault. In warzones, blasts from roadside impro-vised explosive devices (IEDs) andother explosions are a leading causeof TBI for soldiers. Males are 1.5 timesas likely as females to suffer a TBI, andthe two age groups at highest risk arechildren aged 0–4 years and teenagersaged 15–19. African Americans havethe highest death rates from TBI, andit is the fourth-leading cause of deathfor males under age 45.1

More recently, the Iraq andAfghanistan wars have brought theissue to the attention of the public andCongress, as advances in combatprotection and helmets have allowedsoldiers to survive blasts that wouldpreviously have killed them.

Post injury, there is little that can be done for soldiers returning home withTBI. It’s been estimated that some 200,000 returning soldiers have varyingdegrees of TBI, ranging from mild to severe. Symptoms include depression, aninability to concentrate, moodiness, and frustration as the TBI sufferer strug-gles to complete formerly routine tasks. Moreover, much anti-social behaviorexhibited in society may be related to diagnosed and undiagnosed traumaticbrain injuries sustained in battle, on sports fields, on the streets, or aroundthe home. —SC

REFERENCE

1. U.S. Centers for Disease Control and Prevention (CDC). National Center for Injury Pre-vention and Control. Injury prevention and control: traumatic brain injury. CDC website.Available at: www.cdc.gov/traumaticbraininjury/statistics.html. Accessed Aug. 12, 2011.

After the initial brain injury,excessive calcium imbalancesduring the all-important secondarydamage phase cause brain cellmitochondria to swell and burst,releasing calcium that creates acascading avalanche of furthermitochondrial collapse, cellularenergy depletion, and subsequentbrain cell death. By protectingmitochondria, cyclosporine limitsoverall brain damage and eventualdisability.

Limiting the secondary stagebrain damage that occurs afterthe initial injury is a key strategyin treating TBIs. Cyclosporinedoes this by protecting the braincell mitochondria from collapseduring the secondary stage,enabling non-injured brain cellsto continue energy productionand operation while recoveryfrom the initial injury occurs.

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and disability that result. Many of theseare being targeted by a variety of pharma-ceutical compounds and medical treat-ments that are in various stages of clinicaldevelopment—including forcing oxygeninto the brain through the use of hyper-baric chambers. Because it targets the pro-tection of mitochondria inside brain cells,cyclosporine is perhaps the most promis-ing of these.

Role of MitochondriaResearch confirms that mitochondria, thecellular energy (adenosine triphosphate,or ATP) producers inside the brain cells,play a pivotal role in neuronal cell death orsurvival, and that mitochondrial dysfunc-tion in brain injuries is considered an earlyevent that causes neuronal cell death. Theuncontrolled release of signalling mole-cules with resulting overstimulation/stressof brain cells and accumulation of highlevels of intracellular calcium may be the

initial mechanism that leads to neuronalcell death.10

How does this affect brain cells? In-creases in calcium lead to its rapid uptakeinto the mitochondria, which act as cellularsinks for calcium. However, the excessivetransport and uptake of calcium negativelyimpacts mitochondrial energy production,because the driving force for both ATP pro-duction and calcium transport relies onthe “proton motive force” (the proton gra-

dient created over the mitochondrial innermembrane by the respiratory chain). Fur-ther, excessive calcium uptake by mito-chondria, in combination with energyfailure, leads to the formation of proteinchannels (pores) in the inner membrane—the induction of the so-called mitochondr-ial permeability transition (MPT).

The increased permeability of the innermembrane caused by the MPT pores imme-diately collapses mitochondrial functionand structure, because when the pores are

opened, the osmotically active inner com-partment (matrix) of the mitochondria at-tracts water, and the mitochondria swelland pop like balloons. In addition to caus-ing the cessation of energy production,upon induction of the MPT, the stored cal-cium and harmful proteins are then re-leased from mitochondria, resulting in anavalanche of further mitochondrial col-lapse, cellular energy depletion, and sub-sequent cell death. When brain cell deathis repeated millions of times during thecascading biochemical imbalances thatcharacterize the secondary phase, the ex-tent of brain damage and eventual disabil-ity are greatly increased.

Protecting the mitochondria by target-ing the MPT is a viable neuroprotectiveapproach that has emerged in the lastdecade. Published research has foundthat the protein cyclophilin D is an essen-tial component to opening the MPT poresand that cyclosporine binds to cyclophilinD and inhibits the induction of MPT.11,12The result is that mitochondria can absorbmuch more calcium without collapsing, al-lowing them to survive. As mitochondriasurvive to produce energy for brain cells,fewer brain cells die during the secondarystage. This is the core battleground in thewar against TBI.

Cyclosporine ProtectsCyclosporine was discovered in 1969 whenit was first isolated from the fungus Tolyp-

DELIVERY | CYCLOSPORINE


Cyclosporine acts toprotect the brain cell’smitochondria from thecascading biochemicalimbalances that causethese cellular powersources to collapse andstop powering millionsof brain cells. Thisreduces the additionalbrain damage anddisability that occursduring the secondarydamage phase of TBI.

Research confirms that mitochondria, thecellular energy producers inside the braincells, play a pivotal role in neuronal celldeath or survival, and that mitochondrialdysfunction in brain injuries is an earlyevent that causes neuronal cell death.

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cladium inflatum in Norway by researchersworking for Sandoz (now Novartis). Itsimpressive immunosuppressive propertiesled to its use as a pharmaceutical to preventtissue rejection in organ transplant recipi-ents. It has been in use for immunosup-pressive applications since the early 1980sas a commercially successful Novartisproduct called Sandimmune.13

CsA’s ability to protect the mitochon-dria in the brain by binding to cyclophilinD and preventing the induction of the MPTwas discovered in 1993–1994, a period dur-ing which medical researcher Eskil Elmér,MD, PhD, and his Japanese colleague Hi-royuki Uchino, MD, PhD, were conductingexperiments in cell transplantation. Anunintended finding was that CsA was

strongly neuroprotective when it crossedthe blood–brain barrier.14 This startlingdiscovery became the starting point forbasic research and patent applications in apromising new avenue of neuroprotection.

Basic research mapping out CsA’s ex-tensive neuroprotective capabilities hasbeen running continuously since 1993,and many international and independentresearch teams have since conducted andpublished numerous studies confirmingthat CsA is a powerful nerve-cell protectorin TBI, stroke, and brain damage associ-ated with cardiac arrest. Advanced studiesalso show that CsA is useful in protectingmitochondria in heart tissue facing reper-fusion injury during heart attacks (seesidebar).15 (Continued on p. 20)

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Cyclosporine is isolated from the fungus Tolypocladium inflatum. In the early 1990s, NeuroVive’schief scientific officer Eskil Elmér and his Japanese colleague Hiroyuki Uchino discoveredcyclosporine was strongly neuroprotective when it crossed the blood–brain barrier.

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German BoyRecovers AfterSevere Head Injury

ometime in the 1990s, ananonymous 14-year-oldliver transplant patient from

Germany—taking cyclosporine toprevent tissue rejection—was hitby a car and suffered headinjuries. By chance, an anaesthe-siologist was at the scene whenthe accident occurred. He immedi-ately examined the boy andsuspected severe brain damage, asuspicion later confirmed by anearly Glasgow Coma Scale (GCS)score of three.

Although doctors feared theworst—children under 14 with aGCS below eight have a 28%mortality rate or suffer significantbrain disability if they do sur-vive—the patient not only sur-vived but proceeded to make anamazing recovery. He was dis-charged from the hospital fiveweeks later and was able to returnto school after two months. He isnow an adult with a young son.The neuroprotective properties ofcyclosporine were suspected inthe recovery, and the case wasreported in a detailed case studypublished in the Journal of Neuro-surgical Anesthesiology in 1998.1

The study authors stated,“We conclude that neuroprotec-tive properties of cyclosporine Amay have been involved in thegood recovery after severe braininjury in this 14-year-oldpatient.”—SC

REFERENCE

1. Gogarten W, Van Aken H, MoskoppD, et al. A case of severe cerebraltrauma in a patient under chronictreatment with cyclosporine A. JNeurosurg Anesthesiol.1998;10(2):101-105.


6. Cook AM, Whitlow J, Hatton J, Young B.Cyclosporine A for neuroprotection: estab-lishing dosing guidelines for safe and effec-tive use. Expert Opinion on Drug Safety.2009 Jul;8(4):411-419.

7. Sullivan PG, Sebastian AH, Hall ED. Thera-peutic window analysis of the neuroprotec-tive effects of cyclosporine A after traumaticbrain injury. J Neurotrauma. 2011;28(2):311-318.

8. Sullivan PG, Thompson M, Scheff SW. Con-tinuous infusion of cyclosporin A post injurysignificantly ameliorates cortical damagefollowing traumatic brain injury. Exp Neurol.2000;161(2):631-637.

9. Loane DJ, Faden AI. Neuroprotection fortraumatic brain injury: translational chal-lenges and emerging therapeutic strategies.Trends Pharmacol Sci. 2010;31(12):596-604.

10. Mazzeo AT, Beat A, Singh A, Bullock MR.The role of mitochondrial transition pore,and its modulation, in traumatic brain injuryand delayed neurodegeneration after TBI.Exp Neurol. Review. 2009 Aug; 218(2):363-7370. Epub 2009 May 27.

11. Schinzel AC, Takeuchi O, Huang Z, et al.Cyclophilin D is a component of mitochondr-ial permeability transition and mediates neu-ronal cell death after focal cerebralischemia. Proc Natl Acad Sci U S A.2005;102(34):12005-12010.

12. Waldmeier PC, Zimmermann K, Qian T, Tin-telnot-Blomley M, Lemasters, J., CyclophilinD as a drug target. Current MedicinalChemistry. 2003;10:(16):1485-1506.

13. Novartis Pharmaceuticals Corp. Sandim-mune 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 ame-liorates CA1 hippocampal damage followingtransient forebrain ischaemia in the rat. ActaPhysiologica Scandinavica. 1995Dec;155(4):469-471.

15. Piot C, Croisille P, Staat P, et al. Effect ofcyclosporine on reperfusion injury in acutemyocardial infarction. New Engl J Med.2008;359(5):473-481.

16. Neurovive Pharmaceutical AB. Projectoverview: cyclophilin-D-inhibitingcyclosporine-based drugs. Neurovive web-site. Available at: www.neurovive.com/en/Research—Development/Project-overview/. Accessed Aug. 12, 2011.

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Steve Campbell is a writer andcommunications consultant inVancouver, B.C., who writes for and

about pharmaceutical and scientific research,products, and companies. He can be reachedat [email protected].

• Crossing the Blood–Brain Barrier

lthough it is difficult for many drugs, including cyclosporine, to crossthe blood–brain barrier, traumatic brain injury often causes the barrierto 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, thebarrier does not open in the same way as in TBI. NeuroVive is conductingresearch to identify variants of cyclosporine that can penetrate theblood–brain barrier, with a view to providing the brain with neuronal protec-tion under conditions other than TBI. NeuroVive is also evaluating the possibil-ity of administering cyclosporine directly to the brain fluid (e.g., throughlumbar puncture).

In pre-clinical pilotstudies, NeuroVive’sresearchers demon-strated, in collaborationwith scientists in theArmy, that cyclosporinecrosses the blood–brainbarrier in prolongedseizures due to hyperac-tivity in the brain. Incases of stroke, sched-uled cardiac surgery, andcardiac arrest, the braincannot yet be reachedsatisfactorily throughintravenous therapy,because a method ofincreasing the passageof cyclosporine throughthe blood–brain barrierin these conditions has

not yet been found. To this effect, in 2010, NeuroVive and the Dutch brain drugdelivery company to-BBB entered into a joint program to develop therapies forstroke and other acute neurodegenerative diseases.

According to its CSO, Eskil Elmér, MD, PhD, NeuroVive is also conductingresearch to develop advanced cyclosporins, formulations, new chemicalcompounds, or small molecules that allow improved or free passage acrossthe blood–brain barrier. The company is also researching and developingcyclosporine analogue molecules without immunosuppressive effects thatcan be combined with new formulations and technologies.—SC

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.

A network of capillaries supplies brain cells with nutri-ents. Tight seals in their walls keep blood toxins–andmany beneficial drugs–out of the brain.

© DREAMSTIME.COM

FORMULATION

Nanometer-sized particles, typi-cally made of iron oxide, arebeginning to transform theworld of medicine. In particular,

nanomedicine’s impact has been definedby the potential use of nanoparticles in theformulation and delivery of cancer drugs.When a nanoparticle-based drug is de-

veloped, some thought must be put intohow biodistribution, targeting, and post-delivery mechanism of action will be incor-porated into its design. “The research we are doing is really

based on the premise that altering the tem-perature of the tumor can dramaticallychange its response to things like radiationtherapy or chemotherapy,” said TheodoreDeWeese, MD, professor and chairman ofradiation oncology and molecular radia-tion sciences at The Johns Hopkins Uni-versity in Baltimore, Md. Doing that in areproducible way has been a challenge.That was until about four to five years

ago when cancer biologists decided to em-ploy nanoparticles to do the heating “usingso-called iron oxide particles, which, in theright configuration and when placed inan alternating magnetic field, will actu-ally heat to a very high temperature andlead to the sensitization of cancer cells tochemotherapy and radiation therapy,” saidDr. DeWeese. Just heating the tumor bythree degrees nearly doubles its sensitivityto therapy. One of the major challenges in the path

to building a nanoparticle delivery systemfor cancer therapy has been targeting, theprocess by which the nanoparticles arecoated with either antibodies, RNA mole-cules, or small proteins so that they aretargeted to a certain cancer cell type. Dr. De-Weese and his colleagues coat their parti-cles with dextran as well as polyethyleneglycol, which aid in biodistribution of the

drug when it is administered either intratu-morally or intravenously. However, these iron particles, which

range from 80 to 100 nanometers in diame-ter, do not specifically carry a drug. In fact,the iron itself is what is delivered to the tu-mor cell. “When the iron reaches the celland when that cell is placed in an alternat-ing magnetic field, substantial heating ofthe targeted cell results,” said Dr. DeWeese.“Even in the untargeted state, these parti-cles are taken up by pinocytosis. Cancercells like to take up these particles, but non-cancer cells take up the particles as well.So, nonspecific targeting is also possible.”

Targeting a Challenge Although heating the nanoparticle to de-stroy a target cancer cell is one possiblemechanism of action, it is somewhat non-specific.

“The holy grail isto take a highly toxicsubstance and target itwithin a nanoparticleto a specific tissue—andin the case of prostatecancer, that would bethe metastatic tumor,”

said Howard Soule, PhD, executive vicepresident and chief science officer of theProstate Cancer Foundation in SantaMonica, Calif.The toxic substance referred to is a

chemotherapeutic agent for cancer. Just asthey are being developed for solid tumors,nanoparticles are also being crafted to targetprostate cancer cells. The targeting is madepossible by labeling the particles with lig-ands that selectively bind to prostate-spe-cific membrane antigen (PSMA), a clinicalbiomarker that is highly expressed on thesurface of metastatic prostate cancer cellsand many solid-tumor blood vessels.

“So you have a particle filled with thechemotherapy medication decorated witha targeting entity on the outside of thenanoparticles,” said Dr. Soule. “When youintroduce these things systemically to thepatient, the theory is that these particleswill go into circulation and, based on theirspecificity, they will find the tumor.” He ex-plained that the tumor would take up theparticle, degrade it, and then release thedrug inside the tumor cell, thereby sparingbystander (normal) cells. “Targeting is really a complex issue,”

he explained. “These are virus-sized parti-cles that distribute in ways that chemicalsdon’t. However, there are still questionsand challenges about the potential of nan-otherapies for cancer.” For instance, howspecific will a given particle be for a tumor,and how much of the tumor-targetingspecificity is due to the vascular leakinessof the tumor, which is a property of meta-static malignancies? “We just don’t know the answers to

these questions yet,” he said.

Nanoparticles to NanomedicineOmid Farokhzad, MD, an associate profes-sor at Harvard Medical School and directorof the Laboratory of Nanomedicine andBiomaterials at Brigham and Women’sHospital in Boston, Mass., has made someseminal discoveries in the world of nano-medicine. His academic pursuits have ledto the development of a platform that en-ables one to target nanoparticles for anumber of therapeutic applications. That success ended the academic chal-

lenges and opened a new set of issues:commercial scale-up and development.The solution was start a company to licensethe technology from the university so that itcould be further developed and eventuallymarketed. The company, BIND Biosciences,was co-founded in 2007 by Dr. Farokhzadand Robert Langer, ScD, David H. KochInstitute Professor at the MassachusettsInstitute of Technology (MIT).“The company eventually made a

modification to the formulation to makethe particles much more stable and muchmore appropriate from a drug develop-ment standpoint … BIND started human


CAPSULECirca 1980, one of the earliest papers on the use of circulating nanoparticles was published. Since then, there has been sort of revolution in theworld of nanotechnology. The use of nanoparticles to formulate and deliver cancer drugs is affecting the treatment of the disease significantly.

Strides for Small Cancer FightersNanoparticles used to formulate and deliver drugs to cells and tumors show increasing promise> By James Netterwald, PhD

NANOPARTICLES

Howard Soule, PhD


trials of BIND-014, a targeted nanoparticletherapeutic for treatment of solid tumors,in January 2011,” explained Dr. Farokhzad.“The technology is composed of very longcirculating, controlled release, polymericnanoparticles that are targeted to specificreceptors on the surface of disease cells fortargeted and controlled release of drugs.”

BIND’s platform enables the companyto engineer nanoparticles with the appro-priate sizes and surface properties, target-ing the ligand density, circulation times,and drug release profiles that would be re-quired for optimizing a drug’s performancefor various therapies.

“Based on the research of MIT nano-particle guru Dr. Robert Langer, BIND’snanoparticles provide the unique opportu-nity to control the drug load and releaseprofile while actively targeting diseasedcells with ligand-directed receptor-medi-ated binding,” said Jeff Hrkach, PhD, seniorvice president of pharmaceutical sciencesfor BIND. The particle’s surface is coatedwith polyethylene glycol, which enables itto reach its drug target by evading recogni-tion by the immune system. Ligands canalso be attached to the surface of the parti-cles, allowing them to bind directly to thedesired cells or tissues to be treated. BIND’snanoparticles were developed in collabora-tion with Drs. Langer and Farokhzad.

“BIND has spent the last four yearstranslating that academic bench work intomore robust processes for developmentand clinical translation,” said Dr. Hrkach.

BIND’s lead program is a targetednanoparticle loaded with docetaxel, theactive ingredient in Taxotere—a well-knownand successful Sanofi-Aventis cancer drugthat has recently gone off patent. The prod-uct, BIND-014, which is in Phase 1 clinicaltrials for a number of solid-tumor indica-tions, targets PSMA.

“We are working with partners whohave existing approved drugs or candidatesin their pipeline and are looking for oppor-tunities to improve them or expand their ex-isting indications,” said Dr. Hrkach. “Someof these products are currently in clinicaldevelopment and show signs of promisebut have limitations related to their thera-peutic index. Our technology can increasea drug’s efficacy and reduce its toxicity bykeeping the drug sequestered in our long-circulating nanoparticles until they reachand actively bind to their specific targetcells for maximal concentration at the siteof action and minimal systemic exposure.”

The Prostate Cancer Foundation fundsboth the work done by Dr. Langer at MITand that of Dr. Farokhzad at Harvard.

PredictionsTargeting is half the challenge in nanopar-

ticle-based cancer drugs. Nanotechnol-ogy is opening new roads for delivery,however.

“I think that nanotechnology offers ahuge advantage in delivering nucleic acid-based drugs,” Dr. Soule said. “For example,in prostate cancer, a major driving forceis the androgen receptor, a transcriptionfactor that is also currently a non-drug-gable target. There is promise in the use ofnanoparticles on targets like that, whichcan be targeted by using a silencing geneagainst it. By blocking the expression ofandrogen receptor, this would be ground-breaking treatment for castration-resistantprostate cancer.”

Dr. DeWeese predicts nanotechnologywill be one of the ways cancer is treated,especially metastatic cancer. However,there are still many obstacles to over-come—the most challenging of which isthe toxicity of the treatment. “One of thecritical hurdles to overcome in the field isthat the nanoparticles can accumulate inorgans where we would rather they notdistribute, such as the liver,” he noted. “Ifthe particles amass in the non-targeted or-gans to a large degree, this could result inunwanted side effects.” �

PHARMAQUALITY.COM

Editor’s Choice1. 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 RevTher 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.

Dr. James Netterwald is a biomedical writer based in New Jersey who writes articlesand blogs on all things related to the pharmaceutical and biotechnology industry.He started Biopharmacomm LLC in 2009; his clients include medical education compa-

nies, medical advertising companies, science publishing companies, pharma-biotech companies,and public relations companies. More information on his writing can be found onwww.nasw.org/users/netterjr.

IN THE LAB

Maintaining laboratory in-struments is critical to theproductivity of pharmaceu-tical researchers at Merck

Research Laboratories (MRL). In the past,individual MRL departments were respon-sible for arranging their own instrumentmaintenance using original equipmentmanufacturers (OEMs). With the broadarray of instrumentation in their labs, thismeant administration of 120 maintenancecontracts, often by multiple people at mul-tiple sites within the organization.

To curb inefficiencies, MRL initiated aprogram that centralized responsibility forthe maintenance of more than 35,000 as-sets in three facilities with a single service

provider—PerkinElmer OneSource. Usinga combination of asset management mod-els (providing the ideal level of insuranceand service for each instrument), on-siteservice engineers, and third-party parts,the consolidated approach delivers sub-stantial cost savings while enhancing thequality and timeliness of service.

Based on the success of the program,MRL is implementing the model across theorganization, shifting all maintenance re-sponsibilities and contracts to PerkinElmer.A 70-person PerkinElmer OneSource on-siteteam maintains and qualifies more than50,000 assets in six facilities. Assets inthe “maintain” category are serviced byPerkinElmer directly, while those in the

“manage” category are maintained byservice partners under the management ofPerkinElmer OneSource. With a single pointof contact, MRL only has to make one call tomanage the entire program.

The bottom line? Response times havetypically been reduced from a day or two toan hour or two, on-time preventive mainte-nance exceeds 90%, and the cost of assetmanagement has been reduced by 20%since the program’s inception.

Consolidated ApproachWhen MRL was dealing with myriadOEMs, each department spent a consider-able amount of time negotiating and ad-ministering multiple contracts and found


Perfect PartnersMerck Research Laboratories reduces equipment maintenance costs and improves productivity with PerkinElmer OneSource team> By Maurizio Sollazzo, Paul Luchino, and Ted Gresik

OUTSOURCING

A 70-personPerkinElmer OneSource on-siteteam takes com-plete responsibilityfor maintaining andqualifying morethan 50,000 MerckResearch Laborato-ries assets in sixfacilities.


return on invested capital. PerkinElmerOneSource is proving to be that vendor.

Upon selection, a team of 22PerkinElmer OneSource certified servicepersonnel was assigned to provide on-sitesupport at the three MRL facilities at thestart of the program. The program was ad-ministered by a PerkinElmer OneSourcemanagement team that provided a singlepoint of contact for all of the services. Theservices were defined by an SLA that wasdeveloped jointly by MRL and PerkinElmerand included metrics on all maintenanceand qualification details, including re-sponse time, instrument downtime, andcompletion rate.

All assets among the three facilitieswere managed from installation and war-ranty to disposition by PerkinElmer One-Source. Asset management software trackseach piece of equipment and each criticalevent in the life of these assets. Standard-ized operational performance data is de-livered through a comprehensive assetmanagement program.

The BenefitsThe improved reporting provided byPerkinElmer OneSource helps MRL’s man-agers maintain better control over the as-sets in their facilities. Managers now haveaccess to reports that show what equip-

ment they have, where it is, its service his-tory, response time, downtime, total cost ofownership, and other key data. Utilizationinformation for each instrument, regard-less of technology or manufacturer, cou-pled with operational service and financialmetrics, improves decision-making capa-bilities. With this type of information, thelab manager can justify capital requestsusing quantifiable data about instrumentutilization. The lab manager can pinpointthe time when assets become too costly tomaintain and need tobe decommissionedor auctioned. He or she has information to

justify redeploying an underutilized assetto another branch or laboratory to distrib-ute workload.

Recently, MRL decided to rationalizeits clinical areas globally. This changenecessitated moving approximately 800pieces of equipment among MRL loca-tions around the world. PerkinElmer One-Source experts handled the move fromstart to finish, relocating and recommis-

sioning all instrumentation to minimizedowntime and ensure continued regula-tory compliance.

As part of the agreement, PerkinElmerOneSource demonstrated that every pieceof equipment was working in its new loca-tion. Whenever equipment did not per-form exactly as expected, PerkinElmer

OneSource personnel responded and re-paired the items. PerkinElmer OneSourcealso provided reporting to track the loca-tion and status of every asset throughoutthe move.

By streamlining the entire vendor man-agement process, significantly reducing thedaily administration burden on scientistsand allowing them to focus on research in-stead of managing multiple vendors, theconsolidated maintenance program deliv-ers significant cost savings. At the sametime, improvements in record keeping andservice tracking are enabling significantimprovements in purchasing decisions.

In light of these results, MRL is ex-panding the partnership, assigning toPerkinElmer OneSource the vendor man-agement of all its OEM service contractsas well as responsibility for the procure-ment and storage of parts. This approachprovides endless possibilities, all basedon the fundamental approach of lettingspecialized experts do what they do bestso that the laboratory can focus on being alaboratory and generating science. �

IN THE LAB | OUTSOURCING PHARMAQUALITY.COM


Recently, MRL needed to move approximately800 pieces of equipment among its locationsaround the world. PerkinElmer OneSourceexperts handled the move from start to finish.

Maurizio Sollazzo is executive director for Merck; reach him [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 [email protected].

PerkinElmer One-Source personnelservice equipmentfrom most topmanufacturers.


Q.What are the benefits of usingHA in ophthalmic drug delivery?

A.Whether it is to enhance the hydrationand lubrication of corneal surfaces, pro-mote physiological wound healing, or extendthe residence time of topically applied drugsin the eye, the benefits of incorporatinghyaluronic acid (HA) in ophthalmic formu-lations are well documented. As an excipi-ent, HA offers a range of benefits, deliveringnew and improved attributes to existing for-mulations. Due to its exceptional water-bind-ing, viscoelastic and biological properties,this product is compatible with a variety ofophthalmic drugs such as ciprofloxacin,diclofenac, and dexamethasone.

The use of HA as an efficient carrierfor ophthalmic drugs is characterized bya unique set of advantages, including sus-tained and targeted drug release, an ex-cellent safety and purity profile, andunmatched moisturization properties.Formulation using HA decreases filtrationtime, allowing for streamlined manufac-turing processes, and provides optimalprofiles for convenient applications and

increased patient comfort and compliance.HA in ophthalmic drug delivery also in-creases drug retention in the tear fluid,along with drug contact time with the ocu-lar surface, enhancing bioavailability.

Q.How does HA work inophthalmology?

A. HA is a naturally occurring polysac-charide that gives structure to tissues andcontributes to the optimal functioning ofa number of biological systems in the

human body. It works by entrapping thedrug in a viscoelastic matrix and slowlyreleasing it while it is degraded by hylau-ronidases. In dermatology, HA forms afilm at the surface of the skin, protectingthe drug from degradation and forming areservoir that releases the drug topically.

In ophthalmology, HA can interactwith the drug physically in the viscoelasticpolymeric matrix but can also interactchemically with positively charged drugs.The ionic compound formed will enable

INGREDIENTS


CAPSULEOwing to its exceptional water-binding, viscoelastic, and biological properties, hyaluronic acid (HA) provides new benefits for the delivery ofophthalmic drugs. Khadija Schwach-Abdellaoui, PhD, director of biopharmaceutical application development at Novozymes Biopharma,discusses the use of HA in ophthalmology applications.

The Benefits of HA in Ophthalmic DeliveryA Q&A with Novozymes’ Khadija Schwach-Abdellaoui, PhD

HYALURONIC ACID

Dr. Schwach-Abdellaoui isdirector of bio-pharmaceuticalapplicationdevelopmentat NovozymesBiopharma.She earned her

pharmaceutical degree in Lyon, France,and her doctorate in controlled-releasesystems in Montpellier, France. She haswritten more than 46 articles and morethan 60 abstracts for presentations,and has obtained 15 issued andpending patents.

Novozymes says itsbacillus-derived HAdissolves up to 35%faster than originalHA formulations,reducing time andproduction costs.


This reduces time and costs in produc-tion. Pharmaceutical companies are underever-increasing pressure to take new prod-ucts to market faster; working with rawmaterials that are already Q7 cGMP com-pliant will accelerate regulatory processesand significantly reduce testing time, mak-ing HA economically efficient.

Q. How do these developmentsincrease patient comfort inophthalmic treatments?

A.The performance of eye drops and artifi-cial tears is dependent on their rheologicalproperties and primarily relies on the na-ture, molecular weight, and concentrationof the viscosifying agents employed. HAcontributes to the uniform distribution ofophthalmic solutions on the surface ofthe eye while decreasing the drainage rate.This results in increased lubrication andfunction, enhancing comfort for the pa-tient. However, despite these advantages,highly viscous HA preparations can leadto increased blinking frequency, blurryvision, and ocular discomfort. Novozymeshas developed its HA with enhanced rhe-ological properties and optimal viscos-ity profiles, overcoming these issues toprovide improved patient comfort andcompliance.

Q. Can manufacturers be sure ofthe corneal tolerance of HA?

A. The corneal tolerance of HAs of differ-ent origins and molecular weights hasbeen evaluated by Novozymes. The studyinvolved estimating the level of corneallesions (epithelial cell loss) following re-peated applications of HA-containing for-mulations onto the cornea of rabbit eyes(see Figure 1). All HA samples, irrespec-tive of their source, molecular weight, orconcentration, included a percentage ofcorneal lesions lower than 10%. Thisdemonstrates good corneal tolerance andthe biocompatibility of HA for ophthal-mology applications.

Q. Does HA remain stable duringheat sterilization?

A.Size-exclusion chromatography coupled

with multi-angle laser light scattering hasshown that Novozymes’ HA remains re-markably stable during the heat steriliza-tion of ophthalmic solutions. A recentstudy demonstrated that after treatmentat 121 degrees C for 16 minutes, the HA re-tained 82% of its initial molecular weightagainst 60% for a Streptococcus-derived

HA of the same starting chain length. Thisenhanced stability upon heating is mostlikely due to the lower content in heavymetals, including copper and iron, ofNovozymes’ HA. HA-containing formula-tions can therefore be heat-sterilized understandard conditions without compromis-ing final product viscosity. �

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TOOLS OF THE TRADE

Among the many experimentaltechniques available for theidentification of solid forms,including polymorphs, solvates,

salts, co-crystals, and amorphous forms, X-ray powder diffraction (XRPD) stands out asa generally accepted “gold standard.”

While this does not mean that XRPDshould be used to the exclusion of otherexperimental techniques when studyingsolid forms, X-ray diffraction (XRD) hasapplications throughout the drug develop-ment and manufacturing process, rangingfrom discovery studies to lot release. The

utility of XRD becomes evident when oneconsiders the direct relationship betweenthe measured XRD pattern and the struc-tural order and/or disorder of the solid.

XRPD provides information about thestructure of the underlying material,whether it exhibits long-range order as incrystalline materials or short-range orderas in glassy or amorphous materials. Thisinformation is unique to each structure—whether crystalline or amorphous—and isencoded in the uniqueness of the XRPDpattern collected on a well-prepared sam-ple of the material being analyzed.

One must draw a distinction betweencrystalline materials, which give rise toXRPD patterns with numerous well-de-fined sharp diffraction peaks, and glassyor amorphous materials, whose XRPD pat-terns contain typically three or fewer broadmaxima (X-ray amorphous halos). In prac-tice, when using XRPD, one can usuallymeasure a sequence of crystalline materi-als that are progressively more disordered,ultimately resulting in glass. A classifica-tion system has been proposed by Wun-derlich (Table 1) to describe the type ofstructural order and molecular packingpresent in molecular organic solid formsusing three order parameter classes: trans-lation, orientation, and conformation.1

XRPD can be used to identify and char-acterize solid forms of a given moleculeexhibiting long-range crystalline order (e.g.,polymorphs, solvates, co-crystals, and salts)by their unique combination of order pa-rameters. Amorphous solid forms do notexhibit any long-range order but are iden-tifiable and characterized by their uniquelocal molecular order, apparent in the X-ray amorphous diffraction pattern.2

Given XRPD’s sensitivity to structuralorder, some of its typical applications inthe analysis of solid-state properties of adrug substance or product include:

• Identification of existing forms of theAPI;

• Characterization of the type of orderpresent in the API (crystalline and/oramorphous);

• Determination of physical and chemi-cal stability;

• Identification of the solid form of theAPI in the drug product;

• Identification of excipients present in adrug product;

• Monitoring for solid-form conversionupon manufacturing;

• Detection of impurities in a drug prod-uct; and

• Quantitative analysis of a drug product.Where appropriate data are available,

XRPD analysis can determine the solid-form structure and crystal-packing rela-tionship among individual molecules in


CAPSULEX-ray diffraction (XRD) has a broad range of applications in various stages of drug development and manufacturing, such as characterizationand 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.

EDITOR’S NOTEThis is an excerpt of a chapter from the book Pharmaceutical Sciences Encyclopedia: DrugDiscovery, Development, and Manufacturing, published in 2010 by John Wiley & Sons Inc.Read the complete chapter at www.pharmaquality.com.

Uses of X-Ray Powder Diffractionin the Pharmaceutical Industry> By Igor Ivanisevic, Richard B. McClurg, and Paul J. Schields

X-RAY DIFFRACTION

Bruker says the“push-plug tech-nology” on its D8Focus allows theexchange of optics,sampleholders ordetectors withoutrealignment.


the solid. This information is essential tothe understanding of solid-state chemistryof drugs and important from the regulatoryperspective.

Applications in Drug DevelopmentXRD has a broad range of applications invarious stages of drug development andmanufacturing. This section will addressmany of the common XRPD uses from apractical standpoint. In the broadest terms,these applications can be divided betweenAPI characterization and identification.While there is some overlap in both cate-gories, the former is more commonly ap-plied during drug development (before thedrug is on the market), while the latter is di-rected more toward manufacturing, regula-tory aspects, and intellectual property.

API CharacterizationGuidelines from regulatory authorities re-garding the need for characterization of adrug substance under development havebeen clearly stated. Below is an examplerelating to the issue of polymorphism:“Polymorphic forms of a drug substancecan have different chemical and physicalproperties, including melting point,chemical reactivity, apparent solubility,dissolution rate, optical and mechanicalproperties, vapor pressure, and density.These properties can have a direct effect onthe ability to process and/or manufacturethe drug substance and the drug product,as well as on drug product stability, disso-lution, and bioavailability. Thus, polymor-phism can affect the quality, safety, andefficacy of the drug product.” 3

While there are a number of methodsto characterize polymorphs of a drug sub-stance, the two broadly accepted methodsfor providing unequivocal proof of poly-morphism that are recognized by the U.S.Food and Drug Administration are single-

crystal XRD and XRPD.4 Other techniqueslike thermal or spectroscopic methods canbe helpful in further characterizing drugproducts, but only X-ray provides the nec-essary structural information to uniquelyidentify different polymorphs. Therefore,in early drug development, XRPD is oftenused as a primary experimental techniqueand a means of differentiating amongexperimentally generated materials. Fullycharacterizing any material requires theuse of complementary techniques (ther-mal or spectroscopic) but X-ray is typicallydone first because it is fast, is nondestruc-tive, requires little material, and providesthe necessary structural information.

Synchrotron XRD has frequentlybeen used to characterize pharmaceuti-cal materials in applications that requireadditional sensitivity not provided bylaboratory X-ray diffractometers (e.g.,crystallization monitoring).5-6 The trade-off is the greater expense and time in-vestment typically associated with suchmeasurements. Because such applica-tions tend to be specialized, this sectionwill focus primarily on laboratory XRPDmethods.

Qualitative Analysis of Materials(Phase Identification) Because every structurally different crys-talline material exhibits a unique XRPDpattern upon analysis, the use of XRPD for

phase identification was recognized earlyand remains the most common applica-tion of XRPD to pharmaceuticals.7 This so-called qualitative analysis typically referseither to the initial characterization of ma-terial not previously analyzed by XRPD orto the identification of a phase or phasesin a sample of material by comparison toreference patterns. Reference patterns arepreviously collected XRPD patterns of thesame material.

Where available, XRPD patterns cal-culated from, for example, single-crystalstructures can be substituted, but oneshould remember that the temperature atwhich the pattern is calculated can have a

significant effect on the calculated XRPDprofile. When dealing with mixtures ofphases, qualitative analysis can providean estimate of the relative proportions ofdifferent phases in the sample, usuallybased on the comparison of peak intensi-ties for characteristic peaks of the differentphases.

Due to sample artifacts such as pre-ferred orientation and poor particle statis-tics, this type of analysis should never beconfused with quantitative analysis ofmixtures. Databases of known XRPD pat-terns for various pharmaceutical materialsare published annually by the Interna-tional Centre for Diffraction Data and theCambridge Crystallographic Data Centre,


PHARMAQUALITY.COM

Databases of known XRPD patterns forvarious pharmaceutical materials are pub-lished annually by the International Centrefor Diffraction Data and the Cambridge Crys-tallographic Data Centre, which publishesthe Cambridge Structural Database.

Table 1. Types of Solid Forms Described by the Wunderlich Classification System

SOLID FORM

CRYSTALCONDIS CRYSTAL (GLASS)PLASTIC CRYSTAL (GLASS)LIQUID CRYSTAL (GLASS)AMORPHOUS (GLASS)

TRANSLATION

LONG RANGELONG RANGELONG RANGESHORT RANGESHORT RANGE

ORIENTATION

LONG RANGELONG RANGESHORT RANGELONG RANGESHORT RANGE

CONFORMATION

LONG RANGESHORT RANGESHORT RANGESHORT RANGESHORT RANGE


characterization using thermal methods(TGA, DSC), for example, would confirmthat these materials are not solvates ormixtures but actual polymorphs andwould aid in determining the thermody-namically stable polymorph. XRPD pro-vides information about the structure ofmaterials, not thermodynamics, althoughvariable-temperature XRPD has been usedto study changes in structure at differenttemperatures.

One can envision a large number of dif-ferent crystallization experiments (usingdifferent solvents or conditions) performedon the API, some possibly in automatedfashion, with the resulting material char-acterized initially by XRPD. This is in fact acommon approach to polymorphism, salt,and co-crystal screening and is perhapsthe most common application of XRPD inthe drug development process. The lattertwo screens are usually performed whenthe polymorphs of the drug candidate it-self are not sufficiently bioavailable, inan effort to produce a formulation thataddresses the bioavailability problem. AnXRPD pattern is taken—of the API, theguest material (e.g., acid), and the mixtureof the two. If a salt or co-crystal forms, theXRPD pattern of the mixture should bemore than just a sum of the reference pat-terns of the API and the guest.

Therefore, the first application forXRPD during drug development is typi-cally to identify the materials generatedusing different experimental methodolo-gies, often in automated, high throughputscreening environments.9-11 To simplifythis pattern recognition problem, whichoften involves hundreds or thousands ofexperimental data sets per screen, peoplehave developed various computationalapproaches to recognize, sort, and classifyunknown XRPD patterns, either throughcomparison to a known database of mate-rials or simply within the experimental setof unknown patterns.12-15 The latter oftenuses an approach called hierarchical clus-tering.16-17

XRPD data are often cataloged in data-bases using the so-called Hanawalt sys-tem.18-19 In this system, the data are storedas d versus I/Imax pairs. The use of d-spaceeliminates the need to specify the radia-tion source wavelength and allows com-

parison between laboratories using dif-ferent instrumentation.

A similar system is often used for intel-lectual property filings. However, there isconsiderable structural information avail-able in a typical XRPD pattern that can beused to characterize the material. Makinguse of this information usually requireshigh quality laboratory data and the use ofadvanced computational methods. �

REFERENCES

1. Wunderlich B. A classification of molecules,phases, and transitions as recognized bythermal analysis. Thermochim Acta.1999;340/341:37-52.

2. Yu L. Amorphous pharmaceutical solids:preparation, characterization and stabiliza-tion. Adv Drug Deliv Rev. 2001;48(1):27-42.

3. U.S. Food and Drug Administration. Centerfor Drug Evaluation and Research. Guidancefor Industry: ANDAs: Pharmaceutical SolidPolymorphism Chemistry, Manufacturing,and Controls Information. FDA. Available at:www.fda.gov/OHRMS/DOCKETS/98fr/2004d-0524-gdl0001.doc. Accessed Aug. 3,2011.

4. Brittain HG. Polymorphism in Pharmaceuti-cal Solids. New York: Marcel Dekker, Inc;1999.

5. Varshney DB, Kumar S, Shalaev EY, et al.Solute crystallization in frozen systems–useof synchrotron radiation to improve sensitiv-ity. Pharm Res. 2006;23(10):2368-2374.

6. Blagden N, Davey R, Song M, et al. A novelbatch cooling crystallizer for in situ monitor-

ing of solution crystallization using energydispersive X-ray diffraction. Cryst GrowthDes. 2002;3(2):197-201.

7. Jenkins R, Snyder RL. Introduction to X-raypowder diffractometry. In: Winefordner JD,editor. Chemical analysis. Vol. 138. NewYork: John Wiley & Sons; 1996.

8. United States Pharmacopeial Convention.General chapter 941: X-ray diffraction. In:USP 31-NF 26. Rockville, Md.: UnitedStates Pharmacopeial Convention;2008:374.

9. Hertzberg RP, Pope AJ. High-throughputscreening: new technology for the 21stcentury. Curr Opin Chem Biol. 2000;4(4):445-451.

10. Barberis A. Cell-based high-throughputscreens for drug discovery. Eur BiopharmRev website. Winter 2002. Available at:www.samedanltd.com/magazine/12/issue/43/article/1231. Accessed August 3, 2011.

11. Johnston PA, Johnston PA. Cellular plat-forms for HTS: three case studies. DrugDiscov Today. 2002;7(6):353-363.

12. Ivanisevic I, Bugay DE, Bates S. On patternmatching of X-ray powder diffraction data.J Phys Chem B. 2005;109(16):7781-7787.

13. Marquart RG, Katsnelson I, Milne GWA, etal. A search-match system for X-ray powderdiffraction data. J Appl Cryst. 1979;12(6):629-634.

14. Gurley K, Kijewski T, Kareem A. First- andhigher-order correlation detection usingwavelet transforms. J Eng Mech. 2003;129(2):188-201.

15. Gilmore CJ, Barr G, Paisley J. High-through-put powder diffraction. I. A new approach toqualitative and quantitative powder diffractionpattern analysis using full pattern profiles.J Appl Cryst. 2010;37:231-242.

16. Johnson SC. Hierarchical clusteringschemes. Psychometrika. 1967;32(3):241-254.

17. Borgatti SP. How to explain hierarchicalclustering. Connections. 1994;17(2):78-80.

18. Hanawalt JD, Rinn HW, Frevel LK.Chemical analysis by X-ray diffraction. IndEng Chem Anal Ed. 1938;10(9):457-512.

19. Byrn SR, Pfeiffer RR, Stowell JG. Solid-StateChemistry of Drugs. 2nd ed. West Lafayette,Ind.: SSCI, Inc.; 1999.

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Drs. Ivanisevic, McClurg, andSchields are with Solid State Chemi-cal Information, a division of Aptuit

Inc., in West Lafayette, Ind. SSCI offers cGMPcontract pharmaceutical development serv-ices, specializing in crystallization, stability,and polymorphism.

PANalytical’s Empyrean X-ray diffractometer isa 2011 winner of an R&D 100 award in the‘winning technology’ category.


Development of polyethylene glycol-conjugated alendronate, a novel nitrogen-containingbisphosphonate derivative: Evaluation of absorption, safety, and effects after intrapulmonaryadministration in ratsBisphosphonates are widely used for the treatment of bonediseases, including hypercalcemia and osteoporosis. How-ever, the bioavailability (BA) of orally administered bisphos-phonates is low, at approximately 0.9%–1.8%. In addition,the oral administration of bisphosphonates is associatedwith mucosal damage, including gastritis, gastric ulcer, anderosive esophagitis. To develop a new delivery system forbisphosphonates that improves their BA and safety, we de-veloped polyethylene glycol (PEG)-conjugated alendronate,a novel nitrogen-containing bisphosphonate derivative. Weevaluated the absorption and safety of PEG-alendronate inrats following intrapulmonary administration. The BA ofPEG-alendronate after intrapulmonary administration wasapproximately 44 ± 10% in rats, similar to that of alendronate(54 ± 3.9%). Alendronate significantly increased total proteinconcentration and lactate dehydrogenase activity in bron-choalveolar lavage fluid, suggesting that pulmonary epithe-lium was locally damaged by intrapulmonary administrationof alendronate. In marked contrast, PEG-alendronate did not significantly increase the markers following intrapulmonary administra-tion. In an osteoporosis model in rats, intrapulmonary administration of PEG-alendronate effectively inhibited decreases in the width ofthe growth plate to a level similar to that achieved by intrapulmonary administration of alendronate. These results indicate that pul-monary 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-containingbisphosphonate 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-aqueoushumor barrier, and blood-brain barrierDrugs 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 theBRB, BAB, and BBB in rats was determined using the brain uptake index (BUI), retinal uptake index (RUI), and aqueous humor uptakeindex (AHUI) methods. Lipophilic substances showed high permeabilities across the BBB and BRB. The RUI values of these substanceswere 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 inlipophilicities, verapamil, quinidine, and digoxin showed lower permeabil-ity than predicted from those across BBB and BRB, whereas only digoxinshowed a lower permeability across BRB. These low permeabilities were sig-nificantly increased by P-glycoprotein inhibitors. Furthermore, anion trans-porter inhibition increased the absorption of digoxin to permeate into theretina and aqueous humor. In conclusion, this study suggests that effluxtransport systems play an important role in the ocular absorption of drugsfrom the circulating blood after systemic administration.

Toda R, Kawazu K, Oyabu M, Miyazaki T, Kiuchi, Y. Comparison of drugpermeabilities across the blood-retinal barrier, blood-aqueous humorbarrier, and blood-brain barrier. J Pharm Sci. 2011;100(9):3904–3911.E-mail: Kouichi Kawazu ([email protected]).

Effect of PEG–alendronate on the cell viability of osteoclast-like cells derivedfrom RAW264.7 cells. The number of osteoclast-like cells derived fromRAW264.7 cells is expressed as a percentage of the values in the no treatmentgroup. Results are expressed as the mean ± SE of four experiments(**p < 0.01 compared with the no treatment group).

Plot of log UIversus log D7.4 forthe 13 compoundstested (passivediffusion; Table 1).Each symbol rep-resents the mean± SD of three tofour experiments.


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Wyatt Möbius Electrophoretic Mobility InstrumentWyatt Technology announces that its Möbius electrophoretic mobility instrument can measureprecise protein charges. The innovative optical design of the Möbius boosts the sensitivity of mobil-ity measurements, enabling protein net charge characterization at much lower concentrations thanpreviously possible. This unique capability is illustrated in a new application note, titled “MöbiusComputation of Protein Net Charge from Electrophoretic Mobility,” and available for download atwww.wyatt.com/literature/application-notes/mobius.html. The note demonstrates how the Möbiusovercomes the limitations of traditional phase analysis light scattering (PALS) methods, eliminatesundesirable interactions, and facilitates protein charge measurements at low concentrations—allwithout damaging the protein. The Möbius mobility instrument can carry out protein net chargemeasurements with a moderate antibody concentration of 1.0 mg/mL, measurements that are notpossible with conventional PALS instruments.

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NewAge Industries Silcon Med-XNewAge Industries manufactures silicone tubing that’s platinum cured for the high-est degree of purity. Called Silcon Med-X, it’s one of the company’s medical grades ofsilicone tubing and reinforced hose. Silcon Med-X is particularly suited for applications in themedical, biomedical, pharmaceutical, labora-tory, surgical, food, beverage, and health andbeauty industries. NewAge produces peroxide-and platinum-cured silicone tubing. The plat-inum-cured version offers the fewest number ofextractables—compounds that can be drawnout of tubing and adversely affect the fluid flow-ing within. It also contains no plasticizers thatcan leach out and cause flow contamination ortube hardening. Using purer tubing in process-ing and transfer applications ensures a purerend product as well. The elastomer used in Silcon Med-X meets United StatesPharmacopoeia Class VI requirements, and the tubing is produced in a controlledenvironment. 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 steriliza-tion by autoclave or gamma radiation. Silcon Med-X is stocked in 17 sizes, rangingfrom .030” through .625” (5/8”) inside diameter. Other sizes, durometers, and coloredSilcon Med-X are available through custom order. Barbed fittings, including thosemade from FDA-approved polypropylene, are stocked, along with a variety of clamps.

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AES Semi-Gas SystemsSEMI-GAS Systems, a division of AppliedEnergy Systems, Inc. and a manufacturerof industry-leading ultra-high purity gassource and distribution systems, offersbulk specialty gas source systems to de-liver hazardous specialty gases from largevessels at high flow rates. The sourcesystems are designed to supply NH3, HCl,SiH4, N2O, H2 and other hazardous spe-cialty process gases at flow rates from 100standard liters per minute (slpm) to 1,000slpm. SEMI-GAS Systems’ bulk specialtygas source systems consolidate many gascabinets into a single system for high-vol-ume semiconductor production as well asfor high gas volume-consuming processes,as found in LED and solar cell productionapplications. With consideration to thelocal climate, the source systems can beinstalled indoors or outdoors. Sourcevessel heating is incorporated into thesystem to facilitate the liquid-to-gasphase change and to sustain the highgas flow rates.

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Genotoxic Impurities: Strategies

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Genotoxic Impurities: Strategies

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Mitchell N. Cayen

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saioun Katya TEdited by

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Hedley Rees

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