SRI International Biosciences

Pharmaceutical SciencesSRI’s approach to drug formulation is customized according to the needs

of your program. Our drug formulation experience ranges from preparation

of dose formulations for preclinical in vitro and in vivo safety studies to

design of finished drug product dosage forms for clinical trials. We routinely

integrate physicochemical property information, in vitro characterization,

and pharmacokinetic data into the drug development process. Formulation

scientists work closely with analytical chemists who develop and apply

sensitive, selective, and robust methods for establishing the identity, strength,

quality, purity, and stability of active ingredients and drug products.

We have more than 30 years of experience solving challenging formulation,

drug delivery, and characterization problems for small molecule drugs

and biologics. Our extensive expertise can help you maximize the potential

of drug candidates of poor solubility, low bioavailability, short half-life, or

gastric intolerability. Our objective is to develop a product with the therapeutic

amount of drug in the right form, and in a formulation that maintains the drug’s

chemical and biological integrity for delivery at or over the proper time and

rate at the desired site. SRI’s comprehensive services will help you achieve

your goals — from Idea to IND®.

Research on Disease Mechanisms

Clinical Analysis Laboratory

From Idea to IND®

Drug Metabolism, Pharmacokinetics, & Toxicology Services

PreclinicalDevelopment Planning & Regulatory Services

Pharmaceutical Sciences

Drug Discovery

Learn more

Alternative DrugDelivery Systemspage 4

Dosage Form Manufacturingpage 6

Analytical Chemistrypage 5

Stability Studiespage 7

PreformulationStudiespage 2

Formulation Developmentpage 3

SRI specializes in developing “problem” compounds – those with poor solubility, low bioavailability, short half-life, and/or gastric intolerability. We conduct preformulation studies to guide the formulation strategy for your drug candidate. Typical preformulation characterization studies offered include determination of:

• Physicochemicalproperties

• AqueousandpHsolubility,organicsolventsolubility

• Dissociationconstants

• Hygroscopicityandlipophilicity

• pKa,partitioncoefficients,andtissuedistributioncoefficients

• Thermalproperties

• Moisturecontent

• Polymorphism

• Particlesizemorphology

• Drug-excipientcompatibility

Our high-throughput solubility screening system is based on an SRI-developed database of solvent combinations based on compatibility and miscibility at FDA-acceptable concentration levels. Drug candidates are screened against single, binary, and ternary solvent combinations to identify optimal solubilizing agents or cosolvents that will provide the best compatibility and solubility.

SRI has developed an in vitro Ussing system that can estimate drug transport through different sections of the intestine. This information can guide targeted drug delivery approaches and functional excipient selection to develop a product with maximum absorption. While the Ussing system is primarily used to deter-mine absorption through intestinal tissues and thus is useful for development of oral drug delivery formulations, it can be tailored to estimate absorption through other systems such as mucosal cells and skin.

Preformulation Studies

2Every drug formulation is customized to enhance the physicochemical properties of your drug candidate.

Formulation DevelopmentAt SRI, we have the experience and expertise to solve challenging formulation and drug delivery problems. We address the cost parameters and regulatory requirements for formulating new drugs, and we look for simple, economical solutions to dosage design challenges. Our staff has extensive industry experience relating to all types of dosage forms and has worked with new chemical entities, OTC products, generic products, and line extensions. Protection of proprietary information is routinely incorporated into our procedures.

Safety and efficacy are the two most critical factors in drug development. The formulator must design a product that maintains a drug’s chemical and biological integrity for delivery at or over the proper time at the proper rate in the desired location. We start with an understanding of the bulk drug’s physical and chemical properties then screen the compound to determine its permeability characteristics and susceptibility to metabolizing enzymes. Once the pharmaceutical profile of the drug has been determined, the appropriate route of administration can be identified and designed. Excipients are selected to overcome potential problems in manufacturing and stability, and to address factors impacting delivery issues such as solubility and absorption. Bench studies are performed on pilot batches to establish excipient compatibility and dosage form specifications. The final formulation design is optimized to take into account the pharmacokinetic properties of absorption, distribution, metabolism, and excretion.

Dosage forms include solutions, capsules, tablets, emulsions, suspensions, and semisolids. We have developed spray-dried, microencapsulated, and microfluidized formulations. We have also developed specialized alternative drug delivery systems such as bioadhesive nasal gels, biodegradable implants, enteric-coated capsules and tablets, topical gels, and multiparticulate systems.

Formulated drug products are more effective than their individual components used singly.

3

Alternative Drug Delivery SystemsDrug delivery technologies can modify drug release, absorption, distribution,

and elimination profiles to improve product efficacy and safety, as well as patient

convenience and compliance. Oral and parenteral are the most common routes

of drug delivery, but alternative routes of administration are preferred in many

situations. SRI has expertise in the development of these specialized drug

delivery systems:

SRI has been working on formulation and delivery approaches to enable

currently approved drugs to be delivered in a more economical and practical

manner in an approach sometimes referred to as “IV to PO.” We have had

great success in reformulating IV drug products into oral dosage forms.

• Nasalformulations

• Vaginalformulations

• Polymericfilmsandmicrospheres

• Biodegradableimplants

• Transdermaldelivery

• Transmucosalbioadhesivedelivery

• Gels

• Ointments

• Creams

Drug delivery systems can improve efficacy and safety as well as patient convenience and compliance.

4

• Pharmaceuticalanalysis

` ReferencestandardcharacterizationandCertificateofAnalysis

` Bulkpharmaceuticalingredients

` Excipienttestingaccordingtoofficialmonographs

` Structureelucidationofintermediates,impurities,anddegradants

• Methodsdevelopmentandvalidation

` In-houseuse

` Methodtransferinandout

` Validationlevelstailoredtophaseofdevelopment

• Analyticalsupportforpreformulationandformulationdevelopment

` Efficientimmediatefeedbacktoformulators

` Short-termstabilitystudies

` Planningforfinalproductmethods

• Doseverificationforin vivo and in vitroGLPstudies

` Doseconcentrationsandhomogeneityinvehiclemediaordevice

` Short-termdosestabilityunderconditionsofuse

` Testarticlecharacterizationandstability

• QualitycontrolactivitiesandcGMPclinicaltrialmaterials

` Quarantine,testing,andreleaseorrejectionofmaterialsandproducts

` In-processtesting

` Cleaning validation

` StabilitystudiesperICHguidelinesfordrugsubstancesandproducts

Analytical ChemistrySRI has state-of-the-art technology and experienced scientists offering a

broad range of analytical method development and validation, and quality

control analyses of small molecules and biologics. We work closely with drug

development scientists in medicinal chemistry, formulations, pharmacokinetics,

toxicology, and manufacturing to identify, quantify, and characterize materials

to meet R&D needs and be in full compliance with FDA GLP and cGMP

requirements. Our analytical team contributes the following:

We have decades of experience working with hundreds of drugs.5

We can customize our manufacturing capabilities to produce the dosage form and batch size you need.

SRI’s dosage form manufacturing facilities are designed to provide you with a single, high-quality resource for the manufacture and packaging of oral, topical, and parenteral products for nonclinical and clinical studies. These activities are supported by our Quality Control and Quality Assurance Units which inspect, test, and release the products in full compliance with the FDA GLP and cGMP regulations and international regulatory agencies.

Our R&D, GLP, and cGMP facilities and equipment are designed to support early phase development. The low volume batches needed for safety evaluations and early clinical trials present unique challenges, and we are ready to work with you to overcome limited bulk drug supplies and tight turnaround times.

Our extensive collection of manufacturing equipment provides the capabilities needed to produce R&D, pilot, and clinical-scale batch sizes including:

6

Dosage Form Manufacturing: R&D, GLP, and cGMP

Mixing and Blending

• Planetarymixers

• V-Blenders

• Emulsifiers

Solid Dosage Forms

• Capsulefilling,sizes 00to4andDB

• Capsulebander

• Capsulepolisher

• Capsulesorter

• Tabletpress

• Extruder

Milling

• Lowspeedmills

• Highspeedmills

Granulation

• Rollercompactor

• Granulator/oscillator

• Spheronization

Coating

• Pancoater

• Spraycoater

Packaging

• Liquidandsemisolidfillers

• Blisterpacksealer

• Heatsealer

• Laminatedtubesealer

• Vialcapper

Sterilization

• Autoclave

• Depyrogenation

• Sterilefiltration

SRI offers stability storage and testing that adheres to ICH guidelines. Our standard storage conditions include frozen (ultracold and -20°C), refrigerated (5°C), ambient (25°C/60% RH), intermediate (30°C/65% RH), and accelerated (40°C/75% RH). Custom storage conditions and specialized climatic zone considerations can also be accommodated upon request.

In addition to long-term drug substance and drug product stability studies to support ongoing clinical trials, we routinely incorporate short-term stability studies in the evaluation of candidate formulations. We also perform photostability and temperature cycle studies.

Our stability study evaluations are preceded by forced degradation studies to develop sensitive and specific analytical methods so that impurities and degradation products can be tracked and quantified. Our in-house analytical and synthetic chemists can identify impurities through various structure elucidation techniques and synthesize reference standards of the active ingredient and degradation products to support ongoing stability assessments.

To ensure the quality and security of your drug substance and drug products, our stability storage program features:

• Storageunitswithvalidatedconditionsoftemperature,humidity,andlight (visibleandUV)

• Validatedcomputerizedsystemforcontinuousmonitoringoftemperature,humidity,andlight,withcumulativereports

• Emergencypowerback-upforchambersandcomputermonitoringsystems

• Localaudiblealarmsandanautomaticnotificationsystemto24/7on-sitesecuritypersonnelwithprotocolsfornotifyingfacilityengineersandtechnicalstaff

• Adouble-locksystemtoaccesschambers

Stability Studies

7 Stability study failures can be prevented or controlled by formulation development.

Contact Us

SRI Biosciences 333 Ravenswood Avenue Menlo Park, CA 94025-34931.650.859.3000

Center for Advanced Drug ResearchSRI Shenandoah Valley 140 Research DriveHarrisonburg, VA 228021.540.438.6600

Toll-Free: 1.866.451.5998Email: biosciences@sri.com

www.sri.com/biosciences

Menlo Park Headquarters

SRI International333 Ravenswood AvenueMenlo Park, CA 94025-3493 1.650.859.2000

Washington, D.C.

SRI International 1100 Wilson Blvd., Suite 2800Arlington, VA 22209-3915

1.703.524.2053

www.sri.com

SRI International and Idea to IND are registered trademarks of SRI International. All other trademarks are the property of their respective owners.

Copyright 2011 SRI International. All rights reserved. 02/11

About SRI International BiosciencesSRI Biosciences carries out basic research, drug discovery and drug development, and provides contract services. SRI has all of the resources necessary to take R&D from Idea to IND®—from initial discovery to the start of human clinical trials—and specializes in cancer, immunology and inflammation, infectious disease, and neuroscience. SRI’s product pipeline has yielded marketed drugs, therapeutics currently in clinical trials, and additional programs in earlier stages. In its CRO business, SRI has helped government and other clients and partners advance well over 100 drugs into patient testing. SRI is also working to create the next generation of technologies in areas such as diagnostics, drug delivery, medical devices, and systems biology.

About SRI InternationalSilicon Valley-based SRI International is one of the world’s leading independent research and technology development organizations. SRI, which was founded by Stanford University as Stanford Research Institute in 1946 and became independent in 1970, has been meeting the strategic needs of clients and partners for more than 60 years.

Perhaps best known for its invention of the computer mouse and interactive computing, SRI has also been responsible for major advances in drug discovery and development, networking and communications, robotics, advanced materials, atmospheric research, education research, economic development, national security, and more. The nonprofit institute performs client-spon-sored research and development for government agencies, busi-nesses, and foundations. SRI also licenses its technologies, forms strategic alliances, and creates spin-off companies.