About OMICS Group OMICS Group is an amalgamation

About OMICS Group OMICS Group is an amalgamation

About OMICS Group OMICS Group is an amalgamation of Open Access Publications and worldwide international science conferences and events. Established in the year 2007 with the sole aim of making the information on Sciences and technology Open Access, OMICS Group publishes 700+ online open access scholarly journals in all aspects of Science, Engineering, Management and Technology journals. OMICS Group has been instrumental in taking the knowledge on Science & technology to the doorsteps of ordinary men and women. Research Scholars, Students, Libraries, Educational Institutions, Research centers and the industry are main stakeholders that benefitted greatly from this knowledge dissemination. OMICS Group also organizes 1000+ International conferences annually across the globe, where knowledge transfer takes place through debates, round table discussions, poster presentations, workshops, symposia and exhibitions. OMICS International

Conferences OMICS International is a pioneer and leading science event organizer, which publishes around 700+ open access journals and conducts over 500 Medical, Clinical, Engineering, Life Sciences, Pharma scientific conferences all over the globe annually with the support of more than 1000 scientific associations and 30,000 editorial board members and 3.5 million followers to its credit. OMICS Group has organized 1000+ conferences, workshops and national symposiums across the major cities including San Francisco, Las Vegas, San Antonio, Omaha, Orlando, Raleigh, Santa Clara, Chicago, Philadelphia, Baltimore, United Kingdom, Valencia, Dubai, Beijing, Hyderabad, Bengaluru and Mumbai. Systematic Approach to Development of Aqueous Drug

Formulation and DrugDevice Combination Injectable Products & Presented By: Challenges Neervalur V. Raghavan, Ph.D. President, RAGS PHARMA CONSULTING, LLC August 19, 2015 Parenterals & Injectables OMICS Conference August 17-19, 2015 Chicago IL, USA

LECTURE OUTLINE Introduction - Injectable products, Drug-Device Combination products Physico-Chemical Aspects of Drug molecules - Solubility profile in aqueous and mixed solvent systems - pH rate profile of drug and chromatographic profile, potential

for particulate matter pH vs solubility profile in aqueous formulations (buffer, tonicity-adjusting agents, antioxidants, solubilizing agent, preservatives) RAGS PHARMA CONSULTING 4 LECTURE OUTLINE

Selection of Parenteral Dosage Forms - Parenteral product categories - Scientific considerations in selection of a parenteral dosage form Decision Tree for selection of a dosage form for a parenteral drug Preformulation

- Drug Solubility Drug Stability RAGS PHARMA CONSULTING 5 LECTURE OUTLINE Formulation Optimization

- Approaches to minimize drug degradation Formulation considerations in frozen drug development Influence of container compatibility and enhanced packaging Manufacturing Process Development Overview of manufacturing process process flow diagrams Mixing process optimization Mixing process scale up Considerations in solution filtration Sterilization

Process validation RAGS PHARMA CONSULTING 6 PRODUCT DEVELOPMENT OVERVIEW RAGS PHARMA CONSULTING 7 RELEASE & PRODUCT LIMITS For attributes known to decrease over time, the lower one-sided 95%

confidence bound is compared to acceptance criterion. For attributes known to increase over time, the upper one-sided 95% confidence bound is compared to acceptance criterion. For attributes that can either increase or decrease over time, two-sided 95% confidence bounds are compared to acceptance criterion. RAGS PHARMA CONSULTING 8

SHELF-LIFE CONSIDERATIONS RAGS PHARMA CONSULTING 9 10 Selection of Parenteral Dosage Forms RAGS PHARMA CONSULTING PARENTAL DOSAGE FORMS

RAGS PHARMA CONSULTING 11 PARENTAL DOSAGE FORMS CONTD RAGS PHARMA CONSULTING 12 PARENTAL DOSAGE FORMSPACKAGING RAGS PHARMA CONSULTING ENHANCED

13 PARENTAL DOSAGE FORMSPACKAGING CONTD. RAGS PHARMA CONSULTING ENHANCED 14 PARENTAL DOSAGE FORMSENHANCED PACKAGING CONTD. RAGS PHARMA CONSULTING

15 PARENTERAL PRODUCT CATEGORIES RAGS PHARMA CONSULTING 16 DOSAGE FORM DECISION TREE FOR A NEW PARENTERAL 17 DRUG RAGS PHARMA CONSULTING DEVELOPMENT CYCLE FOR A TYPICAL PARENTERAL

18 DRUG PRODUCT RAGS PHARMA CONSULTING SCIENTIFIC CONSIDERATIONS IN DOSAGE FORM SELECTION Proposed drug dose & concentration Type of Administration - Injection - Infusion Type of compound (e.g., quinolone) Aqueous Solubility (pH effects) Aqueous stability (pH effects) Oxidation

Light Stability Buffer effect Container Compatibility Absorption Leachables Drug safety/handling RAGS PHARMA CONSULTING 19 20 PREFORMULATION

RAGS PHARMA CONSULTING PREFORMULATION ACTIVITIES FOR PARENTERAL SOLUTIONS Aqueous Drug Solubility Aqueous Drug Stability RAGS PHARMA CONSULTING 21 PREFORMULATION ACTIVITIES FOR PARENTERAL SOLUTIONS

Aqueous Drug Solubility - pH- solubility profiles Solubility-temperature profile-heat of solution Co-solvents, other solubilizers Partition coefficient RAGS PHARMA CONSULTING 22 PREFORMULATION OF PARENTERAL SOLUTIONS pH- Solubility Profiles

- Many drug substances are either acidic or basic in nature and show differences in aqueous solubility as a function of pH depending on their ionization constants - The relationship between solubility and pH can be defined as follows: pH = pKa + log [Cs ] /[Ca ] Where pKa = negative logarithm of the ionization constant of the acid {Cs } = molar concentration of salt form in water [Ca ]= molar concentration of free acid in water

- Experimentally generated pH- solubility profile is essential to ensure solubility of the drug in the formulation at specified dose and formulation pH RAGS PHARMA CONSULTING 23 PREFORMULATION OF PARENTERAL SOLUTIONS Co-Solvents -

Examples: Ethanol, Propylene Glycol, Polyethylene Glycol Acid Solubilizers - Examples: Hydrochloric acid, lactic acid, methane sulfonic acid Surfactants - Examples: Polysorbate 80, Cremaphor Complexation Agents -

Examples: Cyclodextrin RAGS PHARMA CONSULTING 24 PREFORMULATION OF PARENTERAL SOLUTIONS References on Solubilizers and other Parenteral Excipients - Excipients and their use in injectable products. Sandeep Nema,

R.J. Washkuhn, and R.J. Brendel. PDA Journal of Pharmaceutical Science and Technology. Vol. 51, No. 4. July August 1997 - Solubilizing Excipients in Oral and Injectable Formulations. Robert G. Strickley. Pharmaceutical Research. Vol. 21, No. 2, February 2004 - Compendium of excipients for Parenteral Formulations. Michael F. Powell, Tue Nguyen, and Lisa Baloian. PDA Journal of Pharmaceutical Science and Technology. Vol. 52, No. 5. September October 1998.

RAGS PHARMA CONSULTING 25 PREFORMULATION ACTIVITIES FOR PARENTERAL SOLUTIONS Aqueous Drug Stability - Chemical kinetics Degradation pathways Identification and monitoring of degradation products

RAGS PHARMA CONSULTING 26 PREFORMULATION ACTIVITIES FOR PARENTERAL SOLUTIONS Aqueous Drug Stability Chemical kinetics - Arrhenius plots Micellar effects on kinetics Impact of excipients Example

- pH- rate profiles RAGS PHARMA CONSULTING 27 ACCELERATED STUDIES & USE OF ARRHENIUS RELATIONSHIP Drug degradation rate is a key factor in formulation development -

Many drug degradation reactions are slow and it may take up to several months at room temperature to determine the degradation rate. - In order to expedite the formulation optimization, degradation studies may be carried out at elevated temperatures and rate constants of room temperature can be estimated through Arrhenius relationship between the reaction rate and temperature.

RAGS PHARMA CONSULTING 28 pH Rate Profiles of Penicillin G in 0.5% (w/v) Non-micellar & 30% Micellar Concentrations RAGS PHARMA CONSULTING 29 CEPHALOTHIN - pH-Rate Profile for Hydrolysis of -lactam Ring in Cephalothin at 30C

RAGS PHARMA CONSULTING 30 PREFORMULATION ACTIVITIES FOR PARENTERAL Aqueous Drug Stability Degradation Pathways - Hydrolysis Polymerization Isomerization/epimerization Oxidation Photolysis

RAGS PHARMA CONSULTING 31 PREFORMULATION OF PARENTERAL SOLUTIONS 32 References on Drug Degradation Pathways - Chemical Stability of Pharmaceuticals A Hand Book for Pharmacists. Chapters 4 and 5. Second Edition. Editors: Kenneth A. Connors, Gordon L. Amidon, and Valentino J. Stella. John Wiley and Sons.

- Pharmaceutical Dosage Forms, Parenteral Medications, Volume 1. Kenneth E. Avis, Leon Lachman, and Herbert A. Lieberman, Editors. Marcel Dekker, Inc. - Remington: The Science and Practice of Pharmacy. Loyd V. Allen, Editor-Chair. Pharmaceutical Press. 22nd Edition (2012). - Physical Pharmacy. Alfred martin, James Swarbrick, and Arthur Cammarata. Editors. Lea & Fiebiger.

RAGS PHARMA CONSULTING 33 FORMULATION OPTIMIZATION RAGS PHARMA CONSULTING FORMULATION OPTIMIZATION OF PARENTERAL SOLUTIONS Approaches to minimize drug degradation Formulation considerations in frozen drug development

Influence of container compatibility and enhanced packaging RAGS PHARMA CONSULTING 34 FORMULATION OPTIMIZATIONFORMULATION APPROACHES TO MINMIZE DRUG DEGRADATION Hydrolysis - Determine the optimum pH for pH- rate profiles

- pKa of Commonly used Buffers for Parenterals Calculate change in hydrogen/hydroxyl ion concentration Select bugger if needed based on solution pH and buffer pKa Estimate the buffer concentration based on change in hydrogen/hydroxide ion concentration and buffer capacity of the buffer Acetic acid 4.76 Citric acid

3.15, 4.78, 6.40 Phosphoric acid 2.12, 7.21, 12.67 RAGS PHARMA CONSULTING 35 INFLUENCE OF CONTAINER SYSTEM ON FORMULATION Protection -

Light Water Loss Oxygen Permeation Microbial Ingress RAGS PHARMA CONSULTING 36 CONTAINER SYSTEM DRUG FORMULATION COMPATIBILTY 37

Container Extractables - pH Changes Extractables from the plastic container may migrate into the solution and alter the formulation pH affecting the drug stability - Excessive Levels of Extractables: Presence of solubilizers in the formulation may result in excessive levels of extractables -

Precipitation: Extractable may precipitate die to formulation pH RAGS PHARMA CONSULTING CONTAINER SYSTEM DRUG FORMULATION COMPATIBILTY 38 Drug Adsorption/Sorption to the Plastic Container - Some drugs such as nitroglycerin adsorb to PVC Some drugs may sorb into the plastic, particularly during

autoclave sterilization (high temperature and pressure) RAGS PHARMA CONSULTING FACTORS IN PROCESS SCALE UP RAGS PHARMA CONSULTING 39 CONCLUSION Product Requirements Product Development with Container & Closure System

TEAM EFFORT SUCCESS RAGS PHARMA CONSULTING 40 Let us meet again.. We welcome you all to our future conferences of OMICS International 2nd International Conference and Expo on Parenterals and Injectables On October 24-26, 2016 at Istanbul, Turkey

http://parenterals-injectables.pharmaceuticalconferences.com/

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