HANDBOOK OF SOLUBILITY DATA for PHARMACEUTICALS HANDBOOK OF SOLUBILITY DATA for PHARMACEUTICALS Abolghasem Jouyban Boca Raton London New York CRC Press is an imprint of the Taylor & Francis Group, an informa business CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL © 2010 by Taylor and Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number: 978-1-4398-0485-8 (Hardback) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained.
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For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Jouyban, Abolghasem. Handbook of solubility data for pharmaceuticals / Abolghasem Jouyban. Includes bibliographical references and indexes. ISBN 978-1-4398-0485-8 (hardcover: alk. Drugs-Solubility-Handbooks, manuals, etc.
Drug Discovery. Pharmaceutical Preparations-chemistry. Organic Chemicals-chemistry. QV 744 J86h 2010 RS201.S6J68 2010 615’.19-dc22 Visit the Taylor & Francis Web site at and the CRC Press Web site at To my parents and to my family Contents Preface.ix Acknowledgments.xi Author. Xiii Chapter 1 Introduction. 1 1.1 Solubility Determination Methods.2 1.1.1 Shake-Flask Method.3 1.1.2 Kinetic Solubility Determination.4 1.2 Aqueous Solubility Prediction Methods.4 1.3 Solubility Prediction in Organic Solvents. 15 1.4 The Accuracy Criteria in Solubility Calculation Methods.
23 1.5 Acceptable MPD Range in Solubility Calculations.25 1.6 Solubilization of Drugs by Cosolvency. 30 1.7 Review of Cosolvency Models. 30 1.7.1 Hildebrand Solubility Approach.
31 1.7.2 Solubility–Dielectric Constant Relationship Model. 32 1.7.3 Log-Linear Model of Yalkowsky. 32 1.7.4 Extended Hildebrand Solubility Approach. 36 1.7.5 Williams–Amidon Model. 37 1.7.6 Mixture Response Surface Model. 38 1.7.7 Khossravi–Connors Model.
38 1.7.8 Jouyban–Acree Model.40 1.7.9 Modified Wilson Model.46 1.7.10 Margules Equation.46 1.7.11 General Single Model. 50 1.7.12 Mobile Order and Disorder Theory. 54 1.7.13 QSPR Model of Rytting.
54 1.7.14 Artificial Neural Network Model. 56 1.7.15 COSMO-RS Model. 56 1.7.16 New Models Proposed by Yalkowsky’s Group. 57 1.8 Concluding Remarks. 59 References. 59 Chapter 2 Solubility Data in Organic Solvents. 69 References.
195 Chapter 3 Solubility Data in Binary Solvent Mixtures.203 References.500 Chapter 4 Solubility Data in Ternary Solvent Mixtures. 507 References. 519 vii viii Contents Subject Index. 521 Drug Index.
523 Solvent Index. 527 CAS Number Index. 529 Chemical Formula Index. 535 Preface Aqueous solubility is one of the major challenges in the early stages of drug discovery, and any attempt to increase solubility is of great importance in the pharmaceutical industry. One of the most common and effective methods for enhancing solubility is the addition of an organic solvent to the aqueous solution. In addition to experimental efforts to determine the solubility in mono and mixed solvents, a number of mathematical models are also proposed. The available experimental solubility data in mono and mixed solvents are collected and a brief discussion on the mathematical models is also provided.
The solvents considered are the pharmaceutical cosolvents and other organic solvents that could be used in syntheses, separations, and other pharmaceutical processes. The solutes included are the available data for official drugs, drug candidates, precursors of drugs, metabolites, and degradation products of pharmaceuticals. The aqueous solubility reported by Yalkowsky and He is excluded from the data in this book and readers are instead referred to the Handbook of Aqueous Solubility. The solubilities of amino acids are also considered as they play an important role in peptide drug properties and could be used in the pharmaceutical industry. Abolghasem Jouyban Faculty of Pharmacy and Drug Applied Research Center Tabriz University of Medical Sciences ix Acknowledgments I would like to thank all the people who helped in collecting data, especially Dr.
Shahla Soltanpour, Dr. Elnaz Tamizi, Ali Shayanfar, and Mohammad A.A. My deepest appreciation goes to Prof. (University of North Texas) for his contributions to the solubility investigations, careful review of Chapter 1, and very helpful comments and suggestions.
Many thanks to Prof. Mohammad Barzegar-Jalali (Tabriz University of Medical Sciences), Prof. Pilar Bustamante (University of Alcala), Prof. Hak-Kim Chan (University of Sydney), and Prof. Clark (University of Bradford) for their contributions to the solubility investigations over the last 12 years.
Special thanks are also due to Mohammad A.A. Fakhree for his efforts in developing the “Solvomix” software that is available online at In addition the software can be found at (Service section). Abolghasem Jouyban Tabriz University of Medical Sciences xi Author Abolghasem Jouyban (-Gharamaleki) obtained his PharmD from Tabriz University of Medical Sciences in 1988, his first PhD in pharmaceutical analysis from Bradford University (United Kingdom) in 2001, and his second PhD in pharmaceutics from Sydney University (Australia) in 2004. He is a professor of pharmaceutical analysis at Tabriz University of Medical Sciences and has published more than 140 research articles in international and national peer-reviewed journals.
Jouyban received two gold medals from the Iranian Razi Research Festival in 2000 and 2006 for his academic achievements. Xiii 1 Introduction Before a drug becomes available to its receptors, it should be dissolved in the biological fluids surrounding the receptors; therefore, solubility is an important subject in pharmaceutical sciences. There is a solubility problem with nearly 40% of the drug candidates, and any attempt to predict the solubility is quite important in drug discovery investigations.
The oldest rule for solubility prediction is “like dissolves like.” This rule is applied to a well-known solubility equation, i.e., the Hildebrand equation, in which the solubility of a solute reaches the maximum value when the Hildebrand solubility parameters of the solute and solvent are equal. However, it has been shown that the Hildebrand equation is valid only for solutions with nonspecific interactions.
Water is the unique biological solvent and aqueous solubility is one of the most important physicochemical properties (PCPs) of drugs; it is therefore obvious that simple equations like the Hildebrand equation cannot represent the aqueous solubility of solutes consisting of various functional groups, such as pharmaceuticals. More accurate equations are needed to predict the aqueous solubility of drugs, which will be discussed in detail later on (see Section 1.2). Aqueous solubility is also a key factor in the design of oral, parenteral, and ophthalmic formulations of poorly water-soluble drugs. A comprehensive database of aqueous solubilities of chemicals and pharmaceuticals was collected by Yalkowsky and He 1.
Solubility is defined as the maximum quantity of a drug dissolved in a given volume of a solvent/ solution. For ionizable drugs, the solubility could be affected by the pH of the solution, and the intrinsic solubility (S 0) is defined as the concentration of a saturated solution of the neutral form of the drug in equilibrium with its solid. The United States Pharmacopeia 2 classified the solubilities of drugs into seven classes, as listed in Table 1.1. Aqueous solubility has an essential role in the bioavailability of oral drug formulations. There is an established classification, namely, the biopharmaceutical classification system (BCS), which divides drugs into four classes in terms of their solubility and permeability 3. The BCS classification correlates the in vitro solubility and permeability to the in vivo bioavailability. Soluble and permeable drugs are class I drugs with oral bioavailability being limited by their ability to reach the absorption sites.
Class II drugs are poorly soluble but permeable drugs through the gastrointestinal tract (GI), meaning that their oral absorption is limited by the drug’s solubility and, as a consequence of the Noyes–Whitney equation, by their dissolution rate. Class III drugs are soluble but poorly permeable and their oral bioavailability is limited by the barrier properties of the GI tract. Drugs of class IV are low soluble and poorly permeable compounds with the limitations of classes II and III. The drug candidates of class I possess suitable bioavailabilities and show appropriate drugability potentials; the bioavailability of drug candidates of class II can potentially be improved by developing suitable formulation designs, while those that belong to classes III and IV are most likely to return to the lead optimization phase for the improvement of their PCP 4.
Table 1.2 lists the details of the BCS along with a number of examples for each class 3,5. Alsenz and Kansy 6 reviewed various solubility determination approaches in drug discovery and early development investigations. The poor solubility of a drug/drug candidate could be overcome using various solubility enhancement methods including salt formation; crystal engineering techniques; and the addition of cosolvents, surface active agents, complexing compounds, or hydrotrops to the solution. Preparation of soluble prodrugs is an alternative method to increase low aqueous solubility.
In addition to the experimental efforts, as well as using solubilization techniques, to determine the solubility in water, a number of articles reported the practical possibility of solubility prediction methods. Lipinski et al.
Amendment No.5 to Form S-1 Registration Statement As filed with the Securities and Exchange Commission on February 2, 2011 Registration No. 333-170245 UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 Amendment No. 5 to Form S-1 REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933 PACIRA PHARMACEUTICALS, INC. (Exact Name of Registrant as Specified in Its Charter) Delaware 2834 (State or Other Jurisdiction of Incorporation or Organization) (Primary Standard Industrial Classification Code No.) (I.R.S. Employer Identification No.) 5 Sylvan Way, Suite 125 Parsippany, New Jersey 07054 (973) 254-3560 (Address, including zip code, and telephone number, including area code, of registrants principal executive offices) David M. Stack President and Chief Executive Officer 5 Sylvan Way, Suite 125 Parsippany, New Jersey 07054 (973) 254-3560 (Name, address, including zip code, and telephone number, including area code, of agent for service) Copies to: Joseph K. Wilmer Cutler Pickering Hale and Dorr LLP 950 Page Mill Road Palo Alto, California 94304 (650) 858-6000 Marc D.
Rodgers, Esq. Latham & Watkins LLP 885 Third Avenue New York, NY 10022 (212) 906-1200 Approximate date of commencement of proposed sale to the public: As soon as practicable after this Registration Statement is declared effective. PROSPECTUS SUMMARY This summary highlights information contained elsewhere in this prospectus. You should read the following summary together with the more detailed information appearing in this prospectus, including our consolidated financial statements and related notes, and the risk factors beginning on page 11, before deciding whether to purchase shares of our common stock. Unless the context otherwise requires, we use the terms Pacira, our company, we, us and our in this prospectus to refer to Pacira Pharmaceuticals, Inc.
And its subsidiaries. Overview We are an emerging specialty pharmaceutical company focused on the development, commercialization and manufacture of proprietary pharmaceutical products, based on our proprietary DepoFoam drug delivery technology, for use in hospitals and ambulatory surgery centers. In September 2010, we filed a New Drug Application, or NDA, for our lead product candidate, EXPAREL, a long-acting bupivacaine (anesthetic/analgesic) product for postsurgical pain management. Our clinical data demonstrates that EXPAREL provides analgesia for up to 72 hours post-surgery, compared with seven hours or less for bupivacaine. We believe EXPAREL will address a significant unmet medical need for a long-acting non-opioid postsurgical analgesic, resulting in simplified postsurgical pain management and reduced opioid consumption, leading to improved patient outcomes and enhanced hospital economics. We estimate there are approximately 39 million opportunities annually in the United States for EXPAREL to be used. EXPAREL will be launched by certain members of our management team who have successfully launched multiple products in the hospital market.
EXPAREL consists of bupivacaine encapsulated in DepoFoam, both of which are used in FDA-approved products. DepoFoam, our extended release drug delivery technology, is the basis for our two FDA-approved commercial products, DepoCyt(e) and DepoDur, which we manufacture for our commercial partners. DepoFoam-based products have been manufactured for over a decade and have an extensive safety record and history of regulatory approvals in the United States, European countries and other territories. Bupivacaine, a well-characterized, FDA-approved anesthetic/analgesic, has an established safety profile and over 20 years of use in the United States. EXPAREL has demonstrated efficacy and safety in two multicenter, randomized, double-blind, placebo-controlled, pivotal Phase 3 clinical trials in patients undergoing soft tissue surgery (hemorrhoidectomy) and orthopedic surgery (bunionectomy).
In our pivotal Phase 3 hemorrhoidectomy clinical trial, EXPAREL achieved its primary endpoint by providing a statistically significant 30% reduction in pain, as measured by the area under the curve, or AUC, of the NRS-R pain scores, a commonly used patient reported measurement of pain, at 72 hours and all additional time points measured up to 72 hours. In addition, EXPAREL achieved its secondary endpoints in reducing the use of opioid rescue medication, including 45% less opioid usage compared to the placebo treatment group at 72 hours.
In our pivotal Phase 3 bunionectomy clinical trial, EXPAREL also met its primary endpoint, demonstrating a statistically significant reduction in pain at 24 hours, and this reduction was also statistically significant at 36 hours. The trial also met secondary endpoints related to pain measurement and the use of opioid rescue medication. Overall, EXPAREL has demonstrated safety in over 1,300 subjects. We are initially seeking FDA approval of EXPAREL for postsurgical analgesia by local administration into the surgical wound, or infiltration, a procedure commonly employing bupivacaine. Under the Prescription Drug User Fee Act, or PDUFA, guidelines, the FDA has a goal of ten months from the date of NDA filing to make a decision regarding the approval of our filing. Our NDA for EXPAREL was accepted by the FDA on December 10, 2010 and the PDUFA goal date for our NDA is July 28, 2011.
We are also pursuing several additional indications for EXPAREL and expect to submit a supplemental NDA, or sNDA, for nerve block and epidural administration. Become the foundation of a postsurgical pain management regimen in order to reduce and delay opioid usage. Our Strategy Our goal is to be a leading specialty pharmaceutical company focused on the development, commercialization and manufacture of proprietary pharmaceutical products principally for use in hospitals and ambulatory surgery centers. Aggregate of 167,361 shares of our common stock with an exercise price of $13.44 per share.
Pursuant to the terms of the agreement for the issuance and sale of the December 2010 Convertible Notes, in the event a second closing of the issuance and sale of the December 2010 Convertible Notes occurs, we will issue warrants to the holders of the December 2010 Convertible Notes to purchase an additional 167,361 shares of our common stock with an exercise price of $13.44 per share. However, our existing investors have indicated they will not purchase the additional $7.5 million of December 2010 Convertible Notes in the second closing. The December 2010 Convertible Notes have an interest rate of 5% per year from and after March 31, 2011 and all principal and accrued and unpaid interest on the December 2010 Convertible Notes is due and payable upon the earliest of: (1) a sale of us, (2) the date which is 30 days after the last day of the month that is 33 months after the expiration of the interest only period under the Hercules Credit Facility and (3) 91 days after the date that all obligations under the Hercules Credit Facility are paid in full and the Hercules Credit Facility is terminated. Upon completion of this offering, all principal and interest due under the December 2010 Convertible Notes will be converted into shares of our common stock at a conversion price equal to the price per share of common stock sold in this offering. Purchasers of the December 2010 Convertible Notes included certain holders of more than 5% of our capital stock, or entities affiliated with them. Amendment of 2007 Plan and Option Grant In December 2010, our 2007 Stock Option/Stock Issuance Plan, or the 2007 Plan, was amended to increase the number of shares of common stock authorized for issuance under the 2007 Plan from 1,729,498 shares to 2,546,657 shares. On December 29, 2010, our board of directors granted options for an aggregate of 571,300 shares of our common stock to our employees, executive officers and directors.
The options have an exercise price of $5.49 which was the per share value of our common stock on the date of grant. See Managements Discussion and Analysis of Financial Condition and Results of OperationsStock Based CompensationOptions Granted on December 29, 2010. Novo Nordisk Development and License Agreement In January 2011, we entered into an agreement with Novo Nordisk A/S, or Novo, pursuant to which we granted non-exclusive rights to Novo under certain of our patents and know-how to develop, manufacture and commercialize formulations of a Novo proprietary drug using our DepoFoam drug delivery technology. See BusinessCommercial Partners and AgreementsNovo Nordisk for more information. Risk Factors Our business is subject to a number of risks of which you should be aware before making an investment decision. These risks are discussed more fully in the Risk Factors section of this prospectus immediately following this prospectus summary. These risks include the following: We are dependent on the success of our lead product candidate, EXPAREL, and cannot guarantee that this product candidate will receive regulatory approval or be successfully commercialized. If we are unable to establish effective marketing and sales capabilities or enter into agreements with third parties to market and sell our product candidates, if they are approved, we may be unable to generate product revenues.
If EXPAREL is approved and we fail to manufacture the product in sufficient quantities and at acceptable quality and pricing levels, or to fully comply with cGMP regulations, we may face delays in the commercialization of this product candidate or be unable to meet market demand, and may lose potential revenues. We may not be able to manage our business effectively if we are unable to attract and retain key personnel. Our independent registered public accounting firm has expressed substantial doubt about our ability to continue as a going concern, which may hinder our ability to obtain future financing. We may not receive regulatory approval for EXPAREL or any of our other product candidates, or the approval may be delayed for various reasons, including successful challenges to the FDAs interpretation of Section 505(b)(2), which would have a material adverse effect on our business and financial condition. Corporate History and Information We were incorporated in Delaware under the name Blue Acquisition Corp. In December 2006 and changed our name to Pacira, Inc. In June 2007.
In October 2010, we changed our name to Pacira Pharmaceuticals, Inc. Pacira Pharmaceuticals, Inc. Is the holding company for our California operating subsidiary of the same name, which we refer to as PPI-California. On March 24, 2007, MPM Capital, Sanderling Ventures, OrbiMed Advisors, HBM BioVentures, the Foundation for Research and their co-investors, through Pacira Pharmaceuticals, Inc., acquired PPI-California, from SkyePharma Holding, Inc., which we refer to as the Acquisition. PPI-California was known as SkyePharma, Inc. Prior to the Acquisition. In this prospectus, the term Predecessor refers to SkyePharma, Inc.
Prior to March 24, 2007, or the Acquisition Date, and the term Successor refers to Pacira Pharmaceuticals, Inc. And its consolidated subsidiaries. Our principal executive offices are located at 5 Sylvan Way, Suite 125, Parsippany, New Jersey 07054, and our telephone number is (973) 254-3560. Our website address is www.pacira.com. Information contained on our website is not incorporated by reference into this prospectus, and you should not consider information contained on our website to be part of this prospectus or in deciding whether to purchase shares of our common stock. Pacira ®, DepoFoam ®, DepoCyt ® (U.S. Registration), DepoCyte ® (EU registration), DepoDur ®, EXPAREL, the Pacira logo and other trademarks or service marks of Pacira appearing in this prospectus are the property of Pacira.
This prospectus contains additional trade names, trademarks and service marks of other companies. In the prospectus, references to DepoCyt(e) mean DepoCyt when discussed in the context of the United States and Canada and DepoCyte when discussed in the context of Europe. The Offering Common stock offered by Pacira 6,000,000 shares Common stock to be outstanding after this offering 17,232,876 shares (18,132,876 shares in the event the underwriters elect to exercise their option to purchase additional shares from us in full) Use of proceeds We estimate that the net proceeds to us from this offering, after deducting estimated underwriting discounts and commissions and offering expenses, will be approximately $36.8 million, or approximately $42.6 million if the underwriters exercise their option to purchase additional shares from us in full. We intend to use the net proceeds from this offering as follows: approximately $36.0 million through the fourth quarter of 2011 for the planned manufacture and commercialization of EXPAREL in the United States; and the balance for working capital and other general corporate purposes, which may include the acquisition or licensing of other products or technologies or the acquisition of other businesses in the biotechnology or specialty pharmaceuticals industry. See Use of Proceeds. Risk factors You should read the Risk Factors section and other information included in this prospectus for a discussion of factors to consider carefully before deciding to invest in shares of our common stock. 167,361 shares of common stock issuable upon the exercise of warrants that were issued in the first closing of the issuance and sale of the December 2010 Convertible Notes outstanding as of December 31, 2010, at a weighted average exercise price of $13.44 per share and 167,361 shares of common stock issuable upon the exercise of warrants to be outstanding in the event a second closing of the issuance and sale of the December 2010 Convertible Notes occurs, at a weighted average exercise price of $13.44 per share.
Our existing investors have indicated they will not purchase the additional $7.5 million of December 2010 Convertible Notes in the second closing. Summary Consolidated Financial Data The following tables summarize our consolidated financial data as of the dates and for the periods indicated.
You should read this data together with our financial statements and related notes included elsewhere in this prospectus and the information under Selected Consolidated Financial Data and Managements Discussion and Analysis of Financial Condition and Results of Operations. The consolidated financial data as of December 31, 2008 and 2009, and for the years ended December 31, 2007, 2008 and 2009 have been derived from our consolidated financial statements included elsewhere in this prospectus, which have been audited by J.H. Cohn LLP, an independent registered public accounting firm.
The consolidated financial data as of September 30, 2009 and 2010, and for the nine months ended September 30, 2009 and 2010, have been derived from our unaudited consolidated financial statements included elsewhere in this prospectus. The consolidated financial data as of December 31, 2007 have been derived from our consolidated financial statements not contained herein.
The consolidated financial data as of March 23, 2007, and for the period from January 1, 2007 through March 23, 2007 have been derived from unaudited consolidated financial statements of the Predecessor, SkyePharma, Inc., not included in this prospectus. The unaudited consolidated financial data include, in the opinion of our management, all adjustments, consisting only of normal recurring adjustments, that are necessary for a fair presentation of our financial position and results of operations for these periods.
Our historical results for any prior period are not necessarily indicative of results to be expected in any future period, and our results for any interim period are not necessarily indicative of results to be expected for a full fiscal year. The term Predecessor refers to SkyePharma, Inc. Prior to March 24, 2007, and the term Successor refers to Pacira Pharmaceuticals, Inc. And its consolidated subsidiaries. Our results of operations for the year ended December 31, 2007, while representing a full year for Pacira Pharmaceuticals, Inc., do not reflect the operations of PPI-California until March 24, 2007, after the Acquisition Date.
We have presented the Predecessor for the period from January 1, 2007 through March 23, 2007, as we believe it best presents the continuity of operations of the Successor prior to the Acquisition. See Managements Discussion and Analysis of Financial Condition and Results of OperationsResults of Operations for a discussion of the presentation of our results for the year ended December 31, 2007.
The pro forma balance sheet data give effect to the conversion of all outstanding shares of our Series A convertible preferred stock into common stock and the conversion of $47.5 million aggregate principal amount of secured and unsecured notes and accrued interest thereon held by certain of our stockholders into common stock, as of September 30, 2010. The pro forma as adjusted balance sheet data also give effect to our sale of shares of common stock offered by this prospectus at an assumed initial public offering price of $7.00 per share, after deducting the estimated underwriting discounts and commissions and offering expenses payable by us.