Contributing Editor ABDULLAH A AL-BADR ABDULRAHMAN AL-MAJED Founding Editor KLAUS FLOREY Academic Press is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA 525 B Street, Suite 1800, San Diego, CA 92101–4495, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK 125 London Wall, London, EC2Y 5AS, UK First edition 2016 © 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under 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978-0-12-804784-2 ISSN: 1871-5125 (Series) For information on all Academic Press publications visit our website at http://store.elsevier.com/ PREFACE TO VOLUME 41 The comprehensive profiling of drug substances and pharmaceutical excipients as to their physical and analytical characteristics remains essential to all phases of pharmaceutical development, and such profiles are of immeasurable importance to workers in the field Consequently, the compilation and publication of comprehensive summaries of physical and chemical data, analytical methods, routes of compound preparation, degradation pathways, uses and applications, etc have always been and will continue to be a vital function to both academia and industry As the science of pharmaceutics grows and matures, the need for information similarly expands along new fronts, and this growth causes an equivalent growth in the repository sources where investigators find the information they need The content of the Profiles series continues to respond and expand to meet this need, and so chapters are published that fall into one or more of the following main categories: Comprehensive profiles of a drug substance or excipient Physical characterization of a drug substance or excipient Analytical methods for a drug substance or excipient Detailed discussions of the clinical uses, pharmacology, pharmacokinetics, safety, or toxicity of a drug substance or excipient Reviews of methodology useful for the characterization of drug substances or excipients Annual reviews of areas of importance to pharmaceutical scientists The current volume contains comprehensive profiles of bupropion hydrochloride, calcium carbonate, carbamazepine, dacarbazine, and pioglitazone Particular attention should be drawn to the extraordinarily comprehensive profiles on calcium carbonate and carbamazepine, and those chapter authors are to be congratulated on the depth of their research As always, I welcome communications from anyone in the pharmaceutical community who might want to provide an opinion or a contribution HARRY G BRITTAIN Editor, Profiles of Drug Substances, Excipients, and Related Methodology hbrittain@centerpharmphysics.com vii CHAPTER ONE Bupropion Hydrochloride S.R Khan*, R.T Berendt*, C.D Ellison*, A.B Ciavarella*, E Asafu-Adjaye*, M.A Khan†, P.J Faustino* * Division of Product Quality Research, US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Testing and Research, Silver Spring, MD, United States Rangel College of Pharmacy, College Station, TX, United States † Contents Description 1.1 Nomenclature 1.2 Formula 1.3 Elemental Analysis 1.4 Appearance (Smell, Documented Taste) 1.5 Uses and Applications Method of Preparation 2.1 Synthesis Physical Properties 3.1 Dissociation Constant 3.2 Solubility 3.3 pH 3.4 Partition Coefficient 3.5 Hygroscopicity 3.6 Crystallographic Properties 3.7 Thermal Analysis 3.8 Spectroscopy Methods of Analysis 4.1 Electrochemical Analysis 4.2 Chromatographic Analysis Stability 5.1 Solution Stability 5.2 Solid-State Stability 5.3 Stability in Biological Medium Biological Properties 6.1 Toxicity 6.2 Drug Metabolism and Pharmacokinetics Acknowledgments References Profiles of Drug Substances, Excipients, and Related Methodology, Volume 41 ISSN 1871-5125 http://dx.doi.org/10.1016/bs.podrm.2015.12.001 2 3 3 4 5 5 5 20 20 22 24 24 25 25 26 26 26 28 28 # 2016 Elsevier Inc All rights reserved S.R Khan et al DESCRIPTION Bupropion belongs to the chemical class of aminoketones and is known also by the generic name amfebutamone It is a norepinephrinedopamine disinhibitor (NDDI), which promotes the release of norepinephrine and dopamine, and is administered for the treatment of depression and smoking cessation [1] It is a second-generation antidepressant approved in the United States and in the European Union Bupropion is a trimethylated monocyclic phenylaminoketone compound that differs both structurally from most first-generation tricyclics and second-generation SSRIantidepressants, and is part of a novel mechanistic class of antidepressants that has no direct action on the serotonin system [1,2] Bupropion has a single chiral center, giving rise to two enantiomeric forms Although pure bupropion enantiomers have been synthesized successfully, rapid racemization in solution is observed [3,4] Therefore, this drug is marketed as a racemate, with equimolar ratios of both enantiomers being present in Wellbutrin and Zyban [5] The active pharmaceutical ingredient (API) in marketed bupropion drug products is either bupropion hydrochloride (HCl) or bupropion hydrobromide (HBr) The HCl salt is the more common API, and thus is the focus of the profile reported herein Because the crystal structures of these two salt forms may significantly differ, certain solid-state physicochemical properties (eg, dissolution rate, number of polymorphic forms, stability, etc.) also may differ However, upon dissolution (and dissociation of the chloride and bromide ions from the bupropion), bupropion from either salt form will have the same properties 1.1 Nomenclature 1.1.1 Systematic Chemical Name 1-(3-Chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone; synonym: (Ỉ)-2-(tert-butylamino)-30 -chloropropiophenone 1.1.2 Nonproprietary Names Bupropion, Amfebutamone 1.1.3 Proprietary Names Wellbutrin, Zyban, Voxra, Budeprion, Prexaton, Elontril, or Aplenzin Bupropion Hydrochloride 1.2 Formula 1.2.1 Empirical Formula, Molecular Weight, CAS Number Molecular formula: C13H18ClNOÁHCl Molecular weight: 276.20 CAS Number: 31677-93-7 1.2.2 Structural Formula See Fig 1.2.3 Stereochemical Description Bupropion has a single chiral center that gives rise to two enantiomers Pure enantiomers have been synthesized, and pharmaceutical uses of the pure enantiomers of bupropion, (+)- and (À)-bupropion, are reported [3,4,6] However, in aqueous solution, the enantiomers rapidly interconvert to exist as a 50:50 racemic mixture [3,4] Thus, the drug is marketed as a racemate Racemic bupropion is the API of Wellbutrin and Zyban (marketed by Glaxo Smith Kline) 1.3 Elemental Analysis C 56.53%, H 6.93%, Cl 25.67%, N 5.07%, O 5.79% 1.4 Appearance (Smell, Documented Taste) Crystallization of bupropion hydrochloride from isopropanol and absolute ethanol results in white crystals that possess a bitter, anesthetizing taste 1.5 Uses and Applications Bupropion is second-generation antidepressant indicated for smoking cessation [7,8] In clinical trials, bupropion is being tested as a candidate treatment for psycho-stimulant drug abuse, attention-deficit hyperactivity disorder (ADHD), and obesity Bupropion is available in three bioequivalent oral Figure Molecular structure of bupropion hydrochloride The asterisk denotes the chiral center S.R Khan et al formulations: immediate release (IR), sustained release (SR), and extended release (XL) In 2003, the FDA approved the first XL formulation, Wellbutrin XL 300 In 2006, the FDA approved a generic version of the XL bupropion formulation, Budeprion XL, 300 mg [9] Budeprion XL was voluntarily removed from the market in 2013 [10] METHOD OF PREPARATION See Scheme 2.1 Synthesis The synthesis of bupropion hydrochloride is reported by Mehta et al [3] The ketone was converted to 2-bromo-30 -chloropropiophenone by a reaction of bromine with ketone in dichloromethane The SN2 displacement of bromine by t-butylamine in N-methylpyrrolidinone (NMP) yields as a noncrystalline oil This was converted into the crystalline ammonium hydrochloride salt by reaction with hydrochloric acid The yield improved as a result of using N-methylpyrrolidinone (NMP, also called 2-methyl-2-pyrrolidinone) in place of dimethylformamide (DMF) as a solvent for the amination of In DMF, the reaction can take 3–4 h, whereas in NMP, it is complete in less than 10 at 50–60°C The secondary amine reacts with hydrochloric acid to produce in good yield Cl Cl Cl H3C NH2 Br2 C CH3 H3C H N Br C(CH3)3 O O CH3 O CH3 O N CH3 Cl HCl H.HCl N C(CH3)3 O CH3 Scheme Synthesis of bupropion hydrochloride CH3 Bupropion Hydrochloride PHYSICAL PROPERTIES 3.1 Dissociation Constant Bupropion is a weak base The pKa of bupropion is 7.9 at 25°C [5] 3.2 Solubility See Table 3.3 pH The pH of subsaturated solutions of bupropion hydrochloride are 4.8 (10 mg/mL) and 4.1 (50 mg/mL) in DI water 3.4 Partition Coefficient See Table 3.5 Hygroscopicity Bupropion is very hygroscopic and sensitive to decomposition [14] Bupropion hydrochloride is slightly hygroscopic [15] According to the United States Pharmacopeia, bupropion hydrochloride should be stored in a closed container under refrigerated conditions and should not require drying if stored properly Table Solubility of Bupropion HCl at Room Temperature Solvent Solubility (mg/mL) [11,12] Water 312 Alcohol 193 0.1 N HCl 333 Table n-Octanol/Water Partition Coefficient (log Po/w) [13] System log Po/w n-Octanol/distilled water À1.32 n-Octanol/distilled water (pH 1.2) À0.60 n-Octanol/distilled water (pH 6.0) 0.91 n-Octanol/distilled water (pH 7.4) 1.54 S.R Khan et al 3.6 Crystallographic Properties 3.6.1 Polymorphism Two crystalline polymorphs of bupropion HCl have been reported in the literature [16,17] These polymorphs were shown to be enantiotropically related, where Form is most stable at room temperature, and Form is more stable at elevated temperatures (demonstrated conversion at 190°C) [17] 3.6.2 Single-Crystal Structures A single-crystal structure of the ethanol hemisolvate of racemic bupropion HCl exists in the literature [18] However, due to an apparent difficulty in preparing a single crystal of adequate size and quality, the reported crystal structure for desolvated racemic bupropion HCl is based on a powdered crystalline sample, not a single-crystal sample [16] For desolvated racemic bupropion HCl, the authors obtained the crystal structure by applying the ab initio X-ray powder diffraction (XRPD) technique and a global optimization strategy, adopting the single-crystal structure of the solvate form as a starting point for molecular simulations Table lists the literaturereported crystallographic parameters for Form and its corresponding Table Published Crystal Data for Bupropion Hydrochloride Bupropion HCl Bupropion HCl Bupropion HCl Ethanol (Form 1) [16] (Form 2) [17] Hemisolvate [18] Space group Monoclinic Orthorhombic Triclinic P21/c Pbca P1 Z a b ˚ 14.3406(3) A ˚ 8.7564(2) A ˚ 27.2853(5) A 8.7184(3) A˚ ˚ 7.571(1) A ˚ 9.310(1) A c ˚ 11.8801(2) A ˚ 12.0422(3) A 11.687(1) A˚ α 94.58(1)° β 78.025(2)° V λ ˚3 1459.34(5) A 1.5418 A˚ 2864.7(1) A˚3 ˚ 1.5418 A Temp (K) 293 298 101.49(1)° ˚3 804.5(2) A 1.54178 A˚ 293 Bupropion Hydrochloride ethanol hemisolvate Crystallographic parameters for bupropion HCl Form are not reported in the literature 3.6.3 XRPD Pattern Figure shows an experimental XRPD pattern of anhydrous bupropion HCl The most intense peaks from the experimental pattern are listed in Table This pattern is consistent with the bupropion HCl Form polymorph [16] 3.7 Thermal Analysis 3.7.1 Melting Behavior The melting range of bupropion hydrochloride (polymorph unknown) is reported to be 233–234°C [11] The melting range of bupropion hydrochloride (polymorph unknown) was experimentally determined to be 230.9231.8C using a Kruăss M5000 melting point apparatus (Hamburg, Germany) Decomposition was observed at the melting range Figure Experimental XRPD pattern of bupropion HCl, collected at a wavelength of 1.54060 nm under ambient laboratory conditions ... Properties 6.1 Toxicity 6.2 Drug Metabolism and Pharmacokinetics Acknowledgments References Profiles of Drug Substances, Excipients, and Related Methodology, Volume 41 ISSN 1871-5125 http://dx.doi.org/10.1016/bs.podrm.2015.12.001... content of the Profiles series continues to respond and expand to meet this need, and so chapters are published that fall into one or more of the following main categories: Comprehensive profiles of. .. Division of Product Quality Research, US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Testing and Research, Silver Spring, MD, United States Rangel College of Pharmacy,