Pharmaceutical
`Preformulation and
`Pormulation
`
`........ by Mark Gibson
`
`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1049
`
`Exh. 1049
`
`

`
`Library of Congress Cataloging-in-Publication Data
`
`Catalog record is available from the Library of Congress
`
`This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with
`permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish
`reliable data and information, but the authors and the publisher cannot assume responsibility for the validity of all materials
`or for the consequences of their use.
`
`Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical,
`including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior
`permission in writing from the publisher.
`
`The consent of CRC Press does not extend to copying for general distribution. for promotion, for creating new works, or
`for resale. Specific permission must be obtained in writing from CRC Press for such copying.
`
`Direct all inquiries to CRC Press, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431.
`
`Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for
`identification and explanation. without intent to infringe.
`
`Visit the CRC Press Web site at www.crcpress.com
`
`<6> 2001 CRC Press
`
`No claim to original U.S. Government works
`International Standard Book Number 1-57491-120-1
`5 6 7 8 9 0
`Printed in the United States of America
`Printed on acid-free paper
`
`Exh. 1049
`
`

`
`202
`
`Pharmaceutical Preformulalion and Formuladon
`
`Preformulation as an Al"d . .. in Early Drug Development
`
`203
`
`Figure 6.13 First-order hydrolysis decomposition of a compound (25°C).
`
`2~0
`
`0
`
`0
`
`Carbonate buffering loss
`Container closure problems
`Drug or excipient degradation
`
`v-....._ "
`I • pB= 1.4
`0
`....
`v
`• pB=5.9
`L_
`
`pB =2.2
`pB =3.9
`pB =4.9
`
`I
`
`0
`
`pH = 7.0
`
`Effect of Meta/Ions and Oxygen on Stability
`In formulation terms, the removal of oxygen and trace metal ions, and the exclusion of light,
`may be necessary to improve the stability of oxygen sensitive compounds. Formulation aids to
`this end include antioxidants and chelating agents and, of course, the exclusion of light where
`necessary. Antioxidants are substances that should preferentially react with oxygen and hence
`protect the compound of interest towards oxidation. A list of water and oil soluble antioxi-
`dunts is given in Table 6.8 (Akers 1982).
`Preformulation screening of the antioxidant efficiency in parenteral solutions containing
`epinephrine has been reported by Akers (1979), who concluded that screening was difficult on
`the basis of the redox potential, and was complicated by a complex formulation of many com-
`ponents. Indeed, the most recent study on the preforrnulation screening of antioxidants found
`that the ability of an antioxidant to consume the oxygen in the formulation was a superior in-
`dicator of suitability when compared to redo~ methods (Ugwu and A pte 1999).
`To illustrate the effect of oxygen on a compound that was sensitive to its presence, and
`its effect on the antioxidant (sodium metabisulphite), we performed the following experi-
`
`v
`
`OJ)
`-~
`·~
`2 .,
`
`~
`~
`OJ)
`0
`...l
`
`I ll.
`
`I ~
`
`J
`
`0
`
`50
`
`100
`
`150
`Time(min)
`
`200
`
`250
`
`300
`
`Stability to Autoc/aving
`l'or parenteral N formulations, a sterile solution of the compound is required. A terminal
`sterilization method is preferred, rather than aseptic filtration, because there is a greater as-
`surance of achieving sterility. As noted by Moldenhauer (1998), the FDA requires a written
`justification to explain why a product is not terminally sterilized. Therefore, it is mandatory
`to assess whether the candidate drug is stable to autoclaving as part of any preformulation se-
`lection process. Autoclaving (usually IS min at 121°C) at various pHs is undertaken, after
`which the solutions should be evaluated for impurities, colour, pH and degradation products.
`Clearly, if one compound shows superior stability after autoclaving, then this will be the one
`to choose.
`The effect of the autoclave cycle, i.e., fill, heat-up, peak dwell and cool down, on the the-
`oretical chemical stability of compounds intended for IV injection has been investigated by
`Parasrampuria et al. (1993). Assuming first-order degradation kinetics, i.e., hydrolysis, the
`amount of degradation was calculated for any point during the above process. Although the
`
`Table 6.8
`Ust of water and oil soluble antioxidants.
`Oil Soluble
`Water Soluble
`
`Propyl gallate
`Butylated hydroxyanisole
`Butylated hydroxytoluene
`AscortJyl palmitate
`Nordihydroguaiaretic acid
`<>·Tocopherol
`
`Sodium bisulphite
`Sodium sulphite
`Sodium metabisulphite
`Sodium thiosulphatc
`Sodium fonnaldehyde sulphoxylate
`I and d Ascorbic acid
`Acetylcysteine
`Cysteine
`Thioglycerol
`Thioglycollic acid
`Tiliolactic acid
`
`Exh. 1049