PHARMACEUTICAL
`PREFORMUlATION
`AND
`FORMUlATION
`
`A Practical Guide from
`Candidate Drug Selection to
`Commercial Dosage Form
`
`Mark Gibson
`Editor
`
`lnterpharm Press
`
`Denver, Colorado
`
`APOTEX EXHIBIT 1033
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`- -
`
`Invitation to Authors
`
`( ~ Interpharm Press publishes books focused upon applied technology and regulatory affairs
`e~~ impacting healthcare manufacturers worldwide. If you are considering writing or con-
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`tions editor.
`
`Library of Congress Cataloging-in-Publication Data
`
`Pharmaceutical preformulation and formulation : a practical guide from candidate drug
`selection to commercial dosage form I Mark Gibson, editor.
`p.; em.
`Includes bibliographic references and index.
`ISBN 1-57491-120-1 (hard: alk. paper)
`1. Drugs-Dosage forms. I. Gibson, Mark, 1957-
`[DNLM: 1. Drug Compounding. 2. Biopharmaceutics-methods. 3. Chemistry,
`Pharmaceutical-methods. 4. Dosage Forms. 5. Drug Evaluation. QV 778 P53535 2001]
`RS200 .P425 2001
`615' .14-dc21
`
`2001016816
`
`Commissioned in Europe by Sue Horwood of Medi-Tech. Publications, Stonington, England, on
`behalf of IHS® Health Group, Denver, Colorado, USA. General Scientific Advisor: Dr. Guy Wingate,
`UK Quality Manager, Computer Systems Compliance, Secondary Manufacturing, Glaxo Wellcome,
`Barnard Castle, England.
`
`10987654321
`\
`ISBN: 1-57491="!10-Y ...
`Copyright(© 2001,.-'2002 by'lnterpharm Press, An IHS Health GroupTM company.
`All rights reser~d. · -· · -·
`
`All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a
`retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying,
`recording, or otherwise, without written permission from the publisher. Printed in the United States
`of America.
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`of the mark remains with the lawful owner of the mark. No claim, intentional or otherwise, is made
`by reference to any such marks in this book.
`While every effort has been made by IHS~ Health Group to ensure the accuracy of the information
`contained in this book, this organization accepts no responsibility for errors or omissions.
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`

`

`7
`
`Biopharmaceutical Support in
`Formulation Development
`
`Berti/ Abrahamsson and
`Anna-Lena Unge/1
`Astra Zeneca
`Molndal, Sweden
`
`The pharmaceutical formulation plays an important role in the delivery of a drug to the body.
`The clinical benefit of a drug molecule can thereby be optimised by delivering the right
`amount at the right rate to the right site at the right time. For example, extended-release (ER)
`formulations have been used for a long time to control the rate of absorption and thereby keep
`drug levels within the therapeutic interval during an entire dosage interval. More examples of
`biopharmaceutical properties that can be provided by oral formulations are given in Table 7.1.
`In the future, the pharmaceutical possibilities for improving clinical utility may be extended
`to include she-specific drug delivery systems that reach systemic targets, such as cancer cells
`and the central nervous system (CNS), or gene delivery to cell nuclei. Such areas of drug de-
`livery are, however, outside the scope for the present chapter.
`In order to achieve the potential clinical benefits that can be provided by a formulation,
`as exemplified in Table 7.1, biopharmaceutical input is needed from the start of preformula-
`tion, through formulation development, to documentation for regulatory applications. The
`main objective is to obtain and verify desirable drug delivery properties for a pharmaceutical
`formulation. The key activities are as follows:
`
`Characterisation of relevant physicochemical, pharmacokinetic/dynamic prerequi-
`sites provided by the drug molecule
`Identification of the relevant biopharmaceutical targets and hurdles in formulation
`development
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`
`

`

`240
`
`Pharmaceutical Preformulation and Formulation
`
`Definition of test methods/study designs needed to obtain the biopharmaceutical
`targets in the formulation development and correct interpretation of the study re-
`sults obtained
`Choke of suitable drug form, formulation principles and excipients
`
`In addition, understanding of the physiological processes that may interact with the bio-
`pharmaceutical function of the dosage form is crucial.
`Successful biopharmaceutical input during development can make a significant contri-
`bution to clinical efficiency and tolerability of a drug product. In certain cases, such as poorly
`absorbable drugs or drugs that are degraded in the gut, the biopharmaceutical aspects can
`make the difference between a new useful product or an aborted development programme of
`a potentially very useful drug compound. Additionally, appropriate use of biopharmaceutics
`will also contribute to a time and cost-efficient development process.
`The present chapter is limited to presentations and uses of different biopharmaceutical
`test methods in formulation development, such as
`in vitro dissolution testing,
`bioavailability studies,
`in vitro/in vivo (IVIVC) correlation of drug dissolution,
`use of animal models in in vivo studies of formulations and
`in vivo imaging of formulations by gamma scintigraphy.
`
`This chapter is strongly focussed on oral drug delivery. The relevant principles and meth-
`ods involved in biopharmaceutical characterisation of a drug molecule, mainly applied in the
`preformulation phase, are described in Chapter 4, "Biopharmaceutical Support in Candidate
`Drug Selection':
`
`Table 7.1
`Examples of biopharmaceutical properties of oral dosage forms.
`Biopharmaceutical Target
`Fonnulatron Function
`Increase amount absorbed/
`Dissolution or permeability enhancement
`reduced variability of amount absorbed
`Protection from degradation in Gl tract
`Extended release
`Control rate of absorption
`Pulsed release
`Gastric retention
`Colon release
`Mucoadhesive
`
`Control site of delivery
`
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`Biopharmaceutical Support in Formulation Development
`
`241
`
`IN VITRO DISSOLUTION
`In vitro dissolution testing of solid dosage forms is the most frequently used biopharmaceuti-
`cal test method in formulation development. It is used from the start of dosage form devel-
`opment and in all subsequent phases. Examples of different purposes of dissolution testing in
`research and development are as follows:
`
`Investigation of drug release mechanisms, especially for ER formulations
`To obtain a predefined target release proftle and robust formulation properties re-
`garding influences of physiological factors (e.g., pH and food) on the drug release
`Generation of supportive data to bioavailability studies as an aid in interpretation of
`in vivo results
`Validation of manufacturing processes
`Investigation of effects of different storage conditions
`Batch quality control ( QC)
`A surrogate for bioequivalence studies
`An in vitro dissolution method for batch QC is always defined for a new solid dosage form
`product. However, this method may not be sufficient for all the different aims of dissolution
`testing that might arise. The choice of dissolution method and test conditions should there-
`fore be adapted to best serve their purpose. For example, simplicity and robustness are crucial
`properties of a QC method; whereas physiological relevance may overrule these factors when
`a method is used for in vivo predictions.
`Standard in vitro dissolution testing models two processes; the release of drug substance
`from the solid dosage form and drug dissolution. Drug release will be determined by formu-
`lation factors such as disintegration/dissolution of formulation excipients or drug diffusion
`through the formulation. Drug dissolution will be affected by the physicochemical substance
`properties (e.g., solubility, diffusivity), solid-state properties of the substance (e.g., particle
`surface area, polymorphism) and formulation properties (e.g., wetting, solubilisation). In
`vitro dissolution testing should thus provide predictions of both the drug release and the dis-
`solution processes itt vivo. Therefore, in most situations, the use of in vitro dissolution will be
`meaningless if the method used does not provide some correlation with in vivo data or re-
`semblance with the physiological conditions in the gastro-intestinal ( GI) tract. In order to
`reach this goal, the choice of dissolution apparatus and test medium should be carefully con-
`sidered. Another important aspect in the development and defmition of a new method is that
`it must be designed and operated in such a way that drug release and dissolution are not sen-
`sitive to minor variations in the operating conditions.
`This chapter will provide some practical considerations for developing and using in vitro
`dissolution methods. Aspects of study design and evaluation of in vitro dissolution data will
`also be discussed. For additional information on in vitro dissolution testing, the "FIP Guide-
`lines for Dissolution Testing of Solid Oral Products, (1997), Handbook of Dissolution Testing
`(Hansson 1991), pharmacopoeias and regulatory guidelines are recommended.
`
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`242
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`Pharmaceutical ?reformulation and Formulation
`
`Dissolution Apparatus
`The most well-established apparatuses are those described in the pharmacopoeias. Four meth-
`ods, mainly intended for oral solid dosage forms, are described in the U.S. Pharmacopeia
`(USP) XXIV: the rotating basket method (USP I), the rotating paddle method (USP II), the
`reciprocating cylinder (USP III) and the flow-through method (USP IV). All of these meth-
`ods, except for the reciprocating cylinder, are also described in the European Pharmacopoeia
`(EP), although the equipment specifications are not identical to those in the USP. These
`methods are schematically presented in Figures 7.1 a-d.
`
`USP I. The dosage form is placed in a cylindrical basket that is covered by a mesh.
`The basket is immersed in the dissolution medium and rotated at a speed of between
`25 and 150 rpm. The standard beaker has a volume of 1 L, but 4 L vessels are also
`available. The mesh size in the basket wall can also be varied.
`USP II. The dosage form moves freely in the same type of glass beaker as used for
`USP I. A paddle is rotated at a speed of 25 to 150 rpm. The dosage form may be
`placed in a steel helix in order to avoid floating.
`USP III. The formulation is placed in a cylindrical glass tube with steel screens in the
`bottom and the top. The mesh size of the tubes may vary. This tube is moved up and
`down in a larger tube that contains the dissolution fluid. The amplitude of the inner
`tube movements is 5-40 dips/min, and the volume of the outer tube is 300 mL. Tubes
`containing 100 mL and 1 L are also available. The inner tube can be moved during
`the dissolution process between different outer tubes, which may hold different dis-
`solution fluids.
`USP IV. The formulation is placed in a thermostated flow-cell. The dissolution fluid
`is pumped through the cell in a pulsating manner at a constant rate, typically be-
`tween 4 and 16 mL/min. Before the inlet flow reaches the formulation, it is passed
`through a bed of glass pellets to create a laminar flow. A filter is placed in the cell at
`the outlet side of the formulation. The cell is available in different sizes/designs, and
`tablet holders are available as an option.
`
`USP XXIV and the EP describe four additional apparatuses mainly intended for trans-
`dermal or dermal delivery: the paddle over disc (USP V, EP), the extraction cell method (EP),
`the cylinder method (USP VI, EP) and the reciprocating holder method (USP VII). A large
`number of other non-compendia! methods have been described. Most of them could be cat-
`egorised as
`
`modified USP methods,
`rotating flask methods (Koch 1980) and
`dialysis methods (El-Arini et al. 1990).
`
`An example of a commercially available (VanKel, Cary, N.C., USA) alternative to the stan-
`dard USP II method is one that consists of a glass vessel that has been modified by introduc-
`ing a peak in the bottom (see Figure 7.2). This modification has been introduced to create
`appropriate stirring in all parts of the vessel and thereby avoid formation of poorly agitated
`heaps of undissolved material.
`
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`at the N LM and may be
`Subject US Copyright Laws
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`

`Biopharmaceutical Support in Formulation Development
`
`243
`
`Figure 7.1 Different dissolution apparatuses:
`(a) the rotating basket CUSP I) dissolution apparatus.
`
`(b) The rotating paddle CUSP II).
`
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`244
`
`Pharmaceutical Preformulation and Formulation
`
`Figure 7.1 continued
`(c) The reciprocating cylinder (USP I II) dissolution apparatus .
`
`.
`
`.
`
`.......... . ~. _, ...... ·~· ·~~ .......... _ .•.... --.. --···· _ ...... - .... -~ ..... ~ .. ---·--· ......
`,....:.._:.:.....~'~ ... ~.:.....~ •.. -.. ~~-~--···---·--··-····~·~··· .. -- ~--·~····· .. ····-···--···--·
`......... "~--~~=msm~~
`
`·•
`. .
`
`~
`
`.
`
`... ' . ,..,..,. ...... . . . ..
`
`(d) Flow-through cell (USP IV].
`
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`Biopharmaceutical Support in Formulation Development
`
`245
`
`Figure 7.2 Standard and modified (peak vessel) USP II dissolution apparatuses
`including illustrations of the different flow patterns within the beakers and photographs
`taken at a paddle stirring rate of 100 rpm showing a heap of pellets beneath the paddle
`in the standard method compared to the desirable dispersion of pellets in the modified
`method.
`
`Standard USP vessel
`
`Peak vessel
`
`Conventional
`
`Peali Vessel
`
`The choice of dissolution apparatus will be specific for each formulation, and the follow-
`ing factors should be considered:
`Correlation to i11 vivo data
`Risk for hydrodynamic artefacts
`Regulatory guidelines
`Drug solubility
`Need to change the dissolution medium during dissolution testing
`Ease of operation, in-house know-how and suitability for automation
`
`As a general guideline in the choice of dissolution test apparatus, the simplest and most
`well-established method should be chosen, with respect to both in-house know-how and reg-
`ulatory aspects. In most cases, this is the USP II paddle method or the USP I rotating basket
`method. However, if satisfactory performance cannot be obtained by these methods, others
`should be considered. Primarily, the USP III and USP IV methods, and non-compendia}
`methods could also provide relevant advantages.
`Correlation of the in vitro dissolution to the in vivo dissolution is a crucial property of a
`dissolution test. The major difference in this respect between different apparatus is the
`hydrodynamic conditions. It has been argued for some of the methods, such as the USP IV
`flow-through cell or a rotating flask with baffles, that an in vivo-like situation is created in the
`
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`246
`
`Pharmaceutical Preformulation and Formulation
`
`vitro test. However, this hypothesis has not been verified by any experimental means for any
`method, and it is clear that no apparatus mimics the full complexity of the motility patterns
`in the GI tract. A recommended approach is therefore to evaluate different apparatuses on a
`case-by-case basis using IVIVC studies (see "Bioavailability Studies': p. 257) to reveal which
`method provides the most desirable results.
`The potential for hydrodynamic artefacts (e.g., floating, clogging of material to screens,
`adhesion to equipment of the formulation or variable flow conditions in the vicinity of the
`formulation due to other reasons) is strongly formulation dependent and thus has to be eval-
`uated for each type of formulation. In order to detect artefacts, careful visual inspection of the
`dissolution test equipment is crucial. Video recordings can be used to aid such investigations.
`The present regulatory guidelines in the United States and Europe propose the use of
`USP I and USP II as the methods of choice. Other methods, both compendia! and non-
`compendia!, could be acceptable, but the rationale for not using USP I and II must be clearly
`stated and supported by experimental data. In generic product development, complete disso-
`lution methods, including the apparatus, are provided for many products in the USP and
`should thus be a first choice in a regulatory context. It should be noted, however, that this is
`not applicable in all cases. A dissolution method that is well functioning for a certain formu-
`lation type may provide high variability, artefacts or poor IVIVC for other dosage forms. Thus,
`in particular, for ER formulations or dosage forms containing dissolution enhancing princi-
`ples, different dissolution tests may be needed for different formulations, although the drug
`substance is the same.
`For sparingly soluble substances, the volume in standard vessel methods may not be suf-
`ficient to dissolve the dose. In this case, the USP IV flow-through method is beneficial, since
`it provides a continuous renewal of the dissolution fluid. However, the maximum flow rate
`will limit the apparent solubility in this procedure. Sufficient solubility will not be obtained
`for a rapidly releasing formulation of a drug with very low solubility in relation to the dose.
`In certain cases, it is desirable to change the dissolution medium during the dissolution
`test. For example, a more physiologically relevant medium is desired with changes of the con-
`ditions (e.g. pH) corresponding to the differences along the GI tract. Both USP III and USP
`IV permit such changes without significant interruptions of the dissolution process.
`Irrespective of the chosen apparatus, the equipment must be set up and handled in a way
`that both minimises the variability of the dissolution and avoids artefacts. The most common
`source to such variability or artefacts is hydrodynamic factors, but unwanted chemical reac-
`tions or temperature shifts could also occur. Alterations of hydrodynamics, as well as changes
`of temperature, can both affect the dissolution of a drug substance and the release of a sub-
`stance from the dosage form. Chemical reactions in the test medium may cause degradation
`of the drug substance or some formulation excipient which may affect the dissolution, or may
`lead to misinterpretation of the results. Examples of different sources to variability for the
`USP apparatuses are summarised below:
`
`USP !-dogging of basket screen, positioning of basket
`USP II-adherence of formulation to the beaker wall, floating, "entrapment" of solid
`material in the stagnant area beneath the paddle, positioning of the paddle
`USP III-floating, adherence to tube wall or bottom screen, clogging of screens, dis-
`appearance of undissolved material through the screens
`USP IV-clogging of filter, variations in flow rate
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`Biopharmaceutical Support in Formulation Development
`
`247
`
`Some other factors that potentially could cause problems are not specific for a certain ap-
`paratus. These general factors include vibrations, variations in agitation rate, impurities due
`to poor cleaning or to trace amounts of metals from dissolution equipment, variations in dis-
`solution fluid components and poor quality of dissolution media components. Another fac-
`tor relevant for lipophilic compounds is migration of the drug substance into fillers and
`plastic material.
`
`Choice of Agitation Intensity
`All compendia! dissolution apparatus can be operated at different agitation intensities. The
`three most outstanding aspects to consider when deciding at which level the tests should be
`performed are
`
`correlation to in vivo data,
`1.
`2. variability of dissolution results and
`3.
`regulatory guidelines and pharmacopoeial recommendations.
`
`The U.S. regulatory agency recommends a stirring rate of 50-100 rpm for USP I and 50-
`75 rpm for USP II.
`The above-proposed agitation intensities should be used if IVIVCs cannot be improved
`or the variability in dissolution data can be improved by other settings. The major problem
`associated with a too low agitation is that solid material is not sufficiently well dispersed,
`which will delay the dissolution. On the other hand, the possibility to discriminate between
`different formulations/batches with different dissolution properties might be lost at a too in-
`tensive agitation.
`Sometimes a dissolution test is performed with the aim to investigate the robustness of
`the release properties towards potential changes of the physiological conditions in vivo. In this
`case, tests at different agitation intensities should be considered to model different intestinal
`motilities. The use of more than one apparatus may also be considered.
`
`Choice of Dissolution Test Media
`The choice of dissolution medium is highly dependent on the purpose of the dissolution
`study, but the following aspects should always be considered:
`
`Correlation to in vivo data
`Resemblance of physiological conditions in the GI tract
`Regulatory and pharmacopoeial recommendations
`Drug solubility and stability properties at different pH values
`Known sensitivity of the formulation function for different medium factors
`
`Attainment of IVIVC is a key aspect in the choice of dissolution test medium. However, it
`is not recommended to choose a test medium based only on correlation to in vivo data. The
`dissolution test medium should also be relevant for the physiological conditions in the GI
`
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`
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`248
`
`Pharmaceutical Preformulation and Formulation
`
`tract. Components and physicochemical characteristics of the GI fluids that might be consid-
`ered in the choice of dissolution medium were discussed in Chapter 4. The in vivo conditions
`are not static, but the fluids are constantly changing along the GI tract due to absorption of
`water and nutrients, secretions of enzymes, carbonate, salts and bile and digestive processes. It
`is therefore clear that it is not realistic to reconstitute the full complexity of the in vivo condi-
`tions in an in vitro test. An approach has to be taken where the most relevant factors are in-
`cluded, based on knowledge of the solubility of the drug substance and the release mechanism
`of the dosage form. Examples of some dissolution test media that have been proposed to be
`physiologically relevant are given in Table 7.2 (USP 2000; Dressman et al. 1998).
`Another important aspect in the selection of a dissolution test medium is the need to con-
`sider the saturation solubility of drug in the test medium in relation to the drug dose tested.
`Drug dissolution will depend on the amount of drug in the solution if the dissolved amount
`of drug in the test medium approaches the saturation solubility. This can be understood from
`the Noyes-Whitney equation (see equation 1 in Chapter 4, "Biopharmaceutical Support in
`Candidate Drug Selection>'); the dissolution rate will be· affected by the drug concentration in
`the dissolution medium (Ct) if Ct is not much less than the saturation solubility (Cs). This is
`not a desirable situation since, if Ct controls the rate of dissolution, the test may not be dis-
`criminative for factors related to the formulation performance. Another disadvantage, if Ct is
`significant in relation to Cs, is that the dissolution rate will be dose dependent, and different
`results will be obtained for different strengths of the same formulation. Finally, it can be as-
`sumed, in most cases, that Ct does not affect the in vivo dissolution rate due to the continu-
`ous removal of drug from the GI lumen by the drug absorption process that keeps the drug
`concentrations in the GI tract at a level far below Cs. Consequently, it is desirable to choose a
`
`USP simulated intestinal fluid
`
`Table 7.2
`Examples of dissolution test media including physiological components.
`USP simulated gastric fluid
`2 g/L NaCI
`3.2 g/L pepsin
`0.06 M HCI
`0.05 M KH2P04
`0.015 M NaOH
`10.0 g/L pancreatin
`pH adjusted to 6.8 by HCI or NaOH
`0.01-0.05 M HCI
`2.5 g/L Na Iaury! sulphate
`2 g/L NaCI
`0.029 M KH2P04
`5 mM Na taurocholate
`1.5 mM lecithin
`0.22 M KCI
`pH adjusted to 6.8 by NaOH
`
`Simulated gastric fluid-fasted
`state (Dressman et al. 1998)
`
`Simulated intestinal fluid-fasted
`state (Dressman et al. 1998)
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`Biopharmaceutical Support in Formulation Development
`
`249
`
`dissolution test method that provides a high enough saturation solubility to avoid dependence
`on Ct. Cs should be at least 3-5 times higher than Ct when the total dose has been dissolved.
`Such conditions have been termed "sink conditions''. In the first instance, maximum volume
`or flow of test medium should be used to obtain sink conditions. Adjustment of the pH to a
`level that provides optimal solubility should be considered for proteolytic drugs without ne-
`glecting the aspects of physiological relevance. For drugs with a very low solubility in relation
`to the administered dose, the above-described approaches will not provide sufficient drug sol-
`ubility in the test media. In those cases, a surfactant should be added to the test medium in
`amounts above its critical micelle concentration (CMC) in order to solubilise the drug. The
`solubility can thereby be increased several hundred orders of magnitude. This approach is also
`favoured due to the occurrence in vivo of drug solubilising micelles formed in the presence of
`bile acids. However, the use in vitro of bile acids in standard methods is not recommended due
`to variations in quality and high costs, and it will still be almost impossible to simulate the in
`vivo complexity. Therefore, synthetic surfactants are the first choice, and sodium lauryl sul-
`phate (SLS) has been especially recommended (Shah et al. 1989). Due to the risk of specific
`interactions between the formulation and SLS (of no in vivo relevance) or poor solubilisation
`capacity for certain drugs, other synthetic surfactants may be considered on a case-by-case
`basis. An example of the first case is illustrated in Figure 7.3 where the in vitro dissolution-
`time proftles of a poorly soluble compound, felodipine, are shown for three different
`hydrophilic matrix ER tablets (A-C) when three different surfactants (SLS, CTAB [cetyl-
`trimethylammonium bromide], Tween) were used to obtain sink conditions (Abrahamsson et
`al. 1994). SLS interacted with the gel forming excipient, which led to much less of a difference
`in drug dissolution rate between the three different tablets, compared to the use of the other
`surfactants. It is also important to realise that attainment of sink conditions does not guaran-
`tee that the in vitro results correlate to the in vivo performance, due to other effects. The dis-
`criminating power of a dissolution test may be lost if the solubility of the drug is too
`favourable in the dissolution medium. For example, an in vitro dissolution method including
`SLS in amounts providing sink conditions was used to test three other felodipine ER tablets.
`No difference was obtained in vitro for the three tablets, which contained different forms of
`the drug substance, whereas one of the tablets provided almost no bioavailability in vivo due
`to poor dissolution (Johansson and Abrahamsson 1997). Thus, general recommendations of
`the amount and type of solubiliser to be used in an in vitro test medium may be misleading,
`and the test medium should preferably be based on correlation to relevant in vivo data for
`poorly soluble substances.
`Based on the knowledge of the substance solubility, release mechanisms from the dosage
`forms and known interactions with key excipients, certain components may be of special im-
`portance to include or exclude in the dissolution test medium. This has to be considered on a
`case-by-case basis. Two examples are given below.
`
`Example 7
`Hard gelatine capsules have the potential to be cross-linked during storage, which leads to for-
`mation of non-water soluble capsules. However, this does not affect the in vivo dissolution due
`to the presence of enzymes that digest the gelatine. Thus, the presence of pepsin and pancre-
`atin in simulated gastric and intestinal fluids, respectively, may be especially important in the
`dissolution testing of hard-gelatine capsules (Digenis et al. 1994).
`
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`

`250
`
`Pharmaceutical Preformulation and Formulation
`
`Figure 7.3 In vitro dissolution-time profiles of a poorly soluble compound, felodipine, for
`three different hydrophilic matrix extended release tablets (A-C) when three different
`surfactants (SLS, CTAB, Tween) were used in the dissolution test medium at levels
`providing "sink conditions·:
`
`a) SLS
`100
`80
`
`-g 60 m
`CD a; 40
`a:
`cf.. 20
`0
`0
`
`m 0
`
`1
`
`2
`
`3
`4
`Hours
`
`5
`
`6
`
`7
`
`8
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`b) TWEEN
`100
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`Q) g) 60
`Q) a;
`a::
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`c) CTAB
`100
`~ 80
`m so
`en
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`This material \Vas. copied
`at the NLM a nod may be
`Subject US Copyright Laws
`
`

`

`Biopharmaceutical Support in Formulation Development
`
`251
`
`Example 2
`The ionic concentration in the test medium can affect both the drug solubility and the release
`mechanism for modified-release formulations. One example of the latter case is hydrophilic
`gel matrix tablets, a type of ER tablet that forms a gel layer in contact with the GI fluids.
`Solutes will affect the hydration of the gel matrix and, thereby, affect the drug release rate.
`It has been shown for such tablets that the correlation to in vivo data can be completely lost
`by use of inappropriate ionic compositions in the test medium (Abrahamsson et al.l998a). For
`ER formulations with osmotically driven drug release, a decreased drug release rate approach-
`ing no release will occur for high ionic concentrations in the test medium, and misleading in
`vitro results may be obtained if a relevant ionic composition is not used (Lindstedt et al. 1989).
`The concern for variability in dissolution results is of special significance when setting up
`a specification test method to be used for batch release but may also be considered for other
`tests. In order to reduce variability in dissolution results due to the test medium, the quality
`aspects of the dissolution media components that could affect the drug dissolution and release
`must be identified, and appropriate qualities of the components should be defmed. This is es-
`pecially important for the use of surfactants to provide micellar solubilisation in the test
`medium (Crison et al. 1997). Another potential source of variability is impurities in the com-
`ponents that may alter the solubility or catalyse degradation of labile drugs. It is also impor-
`tant to see that the dissolution test medium is stable, i.e., that the components are not
`degraded or precipitated during the dissolution test period. This is of no concern for plain
`buffer systems but is more relevant for complex media including physiological components.
`Dissolved air in the dissolution medium could, under certain circumstances, be located as
`air bubbles on the surface of the dosage form or released solid material. This will clearly affect
`the dissolution process by reducing wetting and the available surface area for dissolution in an
`uncontrolled way. In order to avoid this problem, the dissolution media has to be deaerated.
`A method for deaeration based on heating and filtration can be found in USP XXIV. Other
`methods have also been described (Diebold and Dressman 1998). It is, however, important to
`realise that the reaeration of deaerated water is a rapid process. The oxygen content increases
`significantly during filling of th