Water-Insoluble
`Drug
`Formation
`
`Rong Liu
`
`Editor
`
`Interpharm Press
`Denver, Colorado
`
`
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`
`R S
`
`203'
`E
`N
`
`J M
`
`Invitation to Authors
`
`E Interpharm Press publishes books focused upon applied technology and regulatory
`”’ affairs impacting healthcare manufacturers worldwide.
`It you are considering
`writing or contributing to a book applicable to the pharmaceutical, biotechnology,
`medical device, diagnostic, cosmetic, or veterinary medicine manufacturing industries,
`please contact our director of publications.
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`
`
`Library of Congress Cataloging-in-Publication Data
`
`Water—insoluble drug formation / Rong Liu, editor.
`p. cm.
`Includes bibliographical references.
`1. Solutions (Pharmacy) 2. Drugs—Solubility. I. Liu, lung.
`
`RS201.S6 W38 2000
`6 l5’.42—dc2 l
`
`10987654321
`
`ISBN: 1—57491—105—8
`
`00-033450
`
`Copyright © 2000 by Interpharm Press. All rights reserved.
`
`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, pho-
`tocopying, recording, or otherwise, without written permission from the publisher. Printed in
`the United States of America.
`
`Where a product trademark, registration mark, or other protected mark is made in the text,
`ownership of the mark remains with the lawful owner of the mark. No claim, intentional or oth-
`erwise, is made by reference to any such marks in this book.
`While every effort has been made by Interpharm Press to ensure the accuracy of the informa-
`tion contained in this book, this organization accepts no responsibility for errors or omissions.
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`
`| This material may be protected by Copyright law (Title 17 US. Code)
`
`|
`
`Alteration of the Solid State of the
`Drug Substance: Polymorphs,
`Solvates, and Amorphous Forms
`
`Michael]. Iozwiakowski
`3M Pharmaceuticals
`
`St. Paul, Minnesota
`
`The maximum solubility of a drug substance is a function of the nature of the solid
`
`phase in equilibrium with a specified solvent system at a given temperature and pres»
`sure. Solubility is an equilibrium constant for the dissolution of the solid into the sol-
`vent and thus depends on the competition of solutezsolvent interactions and
`solicksolid interactions. Alteration of the Solid phase of the drug substance can influ-
`ence its solubility and dissolution properties by affecting the molecular interactions
`in the solid.
`
`A crystal of higher free energy will yield an apparent higher solubility than a lower
`energy stable crystal form of the same molecular structure. In the lowest energy solid
`state, the energetically favorable solid:so1id interactions reduce the escaping tendency of
`the molecules, and thus fewer molecules dissolve in a given solvent under the same set
`of environmental conditions. Crystalline polymorphs, solvates and hydrates. and amor-
`phous forms of drug substances have been used to change the thermodynaniic driving
`force for dissolution and to increase the apparent solubility of poorly soluble drugs.
`Unlike solubilization techniques that change the nature of the solvent environ-
`ment (cosolvent systems, emulsions, rnicellization] or the chemical identity of the dis-
`solved solute [salt formation, cornplexation, pro—drugs), manipulation of the solid state
`of the drug substance results in only a transient change in the system. Since the solvent
`
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`
`526 Water—Ins0lLLb.le Drug Formulation
`
`and the chemical form are identical, the system will ultimately revert to the lowest-
`energy solid phase in equilibrium with the solvent, with the lowest solubility. Crystal
`growth and dissolution have been used to assign relative physical stability for poly-
`morphs by observing the direction of the transformation under a microscope under
`controlled temperature in contact with a solvent. The rate of transformation in contact
`with a solvent is normally too fast to consider solution or suspension dosage forms of
`metastable solids. Systems with unusually large energy barriers, slow reversion kinet-
`ics, or excipients to retard crystallization can be useful in limited circumstances.
`The most practical use of this technique is to alter the solid phase in dry dosage
`forms where molecular mobility is greatly reduced. Metastable forms of solid drugs
`are often stable to physical transformation in the time context required for marketable
`formulations. Tablets, capsules, lyophilized powders, granules for constitution, and
`other solid dosage forms are ideal systems for incorporation of metastable solid
`phases. In most cases, the brief exposure to gastrointestinal (GI) fluids does not result
`in conversion to the lower solubility form prior to generating the desired enhanced
`effect. Solid—state transformations and transformations induced by adsorbed water
`during long—term storage can still be problematic. Any consideration of formulating
`metastable solid phases must balance the expected gain in efficacy with the potential
`for reversion to the less—fav0rable form prior to patient use. This involves both an
`understanding of the phase diagrams (which forms are physically stable under which
`conditions) and the physical principles governing transformation kinetics.
`In this chapter, the theoretical and practical considerations for the use of
`metastable solids in formulations to gain a solubility or dissolution-rate advantage are
`explored. Experiments are suggested that identify the potential solid forms of the drug
`and elucidate the potential advantages and disadvantages. Specific examples of the
`degree of enhancement that can be expected and special considerations for each type
`of solid are covered (polyrnorphs, solvates, and amorphous forms).
`
`THEORETICAL AND PRACTICAL CONSIDERATIONS
`
`Importance of the Solid State of the Drug
`
`Origin of the Effect 0fS0lid State on Solubility
`
`When a medicinal chemist discovers a new chemical entity (NCE) with a desired phar-
`macological effect, structure—activity relationships are used to optimize the series for
`activity. Aqueous solubility, partition coefficient, crystallinity, melting point, particle
`size, and hygroscopicity, all of interest to the formulator of this NCE, will also vary
`within the series of drug candidates. Because the biological activity is often estimated
`by target enzyme binding studies in very dilute media, solubility may not be opti-
`mized simultaneously. If an ionizable drug candidate is selected, the choice of free
`acid/base form versus the salt forms again produces a myriad of possible physical
`properties. The alteration of solubility by judicious choice of the salt was covered in a
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`
`Alteration of the Solid State of the Drug Substance 527
`
`previous chapter. In many cases the chosen salt or acid/ base can crystallize in a vari-
`ety of possible arrangements, each of which has the possibility of different physical
`properties. This includes the possibility of polymorphs, solvates, or noncrystalline
`(amorphous) forms. Thus, the solid phase chosen for development is the third deci-
`sion made by the pharmaceutical scientists that has a major impact on the ultimate
`physical properties of the NCE, including the solubility. In a typical development pro-
`gram, the number of candidates decreases at each stage:
`
`Stage 1. Selection of best chemical structure (100-1000)
`
`Stage II. Selection of acidlbasel salt form (3-25)
`
`Stage III. Selection of solid phase for development (1-3)
`
`Each of these stages produces molecules of Varying solubility by virtue of a change in
`the crystalline lattice, the last stage being the only one in which the chemical identity
`or counterion identity is unchanged.
`Yalkowsky (1981) has developed equations describing solubility as a function of
`both hydrophobicity and crystal lattice forces. This has led to the observation that
`melting point or heat of fusion, both a function of the strength of forces holding mole-
`cules together in the solid state, can correlate with solubility within a homologous
`series. This is because the disruption of the crystal forces is a necessary prerequisite to
`the release of individual molecules into the solvent for dissolution. Grant and Higuchi
`(I990) summarized correlations in the case of diphenylhydantoin derivatives and
`substituted pteridines in their book on organic compound solubility. Wells (1988) has
`noted that in the series of phenols with hydroxy substituents, the high-melting para-
`form (hydroquinone) has a much lower solubility than the ortho— or meta-derivatives.
`Morelock et al. (1994) have used melting points and retention times to correlate with
`aqueous solubility in a series of reverse transcriptase inhibitors. They have found this
`useful in selecting the drug candidate that can possess optimum biological parame-
`ters and in guiding the further synthetic effort. The same factors can govern the solu-
`bility differences between drug—salt forms or solid phases, since, fundamentally, the
`change is brought about by a difference in solidzsolid forces in each case. Wells (1988)
`has shown that riboflavin polymorphs follow a similar inverse correlation with melt-
`ing point. Form 111 melts at 180° to 185°C and is soluble to greater than 1000 mg/mL in
`water. Forms I and II melt at 270° to 290°C and have solubilities of less than 100 mg/ mL.
`The success of altering solubility by manipulating the solid phase of the drug
`depends on which factor dominates the aqueous solubility behavior, the hydropho-
`bicity, or the lattice forces. When the molecule is too lipophilic to have adequate
`aqueous solubility, cosolvents, pro—drugs, or emulsions are effective in increasing the
`solubility. Altering the solid state in this case may have little effect on its solubility,
`since poor aqueous solubility is due to the molecular lipophilicity. In contrast, cosol-
`vents and emulsions do not have much impact if the reason for low solubility is the
`stability of the crystal lattice. When a drug has low solubility and a high melting point
`(>250°C), it is likely that disruption of the lattice is needed to increase the effective
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`
`528 Water—Insoluble Drug Formulation
`
`form (polymorphs or
`solubility. This can be done by altering the crystal
`solvatesl hydrates) or by producing the amorphous form and stabilizing it to sponta-
`neous crystallization. The effect of altering the salt form of the drug is discussed in a
`separate chapter and has also been reviewed by Berge, Bighly, and Monkhouse
`(1977).
`
`Historical Perspective and Definitions
`
`The effect of the solid state on drug solubility has been known for decades, and pio-
`neer articles by Haleblian and McCrone (1969); Shefter and Higuchi (1963); and
`
`Higuchi et al. (1963) have formed the basis for further studies in this area. More recent
`reviews by Shefter (1981), Abdou (1989), Byrn (l982),Wa1l (1986), Brittain (1995), and
`Fiese and Hagen (1986) have summarized the effects of polymorphism or solvate for-
`
`mation on drug solubility. The existence of different internal crystalline arrangements
`for the same chemical structure has been termed polymorphism. Verma and Krishna
`(1966) have observed that the great majority of substances seem to be capable of mul-
`tiple solid states. The work of Kuhnert—Brandstatter in steroids and barbiturates (as
`reviewed by Haleblian and McCrone 1969) seems to indicate that simple organic drug
`molecules with multiple functional groups can arrange into numerous crystal-
`packing structures. McCrone, McCrone, and Delly (1987); Carstensen (1993); and Byrn
`(1982) have reviewed the seven different crystal systems, which are uniquely identi—
`fied by the length of the axes and the angles between them in the unit cell. Many drugs
`crystallize into multiple polymorphic forms, especially monoclinic,
`triclinic, or
`orthorhombic types (Wall 1986; Borka and Haleblian 1990; Giron 1995); this relatively
`common diversity in solid forms gives the formulation scientist variations in physical
`
`properties to exploit.
`In general, the crystalline form with the closest packing (greatest density) and
`the highest melting point is the stable form. The stable form will have the lowest sol-
`
`ubility and the lowest free energy of the different solid phases of the drug. All other
`phases with the same composition are termed metastable forms at this temperature
`and pressure. In practical terms, the energy barrier for conversion to the stable form
`can be high enough that the metastable forms can be examined and formulated. This
`is especially true if the free energy difference is small (leading to a small driving force)
`or if significant bond breaking, molecular motion, and bond formation are required
`for transformation.
`'
`
`If the crystals contain solvent molecules within the lattice structure in defined
`locations and stoichiometry, these are referred to as solvates (hydrates if the solvent is
`water). The term pseudopolymorph has been used historically but is not as specific
`and should be avoided if the composition is known. In most cases, the solvated form
`of the drug is the least—soluble form in that solvent (e. g., hydrates are the low-energy
`forms in water). Due to additional mixing terms, solvates are often more soluble in a
`solvent of different composition than the nonsolvated crystal (Shefter and Higuchi
`1963). The types of solvates that appear in pharmaceutical systems and their proper-
`ties of interest are covered later in this chapter.
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`
`Alteration of the Solid State of the Drug Substance 529
`
`Amorphous forms can be made for most pharmaceuticals by producing the solid
`form faster than the molecules can arrange into a crystalline lattice. Noncrystalline
`solids may have some short—range order but lack the long—range periodicity and reg-
`ular intermolecular bonding of crystalline solids. Their synthesis and properties differ
`markedly from their crystalline forms, as will be described in detail in the section on
`amorphous drugs. In general, amorphous forms are high-energy, low-density solids
`that can yield transient dissolution rates much greater than crystalline solids.
`Liquid crystals are an intermediate state in which the molecules in a crystal can
`undergo a secondary phase transition to a mesophase, which gives them mobility in
`one or two directions. They are birefringent but possess flow properties like a liquid
`phase. Lyotropic liquid crystals forrn upon uptake of water into a system, which
`increases its mobility, and thermotropic liquid crystals can be disrupted by heating
`above a transition temperature. Cromolyn sodium (Cox, Woodard, and McCrone
`1971), the HMG-CoA reductase inhibitor SQ 33600 (Brittain, Ranadive, and Serajuddin
`1995), and the leukotriene D4 antagonist L 660,711 (Vadas, Toma, and Zografi 1991)
`are examples of pharmaceuticals that can form liquid crystals.
`The crystal habit or external shape may differ when drugs are recrystallized from
`different solvent systems without changing the internal structure. The presence of
`additives, the rate of cooling, the degree of agitation, and the degree of saturation can
`all affect crystal habit (Byrn 1982). Habit can affect bulk properties such as density and
`flowability (Carstensen 1993) or influence the ability to filter crystals during purifica-
`tion. Chow and Grant (1988) have shown that the dissolution rate of acetaminophen
`can be altered two or three times by modifying the length-to—width ratio through
`incorporation of additives. In general, habit effects on solubility are transient and of a
`magnitude equivalent to particle-size—reduction techniques.
`In summary, most drugs are developed as crystalline forms, which have the
`greatest physical and chemical stability, so that their purity can be increased during
`recrystallization. Knowledge of the potential polymorphic forms may allow the devel-
`opment scientist to find a metastable form with the prerequisite stability and
`increased dissolution rate to make it the desirable marketed form. Anhydrate forms
`usually give faster dissolution rates and higher aqueous solubilities than the hydrated
`form. Other solvates are not commonly used in pharmaceutical systems due to poten-
`tial toxicity of the solvent but may provide additional solubility enhancement. Amor-
`phous forms have the highest free energy with the greatest degree of solubility
`enhancement but are the most difficult to stabilize against transformation to the sta-
`ble crystal form. The remainder of the chapter describes the advantages and disad-
`vantages of each type of solid and gives numerous examples from the pharmaceutical
`literature where alteration of the solid form resulted in increased solubility.
`
`Methods to Study the Solid State daring Preformulation Screening
`
`After initial selection of the candidate drug and its salt form (if applicable), it is rec-
`ommended that a purposeful effort be undertaken to examine the solid states avail-
`able for development consideration. In the absence of such programs, new crystalline
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`
`530 Water—In5oluble Drug Formulation
`
`forms may be discovered by accident from precipitation of less-soluble phases or a
`
`change in appearance of the bulk drug during scale-up. If sufficient formulation, ana-
`lytical, and toxicology work has been completed and it becomes necessary to change
`the solid state, it may significantly delay the development program. If the newly dis-
`covered form is the more stable modification, it may be difficult to reproduce the
`metastable form. Carstensen (1993) noted that the diazepam tablet development pro-
`
`gram was complicated by the crystallization of a more stable polymorph after clinical
`trials had begun. If both forms can still be synthesized and they prove to be bioequiv—
`alent,
`the consequences of changing the form later in development are greatly
`reduced.
`
`A recent publication by Byrn et al. (1995) suggests a minimal preformulation
`program for examining the drug solid state and the regulatory implications of various
`scenarios. The information that may be useful at this early phase includes the
`
`- Number of solid phases that exist for this drug
`
`0 Relative physical and chemical stability of these phases
`
`0 Solubility of each form in relevant media
`
`° Resistance of metastable forms to conversion during processing
`
`- Possible means to stabilize amorphous or metastable forms, if needed
`
`Another major consideration at this point is to decide on the patentability of any
`new crystal forms discovered to have significant practical advantages over those in the
`original patent. Byrn and Pfeiffer (1992) have listed >350 patents on crystal forms in
`the pharmaceutical patent literature granted for showing advantages in terms of sta-
`bility, formulation, solubility, bioavailability, purification, hygroscopicity, preparation/
`synthesis, recovery, and prevention of precipitation.
`Different crystal forms can be sought by recrystallization experiments varying
`the solvent system, temperature, precipitation method, and level of supersaturation.
`Precipitation methods may include slow evaporation of the solvent, addition of anti-
`solvents, or saturation at high temperatures followed by cooling. The solvent systems
`chosen for study are one of the key aspects of these experiments. Water must be
`included because of its physiological significance, the possibility of contamination of
`crystallization solvents, and the possibility of moisture uptake during storage. Cer-
`tainly the usual recrystallization solvents for the drug synthesis and purification
`scheme and any alternate systems that may be used for scale-up of this process
`should also be studied. Mixtures used in the final steps of the synthetic process should
`be examined, including azeotropes and solvents with small amounts of miscible
`water. A suggested list for solvents that have been known to produce different crys-
`talline forms is provided in Table 15.1 (Wells 1988; Byrn and Pfeiffer 1992; Byrn et al.
`1995).
`
`Solid forms isolated from these systems should be subjected to characterization
`techniques such as hot—stage or polarized light microscopy, differential scanning
`calorimetry [DSC),
`thermogravimetric analysis (TGA), X—ray diffraction (XRD),
`
`
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`
`Alteration of the Solid State of the Drug Substance
`
`531
`
`Table 15.1
`
`Partial List of Solvents for Preformulation Studies Looking
`for Different Crystal Forms
`
`Water
`
`Ethanol
`Acetone
`
`Methanol
`
`Isopropanol
`Acetonitrile
`
`Ethyl acetate
`Dimethylformamide
`Diethyl ether
`
`Hexane
`Methylene chloride
`Glacial acetic acid
`
`Any other solvents used in the last steps of synthesis
`Aqueous mixtures with the above
`
`infrared spectroscopy (IR), FT-Raman spectroscopy, and solid—state nuclear magnetic
`resonance (NMR). The solubility of each new form isolated should be studied in water
`or the solvent/solution of pharmaceutical interest. Composition versus vapor pres-
`sure data should be obtained to understand the stability of any hydrated forms with
`respect to the anhydrate and other stoichiometric hydrates. If the transition to the
`stable form is fast, intrinsic dissolution measurements can be used to estimate the rel-
`
`ative solubilities of new crystal forms.
`The method used to identify new solid phases depends in part on the expertise
`of the investigator and the availability of equipment and in part on the properties of
`the solid phases. Haleblian and McCrone (1969) have demonstrated the power of the
`polarized light microscope and hot—stage microscope in studying the phase relation-
`ships between solid forms versus temperature. Byrn (1982), Wall (1986), and Surya-
`narayanan (1989) have noted that only X—ray diffraction and single crystal X-ray stud-
`ies uniquely identify a solid phase unambiguously, since other methods depend on
`properties that may or may not change with a change in crystal lattice structure. If the
`new phase is a solvate, additional techniques are needed to identify the solvent of
`crystallization and its stoichiometry. Differential scanning calorimetry has been used
`extensively in polymorph investigations since the melting point is often the first indi-
`cation of a new crystalline form (Giron 1995). Other phenomena such as solid~state
`transitions and water-loss endotherrns are often discernible from the thermogram.
`
`Lindenbaum and McGraw (1985) have shown how solution calorimetry can be used
`to assign relative enthalpy differences between polyrnorphs of drugs. It is best to use
`a combination of techniques to elucidate the nature of the new crystal forms, as one
`technique may not be able to differentiate the forms. For example, the two polymor-
`phic forms of arniloride HCl dihydrate could not be distinguished by IR spectra or
`microscopic morphology (lozwiakowslci, Williams, and Hathaway 1993) but are easily
`identified by X-ray diffraction.
`If a metastable form is identified that may be needed to produce the desired or
`optimal pharmacological effect, further studies should be done to define the relative
`stability of this form and the proper storage conditions to prevent conversion. A
`metastable form should not be used when the more stable crystalline form produces
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`
`532 Watenlnsoluble Drug Formulation
`
`the desired effects; in this case the potential benefits probably do not offset the risk of
`conversion between production of the drug pro duct and patient use. The stresses dur-
`ing manufacture of the product need to be studied as well, since compression,
`milling, granulation, and lyophilization can all change the solid state of the drug
`between synthesis and formulation. In some cases, appropriate precautions, resistant
`packaging, or stabilizing excipients can keep the drug in the optimum form despite its
`metastability. Once some of these properties are known, a rational decision can be
`made on whether to proceed with development of a metastable solid based on a ther-
`apeutic need.
`
`Properties Dependent on the Solid State
`
`Once the different solid phases have been identified, their physical properties can be
`compared to find the form that is optimum for drug product development. Verma
`(1966) described polymorphic forms of common substances that illustrated how their
`physical properties can be quite different. The cubic form of carbon (diamond) is
`hard, dense (3.5 g/ cc), brilliantly clear, and a poor conductor. In contrast, the hexago-
`nal form of the same element (graphite) is soft, less dense (2.2 g/cc), dull in appear-
`ance, and a good conductor. Optical properties of different solid forms can change
`their color; mercuric iodide is red (tetragonal form) or yellow (orthorhombic form).
`Drug substances, which tend to be larger organic molecules with multiple
`hydrogen bonding sites, are especially prone to different crystalline arrangements
`that produce variable physical properties. Table 15.2 lists physical and chemical prop-
`erties of pharmaceuticals that have been cited in the literature as depending on the
`solid state of the drug. Some of these may provide significant advantages in drug
`development. Form I of celiprol HCl is much less hygroscopic than the form II poly-
`morph (Narurkar et al. 1988). Form A chlorprop amide forms tablets with greater hard-
`ness than those of form C under identical compression forces (Matsumoto et al. 1991].
`Phenobarbitone also has crystalline forms that differ in compressibility profiles (Shell
`1963). The two polymorphs of methylprednisolone have different chemical stability
`profiles when exposed to identical temperatures and humidities of storage (Munshi
`and Simonelli 1970). Crystal size and shape can alter the filterability or syringeability
`of suspensions and affect the weight uniformity of tablets and capsules.
`
`Properties of Drug Substances Dependent on the Solid State
`
`Table I 5.2
`
`Dissolution rate
`Chemical stability
`Melting point
`Particle size/shape
`Hygroscopicity
`Filterability
`Tablet hardness
`
`Solubility
`Bioavailability
`Flowability
`Compressibility
`Density
`Suspension viscosity
`Color
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`
`Alteration of the Solid State of the Drug Substance 533
`
`While there are numerous examples of miscellaneous physical property differ-
`ences between different solid phases of the same drug substance, the excess free
`energy of metastable states is the most important. The higher energy state, a conse-
`quence of decreased crystal lattice energy, produces a greater molecular mobility and
`thermodynamic escaping tendency in metastable solids. This leads to faster dissolu-
`tion rates and greater solubilities, which can have formulation and therapeutic impli-
`cations for pharmaceuticals. Drugs with poor aqueous solubility are more likely to
`show enhanced bioavailability when metastable solids are used, because their oral
`absorption tends to be dissolution-limited.
`
`Advantages of Using Metastable Solids
`
`Dissolution Rate Improvement
`
`The Noyes—Whitney equation for the dissolution of solids into a solvent (Noyes and
`Whitney 1897) can be used to calculate the rate of drug concentration C increase with
`time t:
`
`E = I<'A(C — C)
`dt
`3
`
`(1)
`
`where A is the surface area of the solid exposed to solvent, CS is the saturation con-
`centration or solubility, and K is a constant including the diffusion coefficient of the
`solute, the thickness of the unstirred diffusion layer, and the volume of solvent. Rotat-
`ing die methods have been developed, such as the Wood’s die apparatus, which main-
`tain a constant surface area during the initial phase of dissolution experiments. Under
`sink conditions, where C5 >> C, and with constant surface area A, the intrinsic disso-
`lution rate (IDR) can be obtained. The IDR (units mg/cmz / min) is directly propor-
`tional to solubility and depends on the intrinsic dissolution properties of the drug in
`the media, not the dissolution method:
`
`IDR : K (Cs)
`
`(2)
`
`Changes in the solid state can influence the dissolution rate through the surface
`area term or the solubility term. Surface area differences can arise from simple particle
`size effects between different crystal forms and also from shape factors. Different crystal
`habits and shapes can alter the exposed surface area without a change in median parti-
`cle size measurements, since these are often calculated by methods that assume spher-
`ical shapes. Abdou (1989) has reviewed the effect of crystalline state on the dissolution
`rate of pharmaceuticals and how this contributes to bioinequivalence of various forms.
`Differences in solubility between different crystal forms alter the driving force for
`dissolution, controlled by the difference between the solution concentration and the
`saturation concentration (C: — C‘). Hamlin, Northam, and Wagner (1965) have shown
`that dissolution rate correlates well with solubility for a large number of pharmaceu-
`tical compounds varying in solubility from 0.01 to 10 mg/mL at 37°C. Nicldasson and
`
`DEFs-JT(Daru) 010476
`
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`
`

`
`534 Water—Ins0luble Drug Formulation
`
`Figure 15.1 Dissolution rates for anhydrous and hydrated [3-cyclodextrin in water at
`40° C. [Source: Reprinted from Carbohydrate Research, Vol. 143, by Iozwiakowski and
`Connors, Aqueous Solubility of Three Cyclodextrins, pp. 51-59, Copyright 1985, with
`permission from Elsevier Science.)
`
`
`
`Solubility(molar)
`
`°—® Anhydrous
`
`o—o Hydrate
`
`0.024
`
`30
`
`90
`
`180
`
`30
`
`Time (min)
`
`Brodin (1984) have shown that using cosolvent mixtures for drugs with poor aqueous
`solubility produces a good correlation between dissolution rate and solubility.
`The dissolution rate improvement for most metastable solids is only transient;
`ultimately the excess solid in equilibrium with the solvent converts to the lowest
`energy phase. Figure 15.1 (lozwiakowski and Connors 1985) illustrates a typical disso-
`lution profile for a metastable solid and a stable solid. In this case, [3—cyclodextrin dis-
`solution profiles were measured in 40°C distilled water and plotted on a molar basis
`(where the molecular weight difference is inconsequential). The concentration of the
`stable form in water at room temperature (a dodecahydrate) gradually increases to
`the limit of its solubility (0.0298 M).
`The metastable form (the anhydrate from oven drying) shows a rapid initial dis-
`solution rate over the first 10 min, peaks at less than 30 min, and then declines to the
`solubility limit as the excess solid converts to the hydrated form, as verified by
`microscopy. The same behavior is exhibited by metastable and stable polymorphic
`forms, e.g., form I and form 11 of meprobamate (Clements and Popli 1973) and form I
`and form II of gepirone HCI (Behme et al. 1985). Ultimately, the same equilibrium sol-
`ubility will be reached regardless of the direction of approach, although the kinetics of
`this transition can vary considerably for different drugs.
`Dissolution rate improvement is often characterized by the intrinsic dissolution
`rates or the change in the initial rate, since in many cases the advantage decreases
`with time. Table 15.3 shows some data from the pharmaceutical literature that indi-
`cates the typical dissolution rate increases that can be obtained by altering the solid
`
`DEFs-JT(Daru) 010477
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`Janssen Ex. 2020
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`
`(Page 12 of 46)
`
`

`
`Alteration of the Solid State of the Drug Substance 535
`
`Table 1 5.3
`
`Comparison of Initial Dissolution Rates of Drugs upon Alteration
`of the Solid State
`
`Drug
`
`Solid Form
`
`Relative Rate
`
`Reference
`
`Sulphathiazole
`
`Tegafur
`
`Diflunisal
`
`II
`I
`III
`
`or
`[3
`y
`I
`II
`III
`IV
`
`Iopanoic Acid
`
`Amorphate
`II
`I
`
`2.3
`1.6
`1.0
`
`1.0
`1.2
`1.0
`1.4
`1.4
`l.3
`1.0
`
`9.5
`1.6
`1.0
`
`Lagas and Lerk (1981)
`
`Uchida et al. (1993)
`
`Martinez-Oharriz et al. (1994)
`
`