`
`
`Solid—State Chemistry
`of Drugs
`
`SECOND EDITION
`
`Stephen R. Byrn
`Ralph R. Pfeiffer
`loseph G. Stowell
`
`° West Lafayette, Indiana
`SSCI, 1nc.
`www.ssci—inc.com
`
`
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`|PR2016-00006
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`SteadyMed - Exhibit 1027 - Page 1
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`IPR2016-00006
`SteadyMed - Exhibit 1027 - Page 1
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`5.1
`
`THERMOGRAVIMETRIC ANALYSIS (TGA)
`
`and measuring the change in some physical property. The most important
`thermal methods for the study of solid-state chemistry are thermogravimet-
`ric analysis (TGA), differential scanning calorimetry (DSC), and thermal mi-
`croscopy (discussed in Section 4.4). Therrnogravimetric analysis measures the change
`in the mass of sample as the temperature is changed. Differential scanning calorimetry
`
`
`involves measuring the difference between the temperature of the sample and 3 refer-
`
`
`ence compound as the temperature of the system is changed, thus providing informa—
`
`
`tion on the enthalpy change of various solid-state processes. Thermal methods of
`
`
`analysis are important analytical tools for characterizing pharmaceutical solids. The use
`
`
`of TGA and DSC in conjunction with thermal microscopy (Section 4.4) can elucidate
`
`many behaviors of solids.
`
`Basically, a thermogravimetric instrument consists of a microbalance connected to a
`
`sample compartment situated in a small oven with computer-controlled temperature
`
`
`programming. A dry nitrogen atmosphere is most commonly used, however, other
`
`
`gases can be employed (the compostion and flow dynamics of the gas are important
`
`
`parameters.) This method measures the change in mass with temperature and is often
`
`
`used to study the loss of solvent of crystallization or other solid —) solid + gas reac-
`
`
`tions. A typical TGA trace is shown in Figure 5.1. In studies of solid-state chemistry,
`
`
`TGA is usually performed in one of three modes:
`
`
`1 . Isothermal mode——the temperature is kept constant.
`2. Quasi-isothermal mode—the sample is heated to a constant mass
`
`
`
`
`through a series of increasing temperatures.
`
`
`3. Dynamic mode—the temperature is raised at a known rate, typi—
`
`cally linear.
`
`Thermal Methods
`
`of Analysis
`
`‘ l
`
`hermal analysis generally refers to any method involving heating the sample
`
`
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`|PR2016-00006
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`Chapter 5 Drugs as Molecular Solids
` 82
`TGA. Obvious]
`
`reaction and the
`
`
`
`mass loss
`
`
`’
`
`I,
`'
`
`time. These plot:
`also been used 1
`
`general, the kinei
`thermogravimetrj
`desolvation of or
`
`
`
`5.2 DIFFEREN'
`
`i
`
`*3J“
`
`
`
`
`
`
`
`
`s of the type shown in Equation 5.1 can
`
`be determined using
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`|PR2016-00006
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`SteadyMed - Exhibit 1027 - Page 3
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`Differential scan
`energy (heat flu:
`DSC sample cor
`The result c
`
`
`
`
`
`state mass loss with T, (the transition temperature)
`
`ding to the point at which tangents to the original
`fl
`Figure 5.1 A typical TGA trace for a single-
`marked. The temperature correspon
`he transition temperature T,.
`baseline and to the slope of the tracing represents t
`
`
`
`emperature regions where no weight
`
`
`The last approach uses high heating rates in t
`here weight changes do occur, thus
`low rates in regions w
`
`
`changes are occurring and s
`g of peaks from overlapping
`avoiding transition temperature overshoot and blurrin
`
`
`
`
`transitions.
`
`
`ber of factors or conditions that affect TGA curves including the
`
`
`There are a num
`f the sample holder (pan), particle size of the
`
`
`heating rate, atmosphere, geometry 0
`t of the sample, thermal conductivity of the
`
`
`sample, nature of the reaction, treatmen
`
`
`sample, and sample weight. The effect of the heating rate has been extensively studied
`(Wendlandt, 1974).
`In general, as the heating rate is increased, the apparent starting
`temperature of the thermal event (Ti) increases. However, this condition can some-
`
`
`
`
`times be corrected by decreasing the sample size.
`For example, an
`The atmosphere can have a dramatic effect on the TGA curve.
`T,- or stop the reaction
`oduct gas can increase
`
`
`f the reaction, particu-
`atmosphere already containing the pr
`he atmosphere can change the course 0
`r the reactant. Knowledge
`completely. In addition, t
`
`
`r the products 0
`
`
`larly if the atmospheric gas reacts with eithe
`RH) is essential to
`
`
`onds to changes in relative humidity (
`
`
`of how the substance resp
`started. For these reasons,
`it is a
`dling of the sample before the scan is
`
`
`
`
`proper han
`ere of dry nitrogen when performing a study.
`prudent practice to use an atmosph
`
`
`the particle size of the sample has
`ton the reaction mechanism,
`Although dependen
`The smaller the particle size,
`the
`
`
`TGA curve in general.
`
`
`cause the smaller particle
`a predictable effect on the
`the lower the value of Ti. This is be
`faster the reaction and
`the nature of the reaction
`
`
`e of the product gas. Obviously,
`
`
`sizes allow more rapid escap
`r for more facile reactions.
`
`
`affects T; which will be lowe
`particular the extent of compression
`In addition, the treatment of the sample, and in
`pression will
`feet the Ti. For example, increased com
`of the sample, will obviously af
`11 have less opportunity to escape.
`
`
`increase T,- since the product gas wi
`ty of the sample will influence T,-. Anomalous ef-
`
`
`Finally, the thermal conductivi
`ature of the sample is not uniform because of poor
`fects may be obtained if the temper
`thermal conductivity.
`The rates of reaction
`
`
`.
`
`f
`
`
`
`
`
`
`
`Hall? 5.2 Cros:
`are [N
`
`
`
`
`
`
`. 5.3 A hyp
`sampl
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`SteadyMed - Exhibit 1027 - Page 3
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` 33
`5.2 Differential Scanning Calorimetry (DSC)
`
`
`TGA. Obviously, isothermal TGA traces can be used to determine the rate of the
`'mply plotting weight loss versus
`reaction and the rate law governing the reaction by 51
`
`
`
`
`time. These plots can then be analyzed as described in Chapter 3. Dynamic TGA has
`
`
`also been used to determine the rates of such gas—evolving reactions. However, in
`general, the kinetic data thus obtained should be substantiated by other data. Isothermal
`
`
`thermogravimetric analysis has been used extensively in our laboratory to study the
`
`
`
`
`desolvation of crystal solvates (Chapter 16).
`solid
`A
`'—-’ B
`
`
`5.2 DIFFERENTIAL SCANNING CALORIMET
`
`
`Differential scanning calorimetry (DSC) is a method which measures the difference in
`energy (heat flux or heat
`) and a sample (S). A typical
`
`
`flow) between a reference (R
`DSC sample compartment is shown in Figure 5.2.
`
`
`The result of a DSC analysis is a thermogram, a plot of AT = T, — T, (temperature
`
`
`solid
`
`+ C
`
`gas
`
`RY (DSC)
`
`outer lid
`
`(5.1)
`
`.u
`
`l
`
`i
`
`(the transition temperature)
`rich tangents to the original
`on temperature T,.
`
`:gions where no weight
`1t changes do occur, thus
`peaks from overlapping
`
`‘GA curves including the
`mm), particle size of the
`:rmal conductivity of the
`5 been extensively studied
`ised, the apparent starting
`this condition can some—
`
`curve. For example, an
`e T, or stop the reaction
`se of the reaction, particu—
`: the reactant. Knowledge
`ridity (RH) is essential to
`For these reasons,
`it is a
`)erforming a study.
`ticle size of the sample has
`naller the particle size, the
`>ecause the smaller particle
`y, the nature of the reaction
`
`it the extent of compression
`increased compression will
`to escape.
`fluence Ti. Anomalous ef-
`lOt uniform because of poor
`
`
`
`inner DSC
`cell lid
`
`
`
`therrnopile
`iunction
`
`
`
`silver
`furnace
`elements
`
`body
`
`
`to op amp
`
`
`The sample pan (S) and the reference pan (R)
`
`
`1996).
`Figure 5.2 Cross section of a Cahn® DSC 4000 cell.
`are positioned in the sensor (Cahn Instruments,
`
`
`
`
`
`
`
`l Exotherm
`
`Time
`
`
`
`re 5.3 A hypothetical DSC thermogram showing the changes that might occur upon heating a
`
`
`Figu
`sample.
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`|PR2016-00006
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`SteadyMed — Exhibit 1027 — Page 4
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`5.1 can be determined using
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`IPR2016-00006
`SteadyMed - Exhibit 1027 - Page 4
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`84
`
`hi
`w
`M
`
`fl
`. M
`
`i
`I
`
`a
`1
`
`.
`
`
`
`
`
`Based on this wc
`of fusion rule
`
`
`
`Chapter 5 Drugs as Molecular Solids
`desolvation process
`
`5.3 shows an idealized DSC trace. The endotherms
`an important influen‘
`
`
`difference) versus T. Figure
`represent processes in which heat is absorbed, such as solvent loss, phase transitions,
`that affect the rate 01
`or melting. The exotherms represent processes such as crystallization or chemical
`
`
`has sublimed or m
`reactions where heat is evolved.
`In addition, the area under a peak is proportional to
`properties upon reh<
`the heat change involved. Thus this method, with proper calibration, can be used to
`Two definition:
`determine the enthalpies (AH)) of the various processes. The method can also be used
`
`
`as an accurate measure of the melting point and purity of the sample.
`In fact,
`the
`
`
`change of melting point is related to the mole fraction of impurities as given by Equa-
`
`
`
`
`tion 5‘2:
`2
`
`
`
`Ts = To _ Tu RX r
`(5.2)
`
`
`FAHf
`
`
`
`
`where T, is the sample temperature, T0 is the melting point of the pure compound, R is
`the gas constant, X,- is the mole fraction of the impurity, F is the fraction of the solid
`melted, and AHf is the enthalpy of fusion of the pure compound. According to the
`
`
`lope is proportional
`
`
`l/F should give a straight line whose s
`ars to fail when purity is less
`
`
`equation, a plot of T5 versus
`1991). However, the equation appe
`to X; (Brittain et al.,
`.
`.
`than 97%. Application of this equation is illustrated by the DSC thermograms shown
`
`
`in Figure 5.4.
`
`
`There are a number of factors other than purity that can affect the DSC curve in—
`eluding heating rate, atmosphere, sample holder, particle size, and sample packing.
`In
`
`
`general, agreaterheatingrate willcause a shift of the peaks to higher temperatures. A
`
`
`
`
`decreased heating rate also usually causes endotherms and exotherms to become
`:
`sharper The shape of the sample holder and whether it is open,
`totally sealed, or
`
`
`3,0
`.
`.
`.
`.
`
`
`J,
`contains a pin prick to vent gases can also affect a DSC curve. When a DSC experi-
`
`
`"
`ment is performed in a closed pan, the resulting atmosphere within the sample holder
`g DSC curve. Obviously, a tightly sealed sample holder
`hanism of a
`can greatly affect the rcsultin
`thereby changing the behavior or mec
`
`would not allow vapor to escape,
`
`
`ergies of polymorpl
`monotropic system
`temperature.
`In at
`(transition) tempera
`high temperature r:
`room temperature (
`cause confusion an
`system is enantioti
`termperature diagr
`reliable rules whi
`monotropic usingt
`l. The h
`dothei
`eratu
`fiotro
`the fcl
`forms
`”
`2. The l
`meltii
`relate
`
`99.6% ..
`
`.
`
`§
`
`
`
`
`
`
`
`
`
`
`
`points but simila
`forty energy—tem
`much more wor]
`calculated the he:
`polymomhs( bas
`the applicability .
`DSC is alsr
`show the DSC st
`containi'tg mixtt
`the higher meltii
`5.6 shows pure
`this same mixtui
`form is convert:
`study of mixtur
`tures of polymt
`DSC thermogra
`DSC can be ust
`
`
`
`
`
`
`
`
`1 40,0
`
`1 45.0
`
`150.0
`
`155.0
`
`Temperature (°C)
`
`
`
`hree ethoxyearbonyl-3-phenylpropyl.L-alanine samples of varying
`iron, 1990).
`Figure 5.4 DSC thermograms of t
`purity from different manufacturers (G
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`|PR2016-00006
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`5.2 Differential Scanning Calorimetry (DSC)
`
`85
`
`desolvation processes. As with TGA, the particle size and packing of the sample has
`an important influence on reactions especially those of desolvation type. Any changes
`that affect the rate of heat transfer should also be taken into account. Thus a sample that
`has sublimed or melted and then recrystallized may show somewhat different DSC
`properties upon reheating.
`Two definitions are often used to describe the relationship between the relative en-
`ergies of polymorphs at different temperatures: monotropic and enantiotropic.
`In a
`monotropic system, one form is the thermodynamically stable form regardless of the
`temperature.
`In an enantiotropic system, one form is more stable below a certain
`(transition) temperature but another form is more stable above that temperature. Thus,
`high temperature recrystallization may lead to one form, whereas recrystallization at
`room temperature could lead to the other form. Enantiotropic systems can sometimes
`cause confusion and problems with crystallization.
`In general, to determine whether a
`system is enantiotropic or monotropic it would be helpful
`to construct an energy-
`terrnperature diagram. Burger and Ramberger (l979a—b) have construeteded two
`reliable rules which assist
`in determining whether a system is enantiotropic or
`monotropic using thermoanalytical results:
`1 . The heat (or enthalpy) of transition rule states that (a) if an en-
`dothermic transition is observed between the forms at some tem—
`perature it may be assumed that the two forms are related enan—
`tiotropically and (b) if an exothermic transition is observed between
`the forms at some temperature it may be assumed that
`the two
`forms are related monotropically.
`2. The heat (or enthalpy) of fusion rule states that if the higher
`melting form has the lower heat of fusion then the two forms are
`related enantiotropically, otherwise they are related rnonotropically.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The endotherms
`)hase transitions.
`ttion or chemical
`s proportional to
`1, can be used to
`can also be used
`ple.
`In fact.
`the
`[5 given by Equa-
`
`(5.2)
`
`e compound, R is
`action of the solid
`According to the
`me is proportional
`when purity is less
`ermograms shown
`
`the DSC curve in-
`ample packing.
`In
`:r temperatures. A
`therms to become
`, totally sealed, 0r
`'hen a DSC experi—
`tthe sample holder
`:aled sample holder
`or mechanism of a
`
`lanine samples of varying
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Based on this work. Grunenbcrg et al. (1996) expanded these rules with the entropy
`of fusion rule (particularly necessary for polymorphs with very different melting
`points but similar ethalpies of fusion) and a heat capacity rule. Since only about
`forty energy-temperature diagrams for pharmaceutical systems have been published,
`much more work needs to be done.
`In related studies. Behme and Brook (1991)
`calculated the heat of fusion of the lower melting of an enantiotropieally related pair of
`polymorphs( based on the heat of transition and the heat capacities) and demonstrated
`the applicability of thermodynamic calculations.
`DSC is also useful for studies of polymorphic mixtures. Figures 5.5 and 5.6
`show the DSC scans of propyphenazone. Figure 5.5 shows the DSC scans of batches
`containing mixtures of Forms 1 and 11 indicating that DSC can detect as little as 5% of
`the higher melting form in the mixtures (Giron-Forcst et al.. 1989). Trace A in Figure
`5.6 shows pure Form 1, trace B shows a mixture of Forms I and II. and trace C shows
`
`this same mixture after heating at 100°C for two days indicating that the higher melting
`
`form is converted to the lower melting form under these conditions. In a more extensive
`
`
`study of mixtures. (Giron, 1986) showed that DSC could be used to quantitatc mix-
`
`
`tures of polymorphs as shown in Figure 5.7. The left panel in Figure 5.7 shows the
`DSC thermograms of Forms I and II of a pharmaceutical; the right panel shows that
`
`
`DSC can be used to analyze mixtures of these two forms (Giron, 1986).
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`SteadyMed - Exhibit 1027 - Page 6
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`5 mg 20 °Clmin
`
`hgure 5.7 Determination of l
`
`Thermal methods have
`
`
`
`-—>
`
`Endothermic
`13% Form ll
`
`5% Form llW...
`
`0% Form u
` j
`
`
`
`I
`100
`102
`105
`107
`110
`a
`
`
`
`Temperature (°C)
`Temperature ( C)
`
`
`Figure 5.5 Melting behavior of batches containing propyphenazone which are mixtures of Form 1
`with a small amount of Form 11 (Giron—Forest er al., 1989).
`
`
`
`
`
`
`
`
`
`
`
`
`
`mixture of Form I and Form II
`
`
`
`
`
`mixture 01 Form l and Form Il
`
`
`(same as above after Isothermal
`treatment for 2 ays at 100 “C
`
`
`
`
`____|__’__|___l__——l————
`
`
`
`1 009590 1 05 °C
` tures of Form I and Form [1 before
`
`
`ity (Giron, 1990). In this
`varying between 10:1 and
`of the heated samples is us
`and the results are compar
`should reflect the actual ;
`determine incompatibilities
`the DSC thermograms oi
`formation; thus, a change
`tive of a stability problem 1
`One advantage of DS
`thus, a study over a Wldt
`however, will have to be
`useful in the study of solic
`combined with other tech
`HPLC.
`
`Figure 5.6 DSC scans of propyphenazone pure Form 1 and mix
`and after isothermal treatment (Giron-Forest et al.. 1989).
`
`5.3 M ICROCALO RIMET
`
`Microcalorimetry is a vex
`given off or taken up by v
`try is used, for example,
`every transformation, eith
`of heat, this method has si
`baum and McGraw (1985
`different crystal forms ha
`However, the difference I
`solvents should remain t1
`diffeI‘Cnce is the heat of tr.
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`SteadyMed - Exhibit 1027 - Page 7
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`5.3 Calorimetry
`
`87
`
`0 Form I
`(A): 41.9 mJ s"
`
`
`5 mg 20 °Clrnin
`a Form II (B): 4.2 mJ s"
`
`
`
`
`
`
`nperature (°C)
`
`zone which are mixtures of Form 1
`1989).
`
`4...,—
`105 °C
`
`id mixtures of Form 1 and For
`11., 1989).
`
`m 11 before
`
`‘
`'
`
`
`‘90
`no
`‘60
`110
`10 20 30 40 50 60 7O 80 90100%Formll
`
`70 60 50 40 30 20
`90 80
`10
`0 lVeForn'Il
`
`
`
`
`Figure 5.7 Determination of ratios of Forms 1 and II of a pharmaceutical (Giron, 1986).
`
`
`
`
`Thermal methods have been successfully used to study drug-excipient compatibil—
`
`
`ity (Giron, 1990). In this procedure, drug and excipient are intimately mixed in ratios
`
`
`varying between 10:1 and 1:10 and each mixture is analyzed by DSC. HPLC analysis
`of the heated samples is used to interpret any changes in the DSC profile of the mixture
`
`
`
`
`and the results are compared with those of the pure components. The ratios analyzed
`should reflect the actual proportions in the formulation; however,
`it is instructive to
`
`
`determine incompatibilities at other concentrations as well.
`It is important to note that
`
`
`the DSC thermograms of mixtures will show some changes simply from eutectic
`formation; thus, a change in DSC melting point for a drug and excipient is not indica-
`
`
`tive of a stability problem by itself.
`
`
`One advantage of DSC is that the sample is subjected to different temperatures;
`thus, a study over a wide temperature range can be rapidly carried. Most results,
`
`
`however, will have to be confirmed by using other methods. Thermal methods are
`
`
`useful in the study of solids but the power of these methods is greatly enhanced when
`
`
`combined with other techniques such as X-ray powder diffraction, microscopy, and
`I‘
`1
`HPLC.
`
`
` 5.3 MICROCALORIMETRY
`
`Microcalon'metry is a very sensitive calorimetrie technique that determines the heat
`
`
`given off or taken up by various processes. For pharmaceutical solids, microcalorime-
`try is used, for example, to measure heats of solution and degradation rates. Since
`
`
`
`
`every transformation, either chemical or physical, occurs with evolution or absorption
`
`
`. of beat, this method has significant potential for the study of transformations. Linden—
`haum and McGraw (1985) have used microcalorimetry to study drug forms. Because
`different crystal forms have different structures, they have different heats of solution.
`
`
`
`2 However, the difference between the heats of solution of two polymorphs in different
`
`solvents should remain the same (Table 5.1) if there is no solvate formation. This
`,.- erence is the heat of transition between the forms at that temperature.
`
`
`
`E
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`Chapter 5 Drugs as Molecular Solids
`88
`Table 5.1 Heats of Solution of Sodium Sulfathiazole
`Solvent
`AHs Form 1
`AHS Form 11
`Aflmm
`(kJ/mol, 25 °C)
`(kJ/mol, 25 °C)
`(kl/moi, 25 °C)
`
`Acetone
`1 1.94
`5.144
`6.798
`
`
`
`774.659 —1 1.47DMF 6.810
`' Lindenbaum and McGraw. 1985.
`
`Studies by Ip et al. (1986) on enalapn'l maleate give similar results showing that
`the heats of transition between the two forms determined by subtraction of the heats of
`solution in two different solvents are within the experimental error. With suitable
`calibration of known mixtures, this phenomenon can sometimes be the basis for
`analyzing mixtures of polymorphs or crystalline and amorphous forms of a compound.
`Of course these comparisons apply only to solids with the same composition (i.e.,
`when the resulting solutions are identical). Also, a hydrate and an anhydrate cannot be
`compared since the heat of the solution of water will be different in different solvents
`Isothermal microcalorimetry has also been used to determine the crystallinity of
`and thus the AH“ans will be different.
`mixtures of amorphous and crystalline antibiotics as shown in Figure 5.8 (Thompson et
`al., 1994). DSC could not be used since the samples decomposed prior to melting.
`In
`contrast to studies by Osawa and coworkers (1988) as well as Pikal and coworkers
`(1978), it was found that the heat of solution was not dependent on water content. The
`importance of initial water content is probably greatest when dealing with hydratable
`ionic species since sodium and quaternary ammonium salts have very high heats of
`Several important papers on the use of microcalorimetry for stability determina-
`hydration (see Figure 5.9).
`tions have appeared. Hansen et al. (1989) studied the kinetics of decomposition of
`lovastatin and other HMG—CoA reductase inhibitors using heat conduction calorime-
`try (the response of the instrument is directly proportional to the rate of heat produced
`in the sample cell). Heat conduction calorimetry has a substantial advantage over
`
`(J/g) -20 0
`
`10
`
`20
`
`30
`
`60
`50
`40
`Percent Crystallinity
`
`100
`
`HeatofSolution
`
`Figure 5.8 Heat of solution of antibiotic 302669 in 0.02 M NazHPO4 at 35 °C as a function of
`percent crystallinity (Thompson et LIL, 1994).
`
`
`
`
`
`
`
`Figure 5.9 The effect of w
`
`conventional microcalor‘
`,uW) can be detected. Tl
`determined after only a
`urement of degradation
`temperature. The rate 1
`calorimeters can also b1
`excipients and stabilize]
`rimetry to establish that
`atmospheres only a sn
`under oxygen atmospl
`atmospheres.
`Further
`change was about -—40
`oxidation. Bond ener;
`group would produce 2
`tion microcalorimetry.
`area of the sample has
`experiments, they Sh(
`produced under identi
`oxygen than others.
`that a single measuren
`used to predict the tot:
`conduction nlicrocalo
`cases and appears to l
`
`
`
`
`
`
`
`
`
`REFERENCESW
`
`Behme, Robert J. and D3
`of carbamazepine th
`analysis" J. Pharm.
`Brittain, Harry 0.. Susan
`Ann W. Newman
`963—973.
`
`Burger. A. and R. Raml
`crystals.
`1. Theory
`
`
`
`
`
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`|PR2016-00006
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`IPR2016-00006
`SteadyMed - Exhibit 1027 - Page 9
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`
`
`LIIIYIIS
`>1, 25 DC)
`t.798
`n.810
`
`llts showing that
`m of the heats of
`r. With suitable
`be the basis for
`5 of a compound.
`:omposition (i.e..
`hydrate cannot be
`different solvents
`
`the crystallinity of
`5.8 (Thompson et
`ior to melting.
`In
`(211 and coworkers
`vater content. The
`rig with hydratable
`very high heats of
`
`stability determina-
`f decomposition of
`duction calorime-
`te of heat produced
`tial advantage over
`
`80
`
`90
`
`1 00
`
`t 35 °C as a function of
`
`
`
`References
`
`89
`
`Sodium Ceiazolin
`Cephaloridine
`
`5 form
`a lorm
`
`
`AHskcal/mol
`
` Sodium Cephalothin
`Amorphous, lreeze dried
`
`
`
`6
`7
`4
`5
`
`
`
`Water, % (w/w)
`
`
`
`Figure 5.9 The effect of water content on the heats of solution of antibiotics (Pik'di et ul., I978).
`
`
`
`
`
`conventional microcalorimetric methods in that extremely small outputs of heat ($0.1
`
`
`HW) can be detected. The heat of decomposition and the kinetics of the process can be
`
`
`determined after only a very small percentage of reaction. This then allows the meas
`
`
`urement of degradation of the material in the early stages of the reaction even at room
`
`
`temperature. The rate law and the activation energy can also be determined. These
`
`
`calorimeters can also be used to study freshly formulated materials and the effects of
`
`
`
`
`excipients and stabilizers on degradation. Hansen et er a]. (1989) also used microcalo-
`
`
`rimetry to establish that oxygen was required for degradation of lovastatin since in inert
`
`
`atmospheres only a small amount of heat was produced whereas the heat produced
`under oxygen atmosphere was 20—90 times greater than that produced under inert
`
`
`atmospheres. Furthermore,
`they used the heat produced to estimate the enthalpy
`
`
`change was about —400 kJ mol'1 which is consistent with what one might expect for
`
`
`oxidation. Bond energy calculations show that reaction of oxygen with a methylene
`
`
`group would produce an enthalpy change of about —600 kJ mol". Using heat conduc—
`
`
`tion microcalorimetry, Hansen and coworkers were also able to show that the surface
`
`area of the sample has an effect on the rate of oxidation. as might be expected.
`In other
`
`
`
`experiments, they showed that
`there was significant
`lot—torlot variation in the heat
`produced under identical conditions. Some lots showed much greater reactivity with
`
`
`oxygen than others. One of the most significant results of this study was the finding
`
`
`
`that asingle measurement of the heat produced per gram of drug for each lot could be
`used to predict the total degradation of that lot under conventional stability testing. Heat
`
`
`conduction mierocalorimetry has been shown to have predictive capability in some
`
`
`cases and appears to be an important addition to other stability studies.
`
`
`
`wwWWWMWW
`REFERENCESWW
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Behme. Robert J. and Dana Brooke (l99l) “Heat of fusion measurement of a low melting polymorph
`of carbamazepine that undergoes multiple-phase changes during differential scanning calorimetry
`analysis" J. Pharm. Sci. 80 986—990.
`Brittain, Harry 0., Susan J. Bogdanowich. David E. Bugay, Joseph DeVincentis, Geoffrey Lewen, and
`Ann W. Newman (1991) “Physical characterization of pharmaceutical solids" lerm. Res. 8
`963—973.
`Burger, A. and R. Ramberger (1979a) “0n the polymorphism of pharmaceuticals and other molecular
`crystals.
`1. Theory of thermodynamic rules" Mikmc/iim. Arm ll 259727l.
`
`
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`|PR2016-00006
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Chapter 5 Drugs as Molecular Solids
`90
`
`
`hism of pharmaceuticals and other molecular
`
`Burger, A. and R. Ramberger (1979b) “On the polymorp
`crystals. 11. Applicability of Thermodynamic rules" Mikrochim. Acta 11 273—316.
`Cahn Instruments (1996) 5225 Verona Road, Bldg. 1, Madison WI 53711-4418.
`
`Giron, D. (1986) “Applications of thermal analysis in the pharmaceutical industry” J. Pharm. Biomed.
`Anal. 4 775—770.
`“Thermal analysis in pharmaceutical routine analysis” Acta Pharm. Jugosl. 40
`Giron, Daniele (1990)
`95457.
`Giron—Forest, D., Ch. Goldbronn, and P. Piechon (1989) “Thermal analysis methods for pharmaco-
`poeial materials” J. Pharm. Biomed. Anal. 7 1421—1433.
`Grunenberg, A., J.70. Henck, and H. W. Siesler (1996) “Theoretical deviation and practical application
`of energy/temperature diagrams as an instrument in performulation studies of polymorphic drug
`substances" Int. J. Pharm. 129 147—158.
`. Bergstrom, and Damaris DeGiaIt—
`Hansen, Lee D., Edwin A. Lewis, Delbert J. Eatough, Robert G
`duction calorimetry" Pharm. Res. 6
`Johnson (1989) “Kinetics of drug decomposition by heat con
`20—27.
`venson, Siegfried Lindenbaum, Alan W. Douglas, S.
`1p, Dominic P., Gerald S. Brenner, James M. Ste
`David Klein, and James A. McCauley (1986) “High resolution spectroscopic evidence and solution
`calorimetry studies on the polymorphs of enalapril maleate" Int. J. Pharm. 28 183—191.
`Lindenbaum, Siegfried and Scott E. McGraw (1985) “The identification and characterization of
`polymorphism in drug solids by solution calorimetry" Pharm. Manufacturing 27—30.
`of pharmaceuticals by high—
`Pikal, Michael J. and Karen D. Dellerman (1989) “Stability testing
`sensitivity isothermal calorimetry at 25 °C:
`cephalosporins in the solid and aqueous solution
`states" Int. J. Pharm 50 233—252.
`tive crystallinity determina-
`Pikal, M. J, A. L. Lukes, John E. Lang, and K. Gaines (1978) “Quantita
`tions for B-lactam antibiotics by solution calorimetry:
`correlations with stability” J. Pharm. Sci.
`67 767—773.
`Osawa, Takashi, Madhav S. Kamat, and Patrick P. DeLuca (1988) “Hygroscopicity of cefazolin
`sodium: application to evaluate the crystallinity of freeze-dried products" Pharm. Res. 5 421—425.
`Thompson, Karen C., Jerome P. Draper, Michael J. Kaufman, and Gerald S. Brenner (1994) “Charac-
`
`terization of the crystallinity of drugs: 802669, a case study” Pharm. Res. 11 1362—1365.
`
`Wendlandt, Wesley W. (1974) Thermal Methods of Analysis, 2nd ed; John Wiley and Sons: New
`
`York, NY: PP 9—13.
`
`
`
`
`
`
`
`
`
`
`
`
`potential for bioequivals
`
`are usually compounds
`
`disperse.
`Examples i
`
`digoxin,
`diphenylhyd:
`
`quinidine, and warfarin.
`
`to ensure that the Unite<
`
`
`
`
`
`
`
`Solubilit
`
`Testing
`
`he rate of disso
`
`important aspen
`and solubility (
`same drug can obviousl
`necessary for both pure
`have the proper dissoluti
`1991; Banakar, 1992).
`'
`dissolution testing and
`USP-NF (United States
`
`
`
`6.1 TESTING
`
`Dissolution tests are 3;
`individual drugs. For e:
`specification that 80%
`carbamazepine tablets m
`be dissolved in 60 m
`laboratories now measu
`variations. For dissolul
`variables (e.g., time prt
`chosen carefully.
`Dissolution tests a
`
`
`
`|PR2016-00006
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`SteadyMed - Exhibit 1027 - Page 11
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`IPR2016-00006
`SteadyMed - Exhibit 1027 - Page 11
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