Pharmaceutical
`Preformulation and
`Pormulation
`
`........ by Mark Gibson
`
`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1007
`
`Exh. 1007
`
`

`
`Library of Congress Cataloging-in-Publication Data
`
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`
`No claim to original U.S. Government works
`International Standard Book Number 1-57491-120-1
`5 6 7 8 9 0
`Printed in the United States of America
`Printed on acid-free paper
`
`Exh. 1007
`
`

`
`3
`
`Preformulation Predictions from
`Small Amounts of Compound
`as an Aid to Candidate
`Drug Selection
`
`Gerry Steele
`AstraZeneca R&D Charnwood
`Loughborough, United Kingdom
`
`Prior to nomination into full development, a candidate drug should undergo a phase tradi-
`tionally called preformulation. Preformulation is the physicochemical characterization of the
`solid and solution properties of compounds and although now relatively old, the definition of
`preformulation proposed by Akers (1976) is particularly apt:
`
`Preformulation testing encompasses all studies enacted on a new drug com-
`pound in order to produce useful information for subsequent formulation
`of a stable and biopharmaceutically suitable drug dosage form.
`
`Furthermore, Wells' book on the subject {1988) closes by exhorting pharmaceutical
`scientists:
`
`Do not neglect these foundations. Good preformulation will inevitably lead
`to simple and elegant formulations and successful commercial products.
`
`The scope of preformulation studies to be carried out will depend not only on the ex-
`pertise, equipment and drug substance available but also on any organizational preferences or
`restrictions. Some companies like to conduct detailed characterization studies, whilst others
`
`21
`
`Exh. 1007
`
`

`
`34
`
`Phannaceutical Preformulation and Formulation
`
`Figure 3.6 Temperature-solubility curve for a hydrochloride salt in methanoi/ HCI.
`
`30
`
`25
`
`20
`
`16
`
`10
`
`::::s
`.g,
`!. g
`:0
`::l 0
`
`Vl
`
`e v
`•
`
`y
`
`v
`!
`
`•
`
`0+-----~----~r-----~-----r----~r---~
`10
`30
`60
`20
`60
`0
`40
`Temperature (°C)
`
`PEG400 and propylene glycol). In addition, the solubility in oils and surfactant systems (e.g.,
`'l\veen 80) may be considered. For reasonably soluble compounds, it m ay well be that only a
`"greater than" figu re can be quoted.
`
`INITIAL STABILITY INVESTIGATIONS
`Knowledge about the chemical and physical stability of a candidate drug in the solid and liq-
`uid state is extremely important in drug development for a number of reasons. In the longer
`term, the stability of the formulation will dictate the shelf life of the marketed product, how-
`ever, to achieve this formulation, careful preformulation work will have characterized the
`compound such that a rational choice of conditions and excipients is available to the formu-
`lation team.
`Candidate drugs being evaluated for development are ofien one of a series of related com-
`pounds that may have similar chemical properties, i.e., similar paths of degradation may be
`deduced. However, this rarely tells us the rate at which they will decompose, which is of more
`importance in pharmaceutical development terms. To elucidate their stability with respect to
`temperature, pH, light and oxygen, a number of experiments need to be performed. The
`major objectives of the preformulation team are, therefore, to identify conditions to which the
`com pound is sensitive and to identify degradation profiles under these conditions.
`The major routes of drug degradation in solution are via hydrolysis, oxidation or photo-
`chemical means. Conners et al. (1 986) have dealt \'ery well with the physical chemistry in-
`volved in the kinetic analysis of degradation of pharmaceuticals, and the reader is referred
`there for a detailed discussion.
`
`Exh. 1007
`
`

`
`Preformula/ion Predictions . .. as an A1d co Cond1date Drug Selection
`
`35
`
`Solution Stability
`Hydrolysis
`M~cbanisticnlly, hydrolysis takes place in two stages. In tlle first instance, a nucleophile, such
`as water or the OH- ion, adds to, for example, an acyl carbon, to form an intermediate from
`which the leaving group then breaks away. The structure of the compound will affect the rate
`at which this reaction takes place, and the stronger the leaving conjugate acid, the faster the
`degradation reaction will take place (Loudon 1991 ).
`Degradation by hydrolysis is affected by a number of factors, of which solution pH, buffer
`salts and ionic strength are the most important. In addition, the presence of co-solvents, com-
`plexing agents and surfactant can also affect this type of degradation.
`As noted, solution pH is one of the major determinants of the stability of a compound.
`Hydroxyl ions are stronger nucleophiles than water; thus degradation reactions are usually
`faster in alkaline solutions than in water, i.e., OH- ions cataly7.e the reaction. In solutions of
`low pH, H + can also catalyze hydrolysis reactions: catalysis by H+ and QH- is termed specific
`acid-base catalysis. Of course, H+ and QH- ions are not the only ions that may be present dur·
`ing an experiment nr in a formulation. It is well known that buff~r ions such as acetate or cit·
`ric acid can catalyze degradation, and in this case the effect is known as general acid-base
`degradation. Therefore, although it is prudent to adjust the pH to the desired value to opti·
`mize stability, this should always be done with the minimum concentration necessary.
`Stewart and Tucker ( 1985) provide a useful, simple guide to hydrolysis and discuss the mech·
`anism of hydrolysis. Table 3.3 shows some examples of the functional groups that undergo
`hydrolysis.
`
`Oxidation
`The second most common way a compound can decompose in solution is via oxidation. Re-
`duction/oxidation (redox) reactions involve either the transfer of oxygen or hyd rogen atoms
`
`Table 3.3
`Examples of classes of drugs that are subject to hydrolysis.
`Cla11
`Example
`Aspirin
`Spirolaclone
`Chloramphenicol
`Sulphapyrazlne
`Phenobarbilone
`Methicillin
`Spironolactone
`Chlorambucil
`
`Ester
`Thiol esler
`Amide
`Sulphonamide
`Imide
`Lactam
`Lactone
`Halogenated aliphatic
`
`Reprinted with permission from Predicttan of drug stabllry- Part 2: Hydroty,;ts. by P. J. Stewart and 1. G. Tucker. In Aust. J.
`1/o<p. ""'""· 1985. Vol l5. poges 11- 16.
`
`Exh. 1007
`
`

`
`6
`
`Preformulation as an
`Aid to Product Design in
`Early Drug Development
`
`Gerry Steele
`AstraZeneca R&D Charnwood
`Loughborough, United Kingdom
`
`,_t'reformulation is usually defined as the science of the physicochemical characterization of
`drugs. However, any studies carried out to define the conditions under which the
`drug should be formulated can also be termed preformulation. This is a broader
`than was used in Chapter 3, and, a~ such, it can include studies on preliminary
`under a variety of conditions. These studies may influence the Product Design
`be conducted at the earliest opportunity at the start of development. In the in-
`drug development and reduced drug usage, preformulation studies should not
`!!Jidertaken on a "check-list" basis. Rather, they should be conducted on a need-to-know
`
`there are many traditional approaches to dosage form design, newer approaches
`expert systems are now becoming available. Expert systems are discussed further in
`8 on Product Optimisation.
`
`Exh. 1007
`
`

`
`176
`
`Pharmaceutical Prelormulation and Formulation
`
`II!
`
`Preformulation as an Aid . .. in Early Dmg Development
`
`177
`
`/' --·-
`
`for example, the same chemical compound can have different crystal structures (poly-
`morphs), external shapes (habits) and hence different flow and compression properties.
`Cartensen et aJ. (1993) have usefully, although briefly, reviewed the physicochemical
`properties of particulate matter, dealing with the topics of cohesion, powder flow, mi-
`cromeretics, crystallization, yield strengths and effects of moisture and hygroscopicity. Buck-
`ton (1995) has reviewed the surface characterization of pharmaceuticals with regard to
`understanding sources of variability. A general overview of the methods available for the phys-
`ical characterization of pharmaceutical solids has been presented by Brittain et al. (1991). York
`( 1994) has also dealt with these issues and produced a hie.rarchy of testing techniques for pow-
`dered raw materials. Finally, there is a book dealing with the physical characteri7_ation of
`pharmaceutical solids, edited by Brittain (1995).
`A number of other studies can be performed on a candidate drug to determine other im-
`p0rtant SOlid-State prOpertieS, for example, particle Slze, powder flOW and COmpreSSiOn and
`polymorphism. Therefore, when a sample undergoes initial preformulation testing the fol-
`lowing parameters should be noted: particle si7_e, true, bulk and tapped density, surface area,
`compression properties and, powder now properties. Some of these factors will be discussed
`in this chapter; others, however, are dealt with in more detail in Chapter II on Solid Oral
`Dosage Forms.
`
`1·
`•
`
`I
`
`.
`
`,.
`
`Particle Size Reduction
`.
`.
`. als . .
`I .
`f h
`ch
`th c
`.cl
`.
`a:
`arac-
`
`Th e partt e stZe o p armaceuttc
`ts tmportant smce tt can auect e tormu atton
`teristics and bioavailability of a compound (Chaumeil1998). For example, sedimentation and
`flocculation rates in suspensions are, in part, governed by particle size, and inhalation therapy
`of pulmonary diseases demands that a small particle size (2-5 JJ.m) is delivered to the lung for
`the best therapeutic effect. Partkle size is also important in the tableting field, since it can be
`very important for good homogeneity in the final tablet. In this respect, Zhang and Johnson
`( 1997) showed that a blended jet-milled compound exhibited a smaller range of potencies
`when compared to those blends where the compound had a larger particle size. It is therefoR!
`important that the particle size be consistent throughout the development studies of a prod-
`uct to satisfy formulation and regulatory demands (Turner 1987).
`Thus, to reduce the risk of dissolution rate-limited bioavailability, and if there is suffid
`compound, grinding in a mortar and pestle should be done to reduce the particle size of
`compound. If larger quantities are available, then ball milling or micronization can be used ..
`reduce the particle size. The main methods of particle size reduction have been reviewed
`Spencer and Dalder ( 1997), who devised the mill selection matrix shown in Table 6. L
`
`.#
`
`Bai/Millmg
`•
`In a review of milling, it was stated that ball milling was "the most commonly used type of
`bling mill in pharmacy" (Parrot 1974). Tndeed, it is probably used most often at the prefo
`lation sta2e to reduce the oarticle size of small amounts of a comoound. ••n~n•llv for.
`
`·
`
`~
`~
`~
`il ~ ~ ~ ~ ~
`~ t ~ -5 ~ i ~ ~
`~
`J: ~ ,f ~ of .J!. ,f ~
`
`., ., .,
`~
`~ ~ ~
`., ~
`a lij ~ ~ ~ 5 5 ~
`..! ~ ~
`c.> ~ ~ e -
`~ of j ~ j' ~ &_
`
`1
`
`1 1
`
`G)
`
`"
`.2
`.!
`~ "'
`:
`- ~ ~
`., ~ ~ il
`8.
`..:
`=~~ ~ :Cm~~~
`CD g Jg
`e c:
`"'
`., o o
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`c:
`"
`i:;
`jg ~ ~
`il;
`:5 -; ~ ~ .!! ~ ~ -; ~
`;;; c
`~ > ~ 5 !l ~ ~ ~
`.!! ~
`~ Jl
`:;
`~
`~
`~
`-
`:E
`,..
`~
`~
`~ il e ~ !
`-
`.ii ~ g .. 5 a ~ "' ~
`:§ ~ ~ ~ j ; 5 ~ -~
`... ~ ~ ~ :3 .S ~ ~ -~
`·i
`~
`
`CD
`
`.!!
`
`.!!
`
`6
`21,
`it,
`8,
`E
`E
`~
`.s.! ~
`~ .c
`-=
`~
`~
`:g
`m 10 !f!
`~ w
`., lii :o g g .,
`.:
`lii
`·g,
`~ ~ ii ~ i i' ~ ~
`.c!co mcc..
`cn.c a
`
`-' < !l ... ::> > <
`
`ijj
`al
`
`Exh. 1007
`
`

`
`178
`
`Pharmaceulical Preformulation and Formulation
`
`milling process and these include rotation speed, mill size, wet or dry milling and amount of
`material to be milled.
`Although ball milling can effectively reduce the particle size of compounds, prolonged
`milling may be detrimental in terms of compound crystallinity and stability. This has been
`illustrated in a study that examined the effect of ball mill grinding on cefixime trihydrate
`(Kitamura et al. 1989). Using a variety of techniques, it was shown that the crystalline solid
`was converted to an amorphous solid after 4 h in a ball mill. The stability of the amorphous
`solid was found to be less than that of the crystalline solid, and the samples were discoloured
`due to grinding.
`It is important to check this aspect of the milling process, since amorphous compounds
`can show increased bioavailability and possible pharmacological activity compared to the cor-
`responding crystalline form. Ball milling may also change the polymorphic form of a cum-
`pound, as shown by the work of Leung et al. (1999) with aspartame.
`Figure 6.1, for example, shows the X-ray powder diffraction (XRPD) patterns of a sam-
`ple of a compound "as received" and after ball milling. After ball milling for 1 h, the sample
`was rendered amorphous, and hence a shorter milling period was used.
`
`Micronization
`If instrumentation and sufficient compound are available, then microni~.ation can be under-
`taken. This technique is routinely used to reduce the particle size of active ingredients so that
`the maximum surface area is exposed to enhance the solubility and dissolution properties of
`poorly soluble compounds. Because of the enhanced surface area. the bioavailability of
`
`Before ball millin: (crysU~IIine)
`
`/
`
`~ g
`~-
`c
`::l
`
`.......... ou'l)
`
`~Affertxl.llmilling(3m.........t.
`
`.
`
`- ~
`
`, . - · ·-
`
`Preformulation as an Aid . .. in Early Drug Development
`
`179
`
`compounds is often improved, e.g .• micronization enhanced the bioavailability of felodipine
`when administered as an extended release tablet (Johansson and Abrahamsson 1997).
`The process involves feeding the drug substance into a confined circular chamber where
`the powder is suspended in a high velocity stream of air. lnterpart.iculate collisions result in a
`size reduction. Smaller particles are removed from the chamber by the escaping air stream to-
`wards the centre of the mill where they are discharged and collected. Larger particles recircu-
`late until their particle size is reduced. Micronized particles are typically less than 10 JJ.m in
`diameter (Midoux et al. 1999).
`
`Effect of Milling and Micronization
`Although micronization o f the drug offers the advantage of a small particle size and a larger
`surface area, it can result in processing problems due to high dust, low density and poor flow
`properties. Indeed, micronization may be counterproductive, since the micronized particles
`may aggregate, which may decrease the surface area. In addition, changes in crystallinity of the
`drug can also occur, which can be detected by techniques such as microcalorimetry (Briggner
`et al. 1994), dynamic vapour sorption (Ward and Schultz 1995) and inverse gas chromatogra-
`phy (Feeley et al. 1998).
`Ward and Schultz (1995) reported subtle differences in the crystallinity of salbutamol sul-
`phate after micronization by ai r jet milling. They found that amorphous to crystalline con-
`versions occurred that were dependent on temperature and relative humidity (RH). It was
`suggested that particle size reduction of the powder produced defects on the surface that, if
`enough energy was imparted, led to amorphous regions on the surface. In turn, these regions
`were found to have a greater propensity to sorb water. On exposure to moisture, these regions
`crystallized and expelled excess moisture. This is illustrated in figure 6.2, which shows the
`
`Figure 6.2 DVS isotherm showing crystallization effects due to moisture.
`
`... -····-·----········----·········/
`
`Exh. 1007
`
`

`
`180
`
`Pharmaceutical Preformulation and Formulation
`
`uptake of moisture, as measured by dynamic vapour sorption (DVS), of a micronized
`development compound. Note how the percent mass change increases and then decreases as
`the RH. is increased between 40 and 60 percent during the sorption phase. This corresponds
`to crystallization of the compound and subsequent ejection of excess moisture. The com-
`pound also exhibits some hysteresis.
`This effect can be important in some formulations, such as dry powder inhaler devices,
`since it can cause agglomeration of the powders and variable now properties. In many cases,
`this low level of amorphous character cannot be detected by techniques such as XRPD. Since
`microcalorimetry can d~tect < 10 percent amorphous content (the limit of detection is 1 per-
`cent or less), it has the advantage over other techniques such as XRPD or DSC. Using the am-
`poule technique with an internal hygrostat, as described by Briggner et al. 1994, and shown
`in Figure 6.3, the amorphous content of a micronized drug can be determined by measur-
`ing the heat output caused by the water vapour inducing crystallization of the amorphous
`regions.
`figure 6.4 shows the calibration curve of heat output versus amorphous content of a de-
`velopment compound. ln this case, the technique is used to crystallize, or condition, these
`amorphous regions by exposure to elevated RHs. Thus, if authentic 100 percent amorphous
`and crystalline phases exist, it is possible to construct a calibration graph of heat output ver-
`sus percentage crystallinity, so that the amount of amorphous character introduced by the
`milling process can be quantified.
`
`Figure 6.3 Internal hygrostat and heat output due to crystallization of an amorphous
`phase measured by isothermal microcalorimetry.
`
`P (ILW)
`
`1001
`
`I ISO\
`I
`J
`I
`I'-
`
`Preformulation as an Aid . .. in Early Drug Development
`
`181
`
`Figure 6.4 Crystallization peak energy versus amorphous content using microcalorimetry.
`~,.00 I
`
`R' . 0.0078
`
`lU.l(l
`
`"" 25JID
`~
`Jj 1().00
`'" £
`" £
`~ :a s 10,00
`
`IS.OO
`
`<ro
`
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`
`:!0.00
`
`31100
`
`0(100
`40.00
`~ro
`Amorllhou.<; Content(%)
`
`70.00
`
`80.00
`
`90.00
`
`10000
`
`Inverse Gas Chromatography
`In addition to the DVS and microcalorimetric techniques for characterizing the surface prop-
`erties of powders, a recently introduced technique known as inverse gas chromatography
`(IGC) can also be used. This technique differs from traditional gas chromatography insofar as
`the stationary phase is the powder under investigation. In this type of study, a range of non-
`polar and polar adsorbates (probes) are used, e.g., alkanes, from hexane to decane, acetone,
`dktbyl ether or ethyl acetate. The retention volume, i.e., the net volume o f carrier gas (nitro-
`required to elute the probe, is then measured. Tite surface partition coefficient (K,) of the
`between carrier gas and surfaces of test powder particles can then be calculated. From
`a free energy can be calculated which can show that one batch may favourably adsorb the
`when compared to another, implying a difference in the surface energetics.
`The experimental parameter measured in IGC experiments is the net retention volume,
`This parameter is related to the surface partition coefficient, K,, which is the ratio
`the concentration of the probe molecule in the stationary and mobile pha.•es
`by
`
`Vn
`A
`K5=- x ... P
`m
`
`( l )
`
`Exh. 1007
`
`

`
`182
`
`Pflarmaceutieal Preformu!ation and Formulation
`
`From K, the free energy of adsorption (-AGA) is defined by
`
`- AGA = RTI{Ks x~ y Yt
`0 r
`
`(2)
`
`is the standard vapour stale (101 KN/m2) and Pis the standard surface pressure,
`where P,
`8
`which has a value of 0.338 m.Nim.
`IGC and molecular modelling have been used to assess the effect of microni1.ation on dl·
`propranolol (York et al. 1998). The samples were jet miUed (microniz£d) to various particle
`° wo1s musured and plotted against their median particle si7;:. This showed that
`si:res and -y
`as the particle si?.e decreased due to the micronization process. the surface of the particles be-
`5
`came more energetic. Interestingly. it was pointed out that the plateau region corresponded to
`the brittle-ductile region of this compound. This observation implied a chaoge in the mecb·
`anism of milling from a fragmentation to an attrition process. The data for -AGASP for the
`tetrahydrofuran (THF) and dichloromethane probes showed that the electron donation of the
`surface increased as the partkle siz£ decreased. Combining these dalo with mole<tdar model·
`ling, which was used to predict which surfactS would predominote, they showed that the elec-
`tron-rich naphthyl group dominated the surface of the unmilled material This led tn the
`conclusion Lhat as the particle size was reduced, this surface became more exposed, leading to
`a greater interaction with the THf and dichloromethanc probes. However, as previowly
`noted, as milling proceeded, the mechanism of W.C reduction changed, which might lead TO
`exposure of the chloride and hydroxyl moieties.
`Therefore, using moisture sorption. microcalorimetric. ICC, molecular modelling and
`other techniques, the consequen= of the particle si1.e reduction process can be assessed.
`Moreover, surfuce energetics can be measured dircctl)' and predictions made about the nature
`of the surface, which tdtimately could affect properties such as the flow uf powders or adhe·
`sian of particles (Pod=ck et al. 19961>).
`
`Particle Size Dis~ibution Measurement
`Washington ( 1992) has discussed the concepts and techniques of particle size analysis and its
`role in pharmaceutical sciences and other industri.,;.lbere are many different methods avail·
`able for particle size analysis. The techniques most readily available include sieving, optical
`microscopy in conjunction with image analysis. electron microsoopy,the Cotdter Counter and
`laser diffractometers. Size cbaract<riution is simple for sphericll particles. but not for irres-
`ular particles where the assigned size will depend on the method of characterization
`Table 6.2 lists particle siz£ measurement methods commonly used and the corresponding
`proximate useful siz£ range (Mullin 1993).
`Figure 6.5 show. the particle size distribution of a micronized powder determined by
`ning elec-non microscopy (SEM) and laser light scattering. The Malvern Mastersizer is
`ample of an instrument that measures particle size by laser diffraction. The use of this
`is based on light scattered through various angles. which is direcdy rdated to the ··
`the particle. Thus, by measuring the angles and int<nSity of scattered light from
`particle size distribution con be deduc.ed.ll should be noted that the particle di:u
`are the same as th<>K that spherical particles wotdd produce under similar conditions.
`shows the data obWned from the laser diffraction analysis shown in Figure 6.5.
`Two theories dominate the theory of light scattering; the Fraunhofer and Mie. In the
`mer. each particle is treatod as spherical and essentially opaque 10 the impinging laser light-
`
`Preformu/ation as an Aid . .. in Early Drug Dcvclopment
`
`183
`
`Table 6.2
`Particle size techniques and size range.
`sw. ~~ange c ...... >
`Melllod
`20-125.000
`
`~120
`
`S~('WOVeflwite)
`Sie\Ong Celeclrofom>ed)
`Sieving (perfonrted plate)
`I.Q00-125,000
`Mitt"""'PY (opticaO
`0.5-150
`Microscopy (electron)
`0.001·5
`Sedimentation (gravky)
`1·50
`Sedimentation (cenutfugal)
`0.01·5
`£1earicalzone sensing (e.g.. Coultts-J
`1- 200
`User Oght scatlcting (F<>unhofer)
`1-1.000
`I.Bser light scattering (qua~·elastic)
`0.001-1
`rrom MuHi't,J. w .. AniJI. A-oc. J0:4M-456 (1983J. Reproduced by penniaion of lhc Royal Socicry o1 Chemistry.
`
`Mit theury, on the other hand. t~ into acrount the diff(rt.nccs in refractive india:s betw'een
`the particles and the suspending medium. If the diameter of the particles is abuve 10 fUll, then
`the size produced by utilizing each theory is essentially the same. However, discrepancitS may
`occur when the diameter of the particles approaches that of the wavelength of the laser source.
`The following are the values reported from diffraction experiments.
`
`D (v, 0. 1) isthe si:a uf particles for which 10 percent of the sample l< below this size
`D (v, 05) is the volume (v) median diameter of which 50 pero:nt of the sample is
`below and above this si:a
`D ( v, 0.9) gives a si1.e of particle for which 90 percent of the sampk is below this size
`D [4,3] is the equivalent vulume mean diameter calculated using;
`u•
`D[4,3]= L.d3
`D (3.21 is the surface area mean diameter; also known as the Sauter mun, where d =
`diameter of each unit
`Log difference represents rhe difference bctwten the observed light energy data and
`the calculated light energy datl for the derived distribution
`Span is the measurement of the width of the distribution ;md is ca1culalcd using
`
`(3)
`
`Span D (v, 0.9) - D (v, 0.1)
`D(v, 0.5)
`. The dispersion of the po1Vder is important in achieving reproducible results. Ideally, the
`dispersion medium should have the following characteristics:
`
`(i )
`
`Exh. 1007
`
`

`
`J
`
`'
`
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`
`100.00
`100.00
`100.00
`100.00
`100.00
`100.00
`under<MI
`Volume
`
`80.00
`64.92
`52.60
`42.75
`34.69
`28.15
`
`Size (J1m)
`
`D (v, 0.9) = 8.54 .,.m
`D [3, 2] = 2.61 IJ.nl
`S.SA = 1.6133 m2Jg
`
`Re<idual: 0.117%
`Obs': 15.8%
`
`100.00
`99.87
`99.08
`97.18
`93.69
`00.21
`80.61
`71.18
`60.67
`under<MI
`Volume
`
`22.84
`18.54
`15.04
`12.21
`9.91
`0.04
`6.52
`5.29
`4.30
`
`Size (J.llll)
`
`49.86
`39.38
`29.72
`21.22
`14.24
`0.90
`5.08
`2.58
`1.09
`under<MI
`Volume
`
`3.49
`2.83
`2.30
`1.86
`1.51
`1.23
`1.00
`0.81
`0.65
`
`0.34
`0.03
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`0.00
`
`Size (J1n1)
`
`undet<Vo
`Volume
`
`Sampler: MS 1
`
`Uniformity= 6.515E-01
`D (v, 0.5) = 3.50 IJ.III
`D [4, 3] = 4.34 ""'
`Density= 1.427 g/cm3
`
`Analysis: Polydisperse
`
`Beam: 2.40 mm
`
`m
`18
`'ol
`10
`
`Particle size distribution of a micronized powder measured using laser diffraction.
`
`Table 6.3
`
`_.-.;,-.....,-ca..:~ • r-~.~
`
`·-··-···-t
`
`.•. -
`
`-~'1!1.·---..;..,.·, -z--_-..,._;.o
`_..:.. ....... ~ .... ~~.....:lA~---..
`_
`
`------
`-·-·
`___ ,, ________ .. ·;
`~~···. _., ......... ·-+ ~~ ..... ~ ·~-~ ....:L_
`
`... --.~1" .. ~-..a...=--~·1
`
`---
`
`----
`
`0
`
`Exh. 1007
`
`

`
`186
`
`Pharmaceutical Preformulation and Formulation
`
`Preformulation as an Aid . .. in Early Drug Development
`
`187
`
`,.
`
`~
`
`In terms of sample preparation, it is necessary to deaggregate the samples so that the pri-
`mary particles are measured. To achieve this, the sample may be sonicated, although there is a
`potential problem of the sample being clisrupted by the ultrasonic vibration. To check for this,
`it is recommended that the particle dispersion be examined by optical microscopy.
`Although laser light diffraction is a rapid and highly repeatable method in determining
`the particle size distributions of pharmaceutical powders, the results obtained can be affected
`by particle shape. In this respect, Kanerva et al. ( 1993) examined narrow sieve fractions of
`spherical pellets, cubic sodium chloride and acicular anhydrous theophylline. Size distribu-
`tions were made using laser light diffraction and compared to results using image analysis.
`The results showed that all determinations using the laser light scattering resulted in a broad-
`ened size distribution compared to image analysis. In addition, it has been pointed out that
`the refractive index of the particles can introduce an error of 10 percent under most circum-
`stances if it is not taken into account (Zhang and Xu 1992).
`Another laser-based instrument, relying on light scattering, is the Aerosizer. This instru-
`ment is for a particle sizing and is based on a time-of-flight principle as described by Niven
`( 1993). The Aerosizer with aero-disperser is specifically designed to carry deaggregated parti-
`cles in an air stream for particle sizing. This instrumentation has been evaluated using a salbu-
`tamol base, terbutaline sulphate and lactose (Hindle and Byron 1995).
`For submicron materials, particularly colloidal par ticles, quasi-elastic light scattering is
`the preferred technique. "11tis has been usefully reviewed by Phlllies (1990). The particle size
`disrributioo of ofloxacinlprednisolone acetate for ophthalmic use has been investigated by
`image analysis photon correlation spectroscopy (PCS) and single particle optical
`(SPOS) (Hacche eta!. 1992). Using these techniques, it was shown that ball milling
`particle size of -
`I ~~om and that increasing the ball-milling time increased the reproducibil-
`ity of diameter of particles. PCS was then used to show that extended ball milling reduced
`particle size to a constant value.
`
`Surface Area Measurements
`The surface areas of drug particles are important because clissolution is a function of this
`rameter (as preclicted by the Noyes-Whitney equation). Surface area can also be quoted
`particle size is difficult to measure (Curzons et al. 1993}.
`Surface areas are usually determined by gas adsorption (nitrogen or krypton}
`though there are a number of theories describing this phenomenon, the most widely
`method is the Brunauer, Emmet and Teller, or BET, method. Adsorption methods for
`area determination have been reviewed in detail by Sing (1992). Two methods are
`multipoint and single-point.
`Without going into too much theoretical detail, the BET isotherm for Type II
`processes (typical for pharmaceutical powders) is given by:
`
`{ c-1 }{ P}
`1
`p
`- - - ---+ - - -
`P
`• ,.{ n
`n\ -
`,.v
`..-\{
`
`s,- VrnonNAcs
`M
`
`(6}
`
`where N is the Arogadro's number, Acs is the cross-sectional area of the adsorbate and M is the
`moleular weight of the adsorbate. lt follows that the specific surface area is given by S/m,
`where m is the mass of the sample. According to the U. S. Pharmacopeia (USP), the data are
`considered to be acceptable if, on linear regression, the correlation coefficient is not less than
`0.9975, i.e., r2 is not less than 0.995.
`Figure 6.6 shows the full adsorption-desorption isotherm of two batches of the mi-
`cronized powder shown earlier in Figure 6.4.
`
`Figure 6.6 Full Type lib adsorption isotherm for two batches of a micronized powder.
`
`. 1
`I
`
`• t ,,
`
`<:;
`
`00 6 i
`~ ., .e •t
`0 "' -o <
`~ ·r
`
`3 -
`
`Exh. 1007
`
`

`
`188
`
`Phannaceulical Prcformularion and Fotmularion
`
`It should be noted that, experimentally, it is nee< Mar)' to remove gases and vapours that
`may be present on the surface o£ the powder. This is usually achieved by drawing a vacuum
`or purging the sample in a flowing stream of nitrogen. Raising the temperature may not
`always be advantageous. For eJ<ample, Phadke and (".oilier ( 1994) examined the effect of de-
`gassing temperature on the surface area of magnesium stearate obtained from two manu.fac-
`turecs. In this study, helium at a range of temperatures between 23 and 6o•c was used in
`single and multipoint determinations. It was fotJ nd that the specific. surface area of the sam-
`ples decreased with an increase in temperature. From other mea:;urements using DSC and
`thermogravimetric analysis (TGA), it was found that raising the t·cmperature changed the
`nature of the samples. Hence, it was recommended that magnesium stearale s