`
`Review
`
`Pharmaceutical Solids: A Strategic Approach to
`Regulatory Considerations
`
`Stephen Byrn,’* Ralph Pfeiffer, Michael Ganey,”-? Charles Hoiberg,” and
`Guirag Poochikian?
`
`eee
`
`Purpose. This review describes a conceptual approachto the characterization of pharmaceuticalsolids.
`Methods. Fourflow charts are presented: (1) polymorphs, (2) hydrates, (3) desolvated solvates, and (4)
`amorphousforms. Results. These flow charts (decision trees) are suggested as tools to develop infor-
`mation on pharmaceutical solids for both scientific and regulatory purposes. Conclusions. It is hoped
`that this review will lead to a more direct approachto the characterization of pharmaceutical solids and
`ultimately to faster approval of regulatory documentscontaining information on pharmaceuticalsolids.eeeeeeeeESeeeEOE
`KEY WORDS: polymorph; hydrate; amorphous form; desolvated solvate.
`
`Interest in the subject of pharmaceutical solids stems in
`part from the Food and Drug Administration’s (FDA’s) drug
`substance guideline that states ‘‘appropriate”’ analytical pro-
`cedures should be used to detect polymorphic, hydrated, or
`amorphous forms of the drug substance. These guidelines
`suggest the importance of controlling the crystal form of the
`drug substance. The guideline also states that it is the appli-
`cant’s responsibility to control the crystal form of the drug
`substance and, if bioavailability is affected, to demonstrate
`the suitability of the control methods.
`Thus, while it is clear that the New Drug Application
`(NDA) should contain information on solid state properties,
`particularly when bioavailability is an issue, the applicant
`may be unsure about howtoscientifically approach the gath-
`ering of information and perhaps whatkind of informationis
`needed. This review is intended to provide a strategic ap-
`proach to remove much ofthis uncertainty by presenting
`concepts and ideas in the form of flow charts rather than a
`set of guidelines or regulations. This is especially important
`because each individual compoundhasits own peculiarities
`which require flexibility in approach. The studies proposed
`herein are part of the Investigational New Drug (IND) pro-
`cess.
`
`Solid drug substances display a wide and largely unpre-
`dictable variety of solid state properties. Nevertheless, ap-
`plication of basic physicochemical principles combined with
`appropriate analytical methodology can provide a strategy
`
`
`
`1 Department of Medicinal Chemistry and Pharmacognosy, Purdue
`University, West Lafayette, Indiana 47907.
`? Division of Oncology and Pulmonary, Food and Drug Administra-
`tion, 5600 Fishers Lane, Rockville, Maryland 20857.
`> Current Address: Pfizer Central Research, Groton, Connecticut.
`* To whom correspondence should be addressed.
`
`for scientific and regulatory decisions related to solid state
`behaviorin the majority of cases. By addressing fundamen-
`tal questions aboutsolid state behavior at an early stage of
`drug development, both the applicant and the FDA are ina
`better position to assess the possible effects of any variations
`in the solid state properties of the drug substance. The re-
`sulting early interaction of the parties with regard to this area
`would not only tend to ensure uniformity of the materials
`used throughoutthe clinical trials but also fully resolve solid
`state issues before thecritical stages of drug development. A
`further benefit of these scientific studies is the development
`of a meaningful set of solid state specifications which criti-
`cally describe the solid form of the drug substance. These
`specifications would thus also facilitate the approval of a
`change in supplier or chemical process.
`Our approachin this review is to suggest a sequence for
`collecting data on a drug substance that will efficiently an-
`swerspecific questions about solid state behaviorin a logical
`order.In ‘‘difficult’’ cases, perhaps where mixtures of forms
`must be dealt with, or other unusual properties are encoun-
`tered, the suggested sequences would still have to be fol-
`lowedasa first stage in this investigation.
`We have chosento present this approach in the form of
`a series of decision trees, or flow charts (algorithms), one for
`each of the most common solid state forms. The charts are
`accompanied by examples from theliterature representing
`the kind of data that would be useful in supporting the var-
`ious decisions.
`Decision trees provide conceptual frameworks for un-
`derstanding how the justification for different crystal forms
`might be presented in the drug application. Industry may
`wish to use these decision treesas a strategic tool to organize
`the gathering of information early in the drug development
`process. Put another way, these decision trees provide a
`thought process that will lead to development of the most
`
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`Byrn, Pfeiffer, Ganey, Hoiberg, and Poochikian
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`appropriate analytical controls. One should also note that it
`is the responsibility of the industry to select the appropriate
`test or tests to identify the phase of the solid and determine
`its relevant pharmaceutical properties. This approachis su-
`perior to simply performing a broad range of tests without
`regard to their relevance.
`Weshould point out that, from a regulatory standpoint,
`if a companycanestablish a specification/test to ensure pro-
`duction of a well defined solid form of the drug substance,
`then it is not necessary to do all of the physical/chemical
`testing outlined in the decision trees. From a scientific stand-
`point, however, such an approachis risky since new forms
`may appear unpredictably during various stages of the de-
`velopment process. The appearance of these new forms usu-
`ally slows the drug approval process and makes planning
`difficult.
`Four decision trees are described in the sections that
`follow: Polymorphs; Hydrates (Solvates); Desolvated
`Solvates; and Amorphous Forms. Polymorphs exist when
`the drug substance crystallizes in different crystal packing
`arrangementsall of which have the same elemental compo-
`sition (Note that hydrates can exist in polymorphs). Hy-
`drates exist when the drug substance incorporates water
`in the crystal lattice in either stoichiometric or non-
`stoichiometric amounts. Desolvated solvates are produced
`when a solvate is desolvated (either knowingly or unknow-
`ingly) and the crystal retains the structure of the solvate.
`Amorphous forms exist when a solid with no long range
`order and thus no crystallinity is produced. It is apparent
`that the appropriate flow chart can only be determined after
`the solid has been characterized using someofthe tests de-
`scribed in the first decision point of the decision trees/flow
`charts (i.e. X-ray powder diffraction, elemental analysis,
`etc.). If there is no interest in marketing or producing an
`amorphous form or desolvated solvate at any stage in the
`process, then the corresponding flow charts do not need to
`be addressed. As already mentioned, it is advisable to inves-
`tigate the drug substance for the existence of polymorphs
`and hydrates since these may be encountered at any stage of
`the drug manufacturing process or upon storage of the drug
`substance or dosage form.
`
`Ali of the flow charts end (see for example Figure 1)
`with an indication of the types of controls which will be
`required based on whether a single morphic form or a mix-
`ture will be produced as the drug substance. Although this
`ending provides a simplistic view of a very complicated pro-
`cess of selecting appropriate controls, it is included toillus-
`trate the consequenceofthe decisions made with regard to
`the drug substance. The reader should realize that the actual
`selection of the appropriate control could be the subject of
`another review which might contain another set of flow
`charts or decision trees.
`
`POLYMORPHS
`
`The flow chart/decision tree for polymorphs is shownin
`Figure 1. It outlines investigations of the formation of poly-
`morphs, the analytical tests available for identifying poly-
`morphs, studies of the physical properties of polymorphs
`and the controls needed to ensure the integrity of drug sub-
`stance containing either a single morphic form or a mixture.
`
`A. Formation of Polymorphs—Have Polymorphs
`Been Discovered?
`
`Thefirst step in the polymorphs decision tree is to crys-
`tallize the substance from a numberofdifferent solvents in
`order to attempt to answer the question: Are polymorphs
`possible? Solvents should include those used in the final
`crystallization steps and those used during formulation and
`processing and mayalso include water, methanol, ethanol,
`propanol, isopropanol, acetone, acetonitrile, ethyl acetate,
`hexane and mixtures if appropriate. New crystal forms can
`often be obtained by cooling hot saturated solutions or partly
`evaporating clear saturated solutions. The solids produced
`are analyzed using X-ray diffraction and at least one of the
`other methods. In these analyses, care must be taken to
`show that the method of sample preparation (i.e. drying,
`grinding) has not affected the solid form. If the analyses
`show that the solids obtained are identical (e.g. have the
`same X-ray diffraction patterns and IR spectra) then the an-
`swerto the question ‘‘Are polymorphs possible?’ is ““No’’,
`
`POLYMORPHS
`Drug Substance
`
`Polymorphs
`Discovered?
`
`Different Recrystallizing
`Solvents (different
`polarity) - vary
`temperature, concentration,
`agitation, pH
`
`Tests for Polymorphs
`- X-Ray Powder Diffraction
`- DSC (Thermoanalytical
`Methods)
`- Microscopy
`-IR
`- Solid State NMR
`
`No
`
`Yes
`
`7—-— No
`
`Yes
`
`Drug
`Substance
`Composition?
`
`Single Morphic Form
`Qualitative Control
`(e.g., DSC or XRD)
`Mixture of Forms
`Quantative Control
`(e.g., XRD)
`
`Monitor Polymorph
`in Stability Studies
`
`.
`Different
`Physical
`Properties?
`
`Different
`- Stability (Chemical
`& Physical)
`- Solubility Profile
`- Morphologyof Xtals
`- Calorimetric Behav.
`- % RHprofile
`
`Figure 1. Flow chart/decision tree for polymorphs.
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`Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations
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`947
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`
`
`and further research is not needed. The work of Miyamaeet
`al. serves as a good example ofsolid state studies of a drug
`substance which exists as polymorphs (1). Powder diffrac-
`tion showedthat there were twocrystal forms (see Figure 2).
`These workersalso carried out single crystal analysis of
`the two crystal forms of the compound. Thestructures are
`shownin Figure 3. While such studies are not required, and
`indeed sometimes not possible, they provide an unequivocal
`confirmation of the existence of polymorphs. Moreover,
`once the single crystal structure of a phase has been deter-
`mined, it is possible to calculate the corresponding X-ray
`powderpattern. This provides an irrefutable standard for
`identifying the phase by that method.
`The DSC thermal curves of the two formsare slightly
`different, as shown in Figure 4 and thus may not be the
`preferred way of differentiating these polymorphs.
`The IR spectra of the two polymorphsare quite simi-
`lar(1), and IR does not appear to be a powerful method for
`differentiating the crystal forms in this case. Thus, for 8-(2-
`methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-
`propynyl)-imidazo{1,2-a}pyridine, powder diffraction ap-
`pears to be the best methodfordifferentiating the two forms.
`Solid-state NMRis another powerful technique for an-
`alyzing different crystal forms (2,3). Figure 5 shows the
`solid-state C-13 NMRspectra of Forms I and II of prednis-
`olone. Differences in the positions of the two resonances in
`the 120 ppm range clearly differentiate the two forms. In
`principle, solid state NMRis an absolute technique in which
`the signal intensity is proportional to the number ofnuclei
`provided appropriate conditions are met. In addition, solid
`state NMRis a bulk technique whichis not very sensitive to
`surface changes. This method appears to be very sensitive
`and will undoubtedly be used more often in the future as a
`tool to detect different crystal forms. However, with present
`technology, errors in solid-state quantitative studies may be
`rather large.
`
`taal
`Form Bnen
`
`fae
`
`Kae
`
`fae
`
`Byzu Be
`Eu
`Waa
`
`Figure 3. Stereoscopic drawings of the crystal packing of both poly-
`morphs of 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-
`methyl-3-(2-propynyl)-imidazo{1,2-a}pyridine viewed along the
`shortest axis (Form A, b-axis; Form B, a-axis) (1).
`
`B. Do the Polymorphs Have Different Physical Properties?
`
`is necessary to examine
`If polymorphs exist then it
`the physical properties of the different polymorphs that
`can affect dosage form performance(bioavailability and sta-
`bility) or manufacturing reproducibility. The properties of
`interest are solubility profile (intrinsic dissolution rate, equi-
`librium solubility), stability (chemical and physical), and
`crystal morphology (including both shape andparticle size),
`calorimetric behavior, and %RHprofile. If there are no dis-
`cernible differences between these physico-chemical prop-
`erties, then the answerto the second questionin the decision
`tree, ‘Different physical properties?”’ is ‘‘No.”’
`The variable physical properties of several drugs with
`different polymorphsare reported in the literature. For ex-
`ample, the dissolution profiles of the polymorphs of chlor-
`amphenicol are significantly different (4). In addition, van’t
`Hoff solubility analysis has been used to elucidate the dif-
`
`Form A
`
`Form B
`
`VY
`=iuoa
`Ss
`uacws
`
`120
`
`140
`
`160
`
`180
`
`200
`
`Temperature,
`
`°C
`
`Diffraction angle
`
`29,
`
`degree
`
`Figure 2. Powder X-ray diffraction patterns of the polymorphs of
`8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-
`propynyl)-imidazo{1,2-a}pyridine (1).
`
`Figure 4. DSC thermal curves of the polymorphs of 8-(2-
`methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-
`propyny])-imidazo{] ,2-a}pyridine (1). These curves show that Form
`A melts whereas Form B undergoes a small endothermic transition
`and then melts at the same temperature as Form A.
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`solid form for production. Usually, this would be the most
`physically stable form when their bioavailabilities are not
`significantly different. Selection of the most stable from
`would, of course, insure that it there would be no conversion
`into other forms.
`Powderdiffraction is often a useful method to determine
`the percentages of polymorphs in a mixture; however, the de-
`tection limit is variable from case to case and can beas high as
`15%. Matsuda (7) carried out a mixture analysis of phenylbu-
`tazone polymorphs. Diffraction lines disappear and appear as
`the ratio of the crystal forms change. Someofthese calibration
`curves developed from this analysis are almost horizontal,
`meaning that any given mixture gives the sameline intensity in
`this mixture range. However, other calibration curves are
`sloped and would appear to allow a reasonable analysis. It is
`fair (although Matsuda did not carry out an estimate) to esti-
`mate the errors in this analysis as + 15%.
`Tanninen and Ylirussi (8) used computercurvefitting to
`carry out a mixture analysis of prazosin. In this particular
`case, they reported a highly accurate analysis, and, in fact,
`showed a calibration curve that could detect 0.5% of one
`form in another. This is obviously a highly accurate mixture
`analysis by powderdiffraction and shows the powerofthis
`method for some applications. However, this analysis re-
`quired extreme care in sample preparation and may be more
`difficult to carry out in a production setting where particle
`size may not be controlled. Similar comments apply to the
`analysis of mixtures by IR, where the accuracy andprecision
`may also vary considerably from case to case. Given the
`analytical problems in dealing with mixtures of forms, it may
`generally be simpler to develop a methodto prepare only one
`crystal form.
`In summary,it is important to determine whether poly-
`morphsare present and to solve any problemsbefore pivotal
`clinical studies are initiated.
`
`D. Determination of the Polymorph Present in the
`Drug Product
`
`In cases wherestability or bioavailability issues exist,
`the solid form present in the drug product should be inves-
`tigated, if possible.
`For bulk drug substances, X-ray powderdiffraction and
`other techniques can identify the polymorph; however, solid
`state NMRappearsto be the best methodforthe study of the
`drug substance in the dosage form (2, 3). Solid-state NMR
`study of three commercial products containing prednisolone
`showedthat the products A and B contain Form I, whereas
`product C contains Form II.. This analysis was possible even
`though these tablets contain approximately 95 mg of excip-
`ients and 5 mg of drug. There are numerous cases, often
`involving complex mixtures or low dose products, where
`solid state NMR (and,
`in fact, any technique) will not be
`sensitive enough to identify the polymorph present in the
`drug product. However, the safety and efficacy is, of course,
`controlled by the potency assays and by the physical tests
`(e.g., dissolution).
`
`HYDRATES (SOLVATES)
`
`The flow chart/decision tree for hydrates (solvates) is
`shownin Figure6. It outlines investigations of the formation
`
`200
`
`180
`
`100
`
`so
`
`Oo
`
`PPA
`
`ara
`200
`150
`100
`50
`0
`
`PPH
`
`Figure 5. Solid state NMR of the two Crystal Forms of Predniso-
`lone (2).
`
`ferent solubilities of two polymorphs of methy! predniso-
`lone(5). This method involves determining the equilibrium
`solubility of each polymorph at various temperatures. The
`log of the equilibrium solubility is then plotted vs 1/T. This
`should give straight lines for each polymorph and the tem-
`perature at which the curvesintersect is the transition tem-
`perature. This technique does not work if the polymorphs
`interconvert.
`For balance, it is important to point out that there are
`also cases where polymorphs exist but they have virtually
`identical dissolution properties(6).
`
`C. Drug Substance Control
`
`The important question lies in the properties that differ
`among polymorphs and whether those properties affect the
`dosage form performance(i.e., quality or bioavailability). If
`they do then from a regulatory standpointit is appropriate to
`establish a specification/test (e.g. powder X-ray diffraction
`or IR) to ensure the proper form is produced. From a pro-
`duction standpoint, it is important to develop a process that
`reproducibly produces the desired polymorph.
`If mixtures of forms cannot be avoided, then quantita-
`tive control is needed to ensure that a fixed proportion of
`formsis obtained. Furthermore, the method of analyzing for
`the proportion of forms would haveto be validated. Aiso, the
`proportion of forms would have to remain within stated lim-
`its through the retest date of the drug substance and poten-
`tially throughout the shelf life of the product; a difficult re-
`quirementif the forms interconvert. Thus, the way to avoid
`a substantial amount of workin this area is to select a single
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`949
`
`HYDRATES (SOLVATES)
`Drug Substance and Solvent
`
`No
`
`Yes
`
`7—— No
`
`.
`Different
`Physical
`Properties?
`Difk
`mcrent
`:
`- Stability (Chemical
`:
`& Physical)
`- Solubility Profile
`- Morphologyof Xtals
`- Calorimetric Behav.
`- % RHprofile
`
`Yes
`
`Drug
`Substance
`Composition?
`
`Single Hydrate
`ualitative Control
`Q
`(e.g., DSC or XRD)
`
`Mixture of Forms
`Quantative Control
`(e.g., XRD)
`:
`Monitor Hydrate
`‘
`a
`in Stability Studies
`
`Hydrates
`Discovered?
`
`Pa
`:
`Different Recrystallizing
`Solvents (different
`polarity) - vary
`temperature, concentration,
`agitation, pH, water content
`Tests for Hydrates
`.
`.
`- X-Ray Powder Diffraction
`DSC/TGA/Hot
`S
`Mi
`ot
`Stage
`El
`entalAt,y .
`- f omental act lysis
`IR
`Prolite
`:
`- Solid State NMR
`- Solution NMR(Solvent
`Content and Amount)
`
`Figure 6. Flow chart for solvates or hydrates.
`
`of hydrates (solvates), the analytical tests available for hy-
`drates (solvates), studies of the physical properties of hy-
`drates (solvates) and the controls needed to ensure the in-
`tegrity of drug substance containing either a single morphic
`form or a mixture.
`
`A. Have Hydrates (Solvates) Been Discovered?
`
`The flow chart for. hydrates (solvates) (Figure 7) is ap-
`plied after the preliminary crystallizations have been com-
`pleted. These are essentially the same as in the polymorph
`decision tree but, in addition, should include solvent-water
`mixtures in order to maximize the chance for hydrate for-
`mation. These experiments can be guided by the moisture
`uptake (% RH) studies. Anysolids that indicate a significant
`change in water contentas indicated by the % RH-moisture
`profile should also be examined. The resulting solid phases
`are preferably characterized by a combination of methods—
`two for phase identity and two to reveal composition and
`stoichiometry.
`With a very few exceptions, the structural solvent con-
`tained in marketed crystalline drug products is water. It is
`nevertheless often desirable to characterize other solvated
`crystalline forms of a drug for several reasons: they may be
`the penultimate form usedto crystallize the final product and
`thus require controlled characterization; they may form if
`the final crystallization from solvents, especially mixed sol-
`vents, is not well controlled; they maybethe actual crystal-
`lized form of a final product that is desolvated during a final
`drying step; they may be the form used in recovery for sub-
`sequent rework. The relevanceofthesepoints will vary from
`case to case, but for the present discussion weshall treat the
`subject of solvates in its broadest form.
`Examples taken from the literature serve to illustrate
`the kind of data that proves usefulin characterizing solvated
`erystal forms. For example, a recent report from our labo-
`ratory showed that IR and solid state NMR was useful for
`the identification of the different crystal forms of dirithro-
`mycin(9). TGA is another powerful method for the analysis
`
`of solvates. For example, one early study showed that TGA
`could differentiate three different hydrated salts of feno-
`profen(10). Combined with IR or other methods, TGAis an
`unequivocal methodfor the verification of the existence of
`solvates. In addition, TGA is a good methodfor looking at
`mixtures of solvated and unsolvated crystal forms, and prob-
`ably can be developed into an analytical method for deter-
`mining the ratios of solvated and unsolvated forms.
`DSCis also a good methodfor detecting solvates since
`there is usually heat change involved in desolvation, espe-
`cially for hydrates(11). Specifically, DSC by itself does not
`prove the existence of a solvate, but once other analytical
`
`—
`
`%
`WATER *
`CONTENT
`
`VAPOR PRESSURE ISOTHERM FOR
`SODIUM CEFAZOLIN (T = 25°C)
`
`
`
`
`SESQUIHYDRATE FORM 5
`
`MONOHYDRATE FORM
`
`% RELATIVE HUMIDITY
`Figure 7. Water uptake vs percentrelative humidity for sodium
`cefazolin.
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`tion profile of theophylline hydrate and anhydrate. Thisfig-
`ure showsthat the anhydrate reaches a muchhighersolubil-
`ity in water, and on extended exposurerecrystallizes to the
`less soluble hydrate. Such differences must be further exam-
`ined for possible effects on bioavailability.
`In our laboratory we have described the different crystal
`forms of hydrocortisone-21-tertiary butylacetate(14). Our
`studies showed that the nonstoichiometric ethanolate is ox-
`ygen-sensitive and, of course, would show different physical
`properties from the stoichiometric ethanolate and the other
`solvates. Prednisolone tertiary-butylacetate also exists as a
`nonstoichiometric hydrate which is oxygen sensitive(15).
`Thus, these are cases where different crystal forms have
`different chemical stability, although there may be nosignif-
`icant differences in solubility.
`
`C. Mixtures of Polymorphs and Hydrates
`
`Other drug substances exist as both polymorphs and
`solvates. For example, furosemide exists in two poly-
`morphs, two solvates, and an amorphous form (16, 17). The
`polymorphsare enantiotropically related, which meansthat
`at one temperature one polymorph is more stable, but at a
`different temperature the other polymorph is physically
`more stable. That is, plots of solubility versus temperature
`cross for the two polymorphs. In addition, the different crys-
`tal forms have different photostability (chemical stability in
`light) and moreover have different dissolution rates. Thus,
`there are significant differences in both chemical and phys-
`ical properties.
`Thefive different forms, or modifications of furosemide,
`give clearly different powder patterns. Thus, powderdiffrac-
`tion is a good methodfor analysis of these different forms.
`There are similarities between the IR spectra of the five
`different forms but there are also some significant differ-
`ences, and expansion andcareful analysis could lead to an
`FT/IR methodfor analysis of these different forms. IR would
`probably be a useful method for analysis at least for pairs of
`these compounds. However,it is not clear whether IR could
`be used to determine the percentages of several different
`forms in a more complex mixture. The DSC and TGAofthe
`different forms are significantly different. As expected, the
`solvates show weight loss in the TGA.
`
`14
`
`THEOPHYLLINE
`
`© ® anhydrous form
`@ hydrate
`y
`
`12
`
`E
`Slo
`
`— z
`
`8
`a -
`ao 6
`
`4
`
`z o
`
`950
`
`data from TGA, NMR, etc. are available, DSC becomes a
`good method for analyzing solvates and determining a per-
`centage of solvates present.
`The three solvates of ethynylestradiol (0.5 acetonitrile,
`1.0 methanol, 0.5 water) provides another interesting exam-
`ple (12). These solvates have different cell parameters and
`are crystallographically completely distinct materials. The
`hemihydrate was obtained from an organic solvent whichis
`not completely miscible with water but was saturated with
`water. In fact, it is known that crystallization from water-
`immiscible solvents containing small but slightly different
`proportions of water can produce different hydrates of a
`substance.
`The DSC/TGAofthe three ethynylestradiol solvates(12)
`are unique and in this case it may be possible to develop
`DSC/TGAinto an analytical procedure for determining the
`proportions of each solvate. The DSC in some of these
`traces appears to show a melt and recrystallization corre-
`sponding to the loss of solvent of crystallization. However,
`the exact interpretation of this is not possible without either
`a DSC microscopeorinterrupting the tracing to analyze the
`sample at various temperatures. The methanolate appears to
`lose solvent in two equal steps, indicating that there may
`also be a hemimethanolate of this compound. Again, confir-
`mation of this would require interrupting the heating and
`analyzing the substance after the first solvent loss has oc-
`curred. In addition, the DSC/TGAtraces suggestthatall of
`the forms are converted to an anhydrous form which then
`melts at a higher temperature. Thus, interrupting any one of
`these thermal curvesjust prior to the final melt could reveal a
`new form that gives the powderpattern for the anhydrate. Un-
`fortunately, no data of this type is provided in the casecited.
`DSC analysis of solvates should be carried out using
`either an open pan or a pan with a pin-prick; otherwise,
`unusual and variable results will be obtained because the
`solvent is not provided a way of escape from the pan. One
`advantage of using an open pan for DSC isthatit reproduces
`the conditions under which the TGA is performed.
`Comparison of the ethinylestradiol powder diffraction
`patterns clearly establishes that these solvates are different
`crystal forms as would be expected from the single crystal
`data(12). In summary, DSC, TGA, and powderdiffraction
`are all good methods for analysis of the different crystal
`forms of ethinylestradiol.
`Figure 7 showsa percentrelative humidity versus water
`uptake study of the type recommended by the USP commit-
`tee on water(13) In this case, there are two hydrates which
`are relatively well behaved insofar as they are completely
`hydrated at about 10% relative humidity and remain uni-
`formly hydrated throughout a wide humidity range. On the
`other hand, the so-called pentahydrate, which really is only
`a pentahydrate at very high humidity, changes water content
`considerably as the relative humidity is changed. The USP
`committee on moisture specifications recommended that
`moisture uptake vs relative humidity studies should be rou-
`tinely performed on all drug substances and excipients (13).
`
`B. Do the Hydrates (Solvates) Have Different
`Physical Properties?
`The physical properties of hydrates are often quite dif-
`ferent from the anhydrate form. Figure 8 showsthe dissolu-
`
`5Oo 2
`
`0.
`
`65
`
`lO & 20 25 30 35 40 45
`TIME X 104s
`Figure 8. The dissolution-time curves for anhydrous and hydrated
`theophylline in water at 25°. The two types of opencircles represent
`successive experiments (18).
`
`50
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`I-MAK1013
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`I-MAK 1013
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`Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations
`
`951
`
`The interconversionofthe different forms of furosemide
`have been analyzed and a diagram constructed. Such a dia-
`gram can be experimentally difficult when so manypairs of
`crystal forms must be studied for possible interconversions
`and underdifferent conditions. It is clear from this diagram
`that many of the forms of furosemide can be converted to
`form I. This study is one of the most complete reports of
`solvates and polymorphs available in the literature and
`serves as a model for studies of such systems for regulatory
`submissions.
`
`D. Determination of the Hydrate Present in the
`Drug Product
`
`Another important area is the analysis of the material
`whichis producedafter wet granulation of a substance which
`can form hydrates. We are aware of cases where the bulk
`drug substance is manufactured and stored as the anhydrate.
`However, upon wet granulation, there is a conversion (either
`partial or complete) to a hydrate. Subsequent drying is some-
`times not adequate to convert the substance back to the
`anhydrate, and a hydrate or a mixture of hydrate and anhy-
`drate remain. The formation of a hydrate and its subsequent
`drying can result in a change in particle size of the drug
`substance (19). It may also be possible to cause transforma-
`tions during other processing steps. It is thus recommended
`that if wet granulation or processing that subjects the drug to
`even brief changes in temperatureorpressure(e.g. milling or
`compression) is contemplated, then extensive studies of the
`ability to convert the drug substanceto a newcrystal form be
`carried out by mimicking the processing step in the labora-
`tory.
`
`DESOLVATED SOLVATES
`
`The term ‘‘desolvated solvates” refers to compounds
`that are crystallized as solvates but undergo desolvation
`prior to analysis. Often these ‘‘desolvated solvates”’ retain
`
`the structure of the solvate with relatively small changes in
`the lattice parameters and atomic coordinates, but no longer
`contain the solvent. In addition, desolvated solvates are apt
`to be less ordered that their crystalline counterparts. These
`formsare particularly difficult to characterize properly since
`analytical studies indicate that they are unsolvated materials
`(anhydrous crystal forms) when, in fact, they have the struc-
`ture of the solvated crystal form from which they were de-
`rived. Several observations may give clues that oneis deal-
`ing with a desolvated form: (1) The form can be obtained
`from only one solvent; (2) On heating, the form converts to
`a structure known to be unsolvated; and (3) The form has a
`particularly low density comparedto other forms of the same
`substance. Experiments that help to clarify whether an ap-
`parently solvent free modification is a desolvated form or a
`true anhydrate include:
`(1) Single crystal X-ray structure
`determination in the presence of mother liquor from the
`crystallization; (2) comparison of the X-ray powder diffrac-
`tion patterns and solid state NMR spectra of the solvated
`and desolvated crystal forms; and (3) determination of the
`vapor pressure isotherm by varying the vapor pressure ofthe
`specific solvent involved. A desolvated form will often take
`up stoichiometric amounts of the relevant solvent. In addi-
`tion, crystals of the form directly isolated from the crystal-
`lizing medium will show a plateau in their isotherm as the
`vaporpressure of the solvent is reduced.
`Figure 9 showsthe flow chart used to address regulatory
`issues