Argentum EX1018
`
`
`
`Argentum EX1018
`
`Page 1
`Page 1
`
`"o
`
`f Drugs
`
`Stephen R. lyrn
`
`
`
`

`

`Sol id(cid:173)
`State
`Chemistry
`of Drugs
`
`STEPHEN R. BYRN
`11
`Department of Medicinal Chemistry
`and Pharmacognosy
`School of Pharmacy and
`Pharmacal Sciences
`Purdue University
`West Lafayette, Indiana
`
`ACADEMIC PRESS 1982
`A Subsidiary of Harcourt Brace Jovanovich, Publishers
`London
`New York
`Paris San Diego San Francisco Sao Paulo Sydney Tokyo Toronto
`
`Page 2
`
`

`

`Contents
`
`PREFACE
`
`Introduction
`
`1
`
`Introduction
`
`I. Crystallization and Properties of Crystals
`II. Properties of Other Solids
`III. Solid-State Chemistry of Drugs
`IV. Stability Testing
`V. Summary
`References
`
`2 Methods of Analysis
`
`I. X-Ray Crystallography
`II. Microscopy and Photomicrography
`III. Thermal Methods of Analysis
`IV. Electron Microscopy
`
`xi
`
`3
`
`4
`10
`12
`19
`26
`26
`
`29
`
`29
`43
`45
`48
`
`vii
`
`Page 3
`
`

`

`viii
`
`V. Infrared Spectros copy of Solids
`VI. Analytical Melhods Requiring Dissolution of the Sample
`VII. Summary
`Bibliography
`References
`
`3 Kinetics of Solid-State Reactions
`I. Theoretical Description of Solid-Stale Reactions and Their Kinetics
`II . Examples of Solid-Slate Kineti c Studies
`III . Summary
`References
`
`Contents
`
`49
`50
`57
`57
`58
`
`59
`
`59
`65
`74
`74
`
`11
`Physical Transformations
`
`4 Polymorphism of Drugs
`I. Generdl Review of Polymorphism
`11. Polymorphism of Sulfonamides
`W . Polymorphism of Steroid
`IV. Polymorphism of Barbiturates
`V. Polymorphism of Other Drugs
`VI. Polymorphism and Hs Pharmaceutical Application
`VII . Summary
`References
`
`5 Loss of Solvent of Crystallization
`I. Loss of Solvent of Crys talllzation
`II. The Mechanism of Desolvation Reactions
`Ill. Summary
`References
`
`111
`Solid-Gas Reactions
`
`6 Solid-State Oxidation Reactions
`I. Oxidations of Rubrene and Tetramethylrubrene
`II . Solid-State Ozonolysis of Stilbenes
`III. Reactions of Oxygen with Free Radicals in the Solid State
`
`79
`
`79
`103
`116
`124
`128
`140
`145
`146
`
`149
`
`149
`171
`185
`186
`
`190
`
`191
`193
`194
`
`Page 4
`
`

`

`Contents
`
`IV. Oxidation of Vitamin D2
`V. Oxidation of Vitamin A
`VI. Oxidation of Vitamin C (Ascorbic Acid) in Tablets
`VII. Oxidation of Polyene Antibiotics
`VIII. Oxidation of Reserpine
`IX. Photooxidation of Dyes Used in Coating Tablets
`X. Solid-State Oxidation Reactions Preceded by Loss of Solvent
`XI. Solid-State Oxidation of Dialuric Acid Monohydrate: The Impor-
`tance of Moisture in Accelerating Solid-State Reactions
`XII. Solid-State Reduction of the Ammonium Oxalate-Hydrogen Perox-
`ide Adduct (NH4hC204 · H202
`XIII. Summary
`References
`
`7 Additions of Gases to Solids-Solid-State Hydrolyses
`I. Reactions of Crystals with Ammonia Gas
`II. Rates of Reaction of Crystalline Carboxylic Acids with
`Ammonia Gas
`III. Reactions of Solids with Ch or Br2
`IV. Solid-State Hydrolyses
`V. Summary
`References
`
`8 Solid-State Decomposition Reactions of the Type
`A (solid) - B (solid) + C (gas)
`I. Solid-State Dehydration of Hydroxyl Compounds
`II. Solid-State Decarboxylation Reactions
`III. Decomposition of Explosives
`IV. Decompositions Which Produce Nitrogen Gas
`V. Summary
`References
`
`Ix
`
`196
`198
`201
`202
`204
`205
`206
`
`213
`
`214
`215
`215
`
`219
`
`219
`
`224
`226
`229
`237
`237
`
`239
`
`239
`246
`252
`252
`255
`255
`
`IV
`
`Solid-State Photochemical Reactions
`
`9 Solid-State Photochemical Reactions
`I. Photochemistry of Solid Cinnamic Acids, Styrylthiophenes, and
`Dienes: The Topochemical Postulate
`II. Solid-State Photochemistry of Anthracenes: Exception to the Topo-
`chemical Postulate
`III. Solid-State Photochemistry of Quinones
`
`259
`
`259
`
`264
`267
`
`Page 5
`
`

`

`X
`
`Contents
`
`IV. Solid-State Photosynthesis of Indigo: The Role of Molecular Confor-
`mation in Solid-State Reactions
`V. Solid-State Polymerizations
`VI. Dimerizations of Pyrones in the Solid State
`VII. Solid-State Photochemi ·try of Nucleic Acids
`VIII. Effec t of Ionizing Radiation on Crystal of Biologically
`Important Compounds
`IX . Solid-State Photochemistry of Drugs and Natural Products
`X. Summary
`References
`
`V
`
`Solid-State Thermal Reactions
`
`10 Solid-State Thermal Reactions
`I. Solid-State Rearrangement Reactions
`II. Thermal R etro Cycload dition Reaction s
`III. Solid-State Therma l Reactions of Drugs and Biologically
`Important Compounds
`IV. Summary
`References
`
`VI
`
`Miscellaneous Topics
`
`11 Miscellaneous Topics in the Solid-State Chemistry
`of Drugs
`I. The Role of Defects in Solid-State Reactions
`II. Solid-So lid Reactio ns
`III. Solid-State Carbon NMR Spectroscopy-A New Metl)od for the
`Study of Solid Drugs
`IV. Conclusion
`References
`
`12 Conclusion
`
`GLOSSARY
`INDEX
`
`271
`272
`273
`273
`
`275
`278
`282
`283
`
`287
`
`287
`298
`
`301
`310
`310
`
`315
`
`315
`317
`
`322
`326
`326
`
`329
`
`333
`341
`
`Page 6
`
`

`

`I
`
`Introduction
`
`Introduction
`
`
`
`
`
`Page 7
`
`

`

`1
`
`Introduction
`
`The branch of science termed solid-state chemistry of drug s is unu su(cid:173)
`ally broad . It includes the areas of ph ysica l pharmacy and indu strial
`pharmacy (including powde r tech nology and formulat ion). Lt also include s
`the areas of stab ility of solids, kinet ics of solid-state reactions, and molec(cid:173)
`ular detail s of solid-state react ions.
`Studies of the molecular details of solid-state reactions aim at providing
`an exp lanation of the product s and rate of the reaction in terms of th e
`mo.lecular change (chemica l reaction) that occurs. The se studies usuall y
`use the crystal structure and other molecular information to provide such
`an explanation.
`The aim of this book is to rev iew the molecular detail s of solid-state
`reactions of drugs and to bring the se details to bear on pharmaceutical
`prob lems. lt is thus an attempt to p rovide a molecular basis for under (cid:173)
`sta nding the solid-state chemis try of drugs. Related aims in the areas of
`bio logy and chemistry (i.e. , attemp ts to put these areas on a molecu lar
`basis) have led to the rapid development of these branches of science. A
`similar rapid development of the area or solid-state chemis try of drugs is
`also expecte d .
`
`3
`
`Page 8
`
`

`

`4
`
`in
`
`1. Introduction
`I. Crystallization and Properties of Crystals
`is one of ordering. During thi proce s
`The proce s of crystallization
`in a solution, a melt, or the gas pha e take
`randomly organized molecule
`in the solid. Th_e regular organization of the solid is
`up regular po ition
`including the
`re ponsible for many of the unique properties of crystals,
`diffraction of x-ray , defined melting point and sharp, well-defined crystal
`involves nucleation. The formation of
`faces.
`The first step in crystallization
`dust in the
`nuclei is not well understood but could be related to impuritie
`of molecules of the compound, a few
`flask, or small conglomer ate
`angstrom s in size.
`Once formed, the nuclei grow into crystals by depo ition of molecule
`on the crystal faces. This is an equilibrium process, with the molecule
`equilibrium between the solution and the solid. (It should be noted that
`dis olution is the rever e proce s .) The rate of crystallization also depends
`on the concentration of the solution, the temperature, and the degree of
`tirring of the olutioo .
`agitation or
`A. FORCES HOLDING CRYSTALS TOGETHER
`to consider the forces responsible for
`At this point it is appropriate
`together.
`crystaJJization and the forces respon sible for holding crystals
`Cry tal s are held together by noncovalent interactions. These interactions
`.
`force
`attractive
`noncovalent
`or
`hydrogen-bonding
`together in his classic
`either
`are
`Kitaigorodskii described the forces holding cry tat
`1961). Both
`"Organic Chemical CrystaJJography"
`entitled
`result in the formation of
`book
`hydrogen-bonding and noncovalent interaction
`in a crystal. Noncovalent attractive
`a regular arrangement of molecule
`interactions, which are sometimes called nonbonded interactions, depend
`on the dipole moments, polarizability, and electronic distribution of the
`molecules. Hydrogen bonding, of course, requires donor and acceptor
`functional groups.
`Another important factor is the symmetry of the molecules. The mole(cid:173)
`ymmetry (or lack of symmetry) determines how it is packed in the
`crystal and, in ome ca ses the overall symmetry of the crystal. Molecules
`cule'
`in a close-packed ar(cid:173)
`with symmetrie s that allo w them to fit together
`rangement form better crystals and crystallize more easily than nonregu(cid:173)
`.
`Kitaigorod kii (1961) has advanced the clo e-packing theory to explain
`lar molecule
`together. Be ugges ts that the basic factor that
`the forces holding crystal
`the packing density . The denser or more closely
`affects free energy i
`the sma ller free energy. This means that the heat of
`packed crystal ha
`
`Page 9
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`

`

`I. Crystallization and Properties of Crystals
`
`5
`
`sublimation (and, to a first approximation, melting point) increases as the
`packing density increases, and that in a series of polymorphs the densest
`table.
`polymorph is the mo t
`Kitaigorod kii (1961) pointed out that symmetry i also important. The
`the number of indepen(cid:173)
`free energy of a crystal undoubt ed ly increa es a
`dent molecules in the crystal increases. This tendency to higher symmetry
`may conflict with the tendency toward close packing. However, clo e
`packin g generally affects the intern al energy of the crystal, while sym(cid:173)
`metry affects its entropy.
`
`B. CRYSTAL HABITS
`The faces of a crystal that grow most rapidly are those to which the
`molecules are bound most tightly. This feature is displayed in the shapes
`of crystals of organic ring compound . Molecule s containing planar
`aromatic or nonaromatic rings such as cytosine, caffeine, or theopbylline
`u ually form needlelike crystals. The relatively strong interaction between
`the planes of these ring (i.e. , pi-pi interaction) causes more rapid growth
`in the stacking direction than in other directions. Thus in these crystal
`the rings are arranged perpendicular to the needle axis.
`In this case the ext ernal hape of the cry stal its habit, reflects the
`internal structure. Thus a knowledge of the crystal habit sometimes pro(cid:173)
`vides important information on its molecular organization. The relation(cid:173)
`ship between the external shape of the crystal and its internal structure
`can be confirmed by determination of the crystal structure.
`It is not uncommon for the same compound to crystallize in several
`different crystal habits, as shown in Figure 1. Although crystal habits have
`the same internal structure and thus have identical single crystal- and
`, they can stiJI exhibit different pharmaceutical
`powder-diffr action pattern
`properti es owing to the fact that di.lferent crystal faces are developed
`(Haleblian, 1975).
`Before discussing the different pharmaceutical properties of crystal
`habits, it is important to point out crystallization conditions that can affect
`the habits that occur:
`l. Supersaturation. The extent of supersaturation may affect which
`habit grows.
`2. Rate of cooling and degree of solution agitation. When naphthalene is
`crystallized by rapid cooling it gives thin plates, while when it is
`slowly crystallized by evaporation it gives compact crystals.
`3. Presence of cosolutes, cosolvents, and adsorbableforeign ions. When
`NaCl is crystallized from water only cubic [100) faces are devel(cid:173)
`oped, while octahederal [ 111) faces grow when N aCI is crystallized
`in the presence of urea.
`
`Page 10
`
`

`

`6
`
`1. Introduction
`
`{al
`
`(bl
`
`(dl
`(cl
`FIGURE 1. Different crystal habits of a drug: (a) tabular, (b) prismatic, (c) plate, and
`(d) needle.
`Once the cry tals obtained have been hown to have habits it i often
`are best characterized
`these habits. Habit
`to characterize
`necessary
`using instruments caUed reflecting or optical goniometers. A reflecting
`goniometer is shown in Chapter 2 in Figure 9 (p. 38).
`related
`Crystal habits influence everal pharmaceutical characteristic
`to the physical hape and nature of the crystal.
`influenced by mo tly
`i
`l. Susp e11sion syrin ge (I/Jifit_ . This parameter
`a uspension of plate- haped
`mechanical factors. For example
`crystals may be injected through a small needle with greater ease
`than one of needle-shaped cry tals .
`i de(cid:173)
`2. Tabl etin g hefwl'i or . Behavior upon compression of crystaJ
`pendent upon the habit present ; however , no generalization can be
`made. rt is quite reasonable to expect platelike crystals to exhibit
`different tableting behavior from needle . However, a priori, it i
`in behavior.
`difficult to predict the difference
`
`C. POLYMORPHS
`Cry tallization can also result in the formation of several different ol(cid:173)
`vates and/or anhydrates which have different crystal habits and different
`. These different olvates and/or anhydrates wilJ
`x-ray diffraction pattern
`be referred to as p ofym orph s . Polymorphs are thus different cry tal forms
`of the same compound., and are detected by x-ray diffraction. Polymorph s
`have different phy ical and chemical properties. They can be i.ntercon (cid:173)
`verted by pha se tran formations or a solvent-mediated process. Pha se
`tran formations can be induced by heat or mechanical str:esse . Different
`
`Page 11
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`

`

`I. Crystallization and Properties of Crystals
`
`7
`
`polymorphs have different dissolution rates and bioavailability. No rules
`exist that allow prediction of whether a compound will exhibit polymorph(cid:173)
`ism; however, polymorphism is widespread in pharmaceuticals, particu(cid:173)
`larly in steroids, sulfonamides, and barbiturates .
`Two special types of polymorphism are termed conformational and con-
`figurational polymorphism. Conformational polymorphism occurs when a
`molecule adopts a significantly different conformation in different crystal
`polymorphs. The term "significantly different" is open to interpretation;
`however, it implies torsion or dihedral angles different by at least three
`standard deviations. For example, the Schiff's base p-(N-chlorobenzyli(cid:173)
`dene)-p-chloroaniline crystallizes in two polymorphs. The stable form
`belongs to the triclinic crystal system, while the unstable form belongs
`to the orthorhombic crystal system. Both polymorphs are disordered
`but, strikingly, the conformation of the Schiff's base is different in the
`two polymorphs. Thus, these forms are termed conformational poly(cid:173)
`morphs (Bernstein and Hagler, 1978).
`Conformational polymorphism involves the crystallization of different
`conformers in different crystalline forms, but this term does not ade(cid:173)
`quately describe cases where different types of isomers crystallize in dif(cid:173)
`ferent forms. Thus a new term-configurational polymorphism-is defined.
`Configurational polymorphism exists when different configurations (i.e.,
`cis-trans isomers or tautomers) crystallize in separate crystalline forms. Of
`course the crystallization of cis and trans isomers of the same compound
`in different crystalline forms is well known and occurs whenever the pure
`isomer is crystallized. Similarly, crystallization of a pair of pure tautomers
`leads to what may be called tautomerizational
`in separate crystals
`polymorphs. The crystallization of equilibrating isomers in configurational
`polymorphs is of significantly more interest. When this occurs, the phe(cid:173)
`nomena of configurational polymorphism can be used to isolate and study
`the individual isomers.
`Polymorphism is very common in the pharmaceutical area. Because
`they have different crystal structures, polymorphs have different chemical
`and physical properties. Polymorphs of the same substance show different
`melting points, different chemical reactivities, different dissolution rates,
`and different bioavailabilities.
`
`D. CRYSTAL SOLVATES
`Upon crystallization, drugs often entrap solvent in the crystal. This
`solvent can be in stoichiometric or nonstoichiometric amounts. Crystals
`that contain solvent of crystallization are termed solvates. If water is the
`solvent of crystallization, the solvates are called hydrate s . Crystal solvates
`
`Page 12
`
`

`

`1. Introduction
`
`8
`and hydrate are e ·tremely important for drugs. In particular, antibiotic .
`are well known for cry tallizing with solvent in the crystal. Determination
`of the crystal structure reveals the nature of interaction of the solvent with
`the host molecules. A knowledge of this interaction is extremely helpful in
`understanding and explaining the behavior of solvates.
`Crystallization al o results in crystals that contain no solvent of crystal(cid:173)
`lization. Such crysta ls are termed anhydrates. Here, the term anhydrate
`refers to crystals that do not contain solvent of crystallization.
`A classification scheme for solvates needs further discussion. Crystal
`solvates exhibit a wide range of behavior. Some solvates are very stable
`to bring about desolvation; however,
`and require vigorous conditions
`upon desolvation, a different crysta l form i produced. Other olvates are
`much less stab l.e but also give a different crystal form upon de olvation.
`Still other solvates are relatively unstable but do not give a different
`cry tal form upon desolvation.
`The fore s holding solvates togetber exp lain these type of behavior.
`an import a nt role in
`the solvent play
`in some solvate
`For example,
`holding the crysta l together. Formation of a hydrogen-bonding network
`the solvent i quite common. When the e olvates lose ol(cid:173)
`that include
`in a new crystal form.
`vent, the crystal collapses and recrystallizes
`In other solvates, the solvent plays. little or no role in holding the crystal
`together. In these cases, a network of hydrogen bonds and nonbonded
`interactions holds the host molecules together. The olvent molecules are
`fillers tbat occupy voids in the cry tat. De olvation of these solvates doe
`not destroy the crysta l. For example, Pfeiffer el al. (1970) described the
`behavior of several cepha losporin solvates that can be de olvated and
`resolvated al will without destruction of the original crystal lattice and
`without greatly changing the powder diffraction pattern of the crystal.
`Thi s behavior was termed crystal pseudopol y m11rphism.
`Based on these considerations a new classification scheme for crystal
`solvates is proposed. This classification scheme is based on the crystallo(cid:173)
`graphic behavior of solvates rather than the stability. Solvates that tran -
`form to another crystal form (different x-ray powder-diffraction pattern)
`upon desolvation are pol y morphi c .wh ates. Solvates that remain in the
`are
`similar x-ray powder diffraction pattern)
`ame crysta l form
`table and
`s of olvate contain
`psemlopo/ y 111orphic soh ates. Both clas
`unstable members. An important difference between these two classes is
`that pseudopolymorphic solvates are readily resolvated, while polymor(cid:173)
`phic olvates are resolvated only after a phase transformation.
`Table l lists the clas ificatipn of a few solvates Lhat hav been investi(cid:173)
`gated at Purdue University or described in publications.
`
`Page 13
`
`

`

`I. Crystallization and Properties of Crystals
`
`9
`
`TABLE I
`Classification of Solvates
`
`Polymorphic solvates
`
`Cytosine hydrate
`5-Nitrouracil hydrate
`
`Deoxyadenosine hydrate
`
`Pseudopolymorphic solvates
`
`Cephalexin hydrate
`Hydrocortisone tert-butylacetate
`ethanol ate
`
`Another possible classification cheme for solvates makes use of dia(cid:173)
`gram of vapor pre s ure ver a s compo sition . Th ese are con stmc ted by
`equilibr atin g the cry tal with vapo r in a clo ed containe r. Diagrams of
`vapor pressure versus compo ition are dete1mined eas ily for wat er be(cid:173)
`cause a range of salt solutions with different water vapor pre s ures is
`available. However, for oth er solvent s these diagrams a re more difficult to
`determine because of the difficulties inherent in measuring their vapor
`pr e sure s .
`Diagra ms of vapor pre ure ver sus composition have been prepared for
`a few solvates. For exa mple, Pfeiffer et al. (1970) measured vapor
`pressure versu compo sition for cephaloglycin - water, cephalexin - wat er ,
`and cep halex.in- ace tonitrile (F igure 2). At Purdue, the vapo r pre sure
`ver us compo sition of dialuric acid-wa ter bas been mea ured .
`Diagram s of vapor pre ssure ver sus com_po ition how the condition
`under which a given solvate or anhydrat e exist. Howev er, examination of
`th e publi hed diagram shows that there is no obvio us trend, that could be
`u ed a a mean of clas ification of cr ystal solvates . Thu s clas ification
`
`!Oil
`
`r.o
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`20
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`60
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`I
`MOLE S ACUONIT R ILl
`MOLlS WAHR
`M U Ll S WAil! <
`(c)
`(b)
`(a)
`FIGURE 2. Vapor pressure versus composition for (a) cephaloglyc ln- water and (b)
`cephalexln - water . The th ird diagram (c) is a plot of the volume percent acetonltrile In
`trlethylene glycol (TEG), which was present in a solution used to prov ide a range of
`acetonitrll e vapor pressures whose exact magn itude was nor determined . (Pfeiffer et
`al., 1970. Reproduced with permission of the copyright owner.)
`
`Page 14
`
`

`

`10
`based on the x-ray diffraction pattern of solvates and desolvated crystals
`to be the scheme of choice.
`appears
`
`1. Introduction
`
`II. Properties of Other Solids
`
`in the
`to crystals are encountered
`A number of otber solids in addition
`study of solid pb arma ceuticals. The properti es of these olids a re also of
`interest.
`
`A. AMORPHOUS SOLIDS
`shape and canno t be identified as
`solids have no crystal
`Amorphous
`either habit or polymorphs. The most common amorphous solid is a glass
`in which the atoms and molecules exi st in a nonuniform array.
`in terms of the size of the
`An w11orphous fo rm can al o be understood
`the size of the crystals
`crystallit es. Starting with a crystalline material,
`could be taken at
`would be reduce d in stages and an. x-ray photograph
`the
`tage. The line on the photograph would become diffuse when
`each
`reduced
`i
`bout 10- 5 cm. As the cry tal size
`ize fall below
`crystal
`is
`limit
`the
`diffuse until
`increasingly
`line would become
`the
`further
`reached at about 10-s cm, the region of atomic di men ions. At this point it
`it i no longer an
`ince , by definition,
`for a cry tal to exist
`impossible
`i
`form s give no diffrac(cid:173)
`ordered array of atom or molecules. Amorphous
`less than 10-~ A.
`tion pattern and thus have crystal sizes
`or by
`crystals can be prepared by r a pid crystallization
`Amorphous
`form
`lyophilization. For example, rapid crystallization gave an amorphous
`1960), an d
`and Hashimoto,
`(K imura
`palmitate
`of chloramphenicol
`(J. Haleblian et
`lyophilization gave the am orphous form of fluprednisolone
`al. , 1971).
`by x-ray powder diffraction,
`solid s are best characterized
`Amorphous
`since these olids give very diffu se lines or no crystal diffraction patt ern at
`all.
`While amorphous so lids often have de sira ble ph armace utical properties
`, they are not usually markete d because of
`rate
`su c h as rapid dissolution
`are an
`form
`talJine , amorphous
`they are noncry
`instability. Since
`their
`to a more sta ble forrn. In add ition ,
`form which tend to crystallize
`energetic
`than their crystalline
`reactive
`forms are often more chemically
`arnorphou
`(P ikal et al., 1977).
`counterpart
`forms are used and a re desirable.
`in some ca es amorphous
`However
`and Macek , 1960) .
`novobiocin Mullins
`i
`examp.le
`excellent
`An
`talline and an a morphous form. The cry talJine
`exists in a cry
`Novobiocin
`
`Page 15
`
`

`

`II. Properties of Other Solids
`
`11
`
`TABLE II
`Plasma Levels ( µ,g!ml) of Novobiocin in Dogs after Administration of Different Forms of
`Novobiocin°
`
`Form administered
`
`Sodium novobiocin
`Amorphous novobiocin acid
`Crystalline novobiocin acid
`
`° From Haleblian (1975).
`
`Hours after dose
`
`0.5
`
`0.5
`5.0
`
`1.0
`
`0.5
`40.6
`
`2.0
`
`3.0
`
`4.0
`
`5.0
`
`10.4
`16.9
`22.2
`14.6
`20.2
`23.7
`22.3
`29.3
`Not detectable at any time
`
`6.0
`
`6.4
`17.5
`
`form i poorly absorbed and doe not provide therapeutically active blood
`i
`is readily absorbed and
`form
`the amorphous
`in contrast,
`levels·
`how that the amorphous form is
`therapeutically active. Further studie
`70 times more soluble than the crystalline one in 0.1 N HCI at 25°C when
`particles < 10 µ,m are used.
`Table II shows data for the plasma levels of novobiocin's amorphous
`and crystalline for.ms and for sodium novobiocin which also gives detect(cid:173)
`in solution.
`able plasma levels but is chemically unstable
`the amorphous form is slowly
`are taken,
`pecial precaution
`Unless
`to the cry talline form. Several additive have been developed
`converted
`to retard this conversion, with methylcellulose and several alginic acids
`being most effective.
`
`B. HYGROSCOPIC SOLIDS
`there is no clear definition of hygroscopic solids. In(cid:173)
`Unfortunately,
`stead, a solid is hygroscopic when it takes up moisture from the atmo(cid:173)
`is determined by both a kinetic term and a ther (cid:173)
`sphere. Hygroscopicity
`modynamic term. For example, at equilibrium a olid may only take up a
`small amount of water but because the uptake is rapid the solid would be
`the solid may absorb a large amount of
`termed hygroscopic. Likewise,
`low, such a solid is not
`water at a very slow rate. Because the rate is
`termed hygroscopic.
`In addition, the relative humidity of the atmosphere play an obviously
`In
`important .role in determining whether or not a solid is hygroscopic.
`high relative humiditie s, many olids are hygroscopic. In atmospheres of
`low humidity, only a few olids will be hygroscopic.
`is surface area. The larger the
`A third factor influencing hygroscopicity
`surface area of the solid, the more rapid the uptake of moisture. This is
`ites for condensation
`becau se solids with a larger surface area have more
`and adsorption of water molecules. In general, amorphous olids are often
`
`Page 16
`
`

`

`12
`hygroscopic because of their large surface area and possibly because of
`their disordered structure.
`
`1. Introduction
`
`C. LYOPHILIZED POWDERS
`lyophilized
`Many antibiotics and some other drug are marketed a
`powders . Lyopbilized powders are produced by freeze drying a solution
`to a very low moisture onteot. Freeze drying i accomplished by placing
`tbe olution under high vacuum at a low temperature. These p wders are
`recon tituted before u e by adding water.
`from cry tallioe to amorph(cid:173)
`range
`The nature of lyophilized powder
`the solid crystallizes during freeze drying. In many
`ous. In ome case
`more case an amurphous, hygro copic powder is formed. Lyophilized
`ry talline solid
`powders sometimes cry tallize upon storage to form a
`lower di olution rate.
`with a much
`
`Ill. Solid-State Chemistry of Drugs
`The cientific di cipline of solid-state chemi try of drug emphasizes
`studie of the chemical properties of the vario'LI solids ju t discus eel.
`and polymorphic trans(cid:173)
`olid-state pha e transformation
`include
`in which solvent of cry tallization is lost, and a
`Thi.
`reactions
`formations
`broad range of solid-state ch emica l reactions.
`A. CRITERIA FOR SOLID-STATE REACTIONS
`for solid- tate reactions. This
`to establish criteria
`is necessary
`and to avoid
`It
`to focus on true olid-state reaction
`enables re earcher
`in a liquid a a solid-state reaction.
`identificati a of a reaction that occur
`Morawetz 1966) uggests four criteria for determining whether a reac(cid:173)
`tion i a true olid-state reaction:
`I. A reaction occur s in the s lid when the liquid reaction doe not
`occur or i much slower. Thi criter ion is particularly important for
`determining whether a reaction i a true solid- tate reaction.
`are
`2. A reaction occUT in the solid when pronounced difference
`.
`found in the reactivity of closely related compound
`in the solid when different reaction products are
`3. A reactio n occur
`formed in the liquid state.
`in the oJid if the same reagent in different cry tal(cid:173)
`4. A reaction occur
`line modifications ha different reactivity or leads to dill'erent reac(cid:173)
`tion products.
`
`Page 17
`
`

`

`Ill. Solid-State Chemistry of Drugs
`
`13
`
`A fifth and very important criterion can be added (Paul and Curtin,
`1973). A reaction occurs in the solid if it occurs at a temperature below
`the eutectic point of a mixture of the starting material and products.
`This criterion can best be understood using the phase diagram shown in
`Figure 3.
`Each solid-state reaction can be represented by a phase diagram, from
`which important insights can be gained. It is particularly instructive to
`the diagram of temperature versus composition (at constant
`consider
`pressure) for a two-component mixture of A and B where A goes to B
`upon heating. At least four cases can be visualized (see Figure 3).
`
`Case 1: Solution reaction. This case is understood by visualizing that
`component A is heated to temperature Z. At temperature Y, melting oc(cid:173)
`curs. The reaction then continues in liquid until 100% of B is formed.
`Case 2: Melting before reaction. This case is understood by visualizing
`that component A is heated to temperature Y, at which point melting
`occurs. Component A then reacts to form B until point Q is reached. At
`this point, B crystallizes and the reaction continues in a mixture of liquid
`and crystalline B until 100% B is formed.
`Case 3: Reaction before melting. This case is understood by visualizing
`that component A is heated to temperature X. As soon as some B is
`formed, solid A + liquid will exist until point U is reached. The mixture
`will liquify until point Tis reached. At this point, B will crystallize and the
`reaction will continue in a mixture of liquid + crystalline B until reaction
`is complete.
`Case 4: Solid-state reaction. This case is understood by visualizing that
`
`z
`
`~ y
`~
`Q)
`0..
`E
`~ X
`
`w
`
`Solid B
`• Liquid
`
`Solid A
`
`•
`
`Solid B
`
`WO
`%8
`0
`FIGURE 3. Hypothetical phase diagram of a solid A and its solid-state reaction
`product B.
`
`Page 18
`
`

`

`1. Introduction
`
`14
`component A is heated to point W. The reaction then occurs completely in
`the olid state until 100% B is formed.
`Thus only Case 4 depict a true olid-state reaction. From this discu -
`ion it is clear that care mu t be taken to ensure that the reaction is being
`carried out at a temperature below the eutectic temperature of the reac(cid:173)
`to be mre that the reaction takes place in the solid
`tants and products,
`state.
`
`B. STEPS IN A SOLID-STATE REACTION
`that the reaction is occuring in the solid
`Once it has been established
`state, the reaction is understood in terms of a four-step process (Paul and
`Curtin, 1973).
`l. Loosening of molecules at the reaction site. It is rea onable to assume
`that the extent of loosening required depends on the distortion of the
`reaction cavity required to accomplish the next step.
`2. Molecular clwn ge . Thi step is simila r to the corresponding olution
`are broken and the product
`the reactants bond
`reaction where
`formed .
`bond
`3. Solid-solution for111atio11. During the early stage s of the reaction , a
`solid olution of the product in the starting crystal is formed· how(cid:173)
`reaches a certain point the
`ever, after the product concentration
`product will separate.
`4. S ,pam 1ion of product. This step often gives randomly oriented crys(cid:173)
`tals or cry tal with an orientation governed by the crystal of the
`tarting material. Tbjs latter case is termed a topotactic reaction and
`will be discussed further.
`Mvlecular Low ·e11i11g. Solid-state reactions begin at one or more nuclea(cid:173)
`in
`ites and spread through the crystal. In some cases particularly
`tion
`desolvations and some thermal reactions, a reaction begins at a nucleation
`site and spreads through the crystal in a front that advance at a mo.re or
`less linear rate through the crystal.
`ites for reaction are developed during crystallization or can
`Nucleation
`sometime be produced by mechanical deformation such as pricking with
`a pin or cutting the cry tal. Nucleation s ite can also sometimes be pro(cid:173)
`duced by expo ing the starting crystal to product crystals. In other cases
`neither mechanical deformation nor expo ure to product crystals nu(cid:173)
`thi s variability in nucleation and the ran(cid:173)
`cleates the reaction. Obviously
`that are pre eat