6.2
`
`ROLE OF PREFORMULATION IN
`
`DEVELOPMENT OF SOLID
`
`DOSAGE FORMS
`
`OMATHANU P. PERUMAL AND SATHEESH K. PODARALLA
`
`South Dakota State University, Brookings, South Dakota
`
`Contents
`
`6.2.1
`
`Introduction
`
`6.2.2
`
`6.2.3
`
`6.2.4
`
`6.2.5
`
`Physical/Bulk Characteristics
`6.2.2.1 Crystallinity and Polymorphism
`6.2.2.2 Hydrates/Solvates
`6.2.2.3 Amorphates
`6.2.2.4 Hygroscopicity
`6.2.2.5 Particle Characteristics
`
`6.2.2.6 Powder Flow and Compressibility
`
`Solubility Characteristics
`6.2.3.1
`pKa and Salt Selection
`6.2.3.2 Partition Coefficient
`
`6.2.3.3 Drug Dissolution
`6.2.3.4 Absorption Potential
`
`Stability Characteristics
`6.2.4.1
`Solid—State Stability
`6.2.4.2 Solution-State Stability
`6.2.4.3 Drug—Excipient Compatibility
`Conclusions
`
`References
`
`Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad
`Copyright © 2008 John Wiley & Sons, Inc.
`
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`6.2.1
`
`INTRODUCTION
`
`The advent of combinatorial chemistry and high—throughput screening (HTS) has
`exponentially increased the number of compounds synthesized and screened during
`the drug discovery phase. However, the overall efficiency of the drug discovery
`process is still exceedingly low (only 1 in 10,000 makes it to the market). Drug dis-
`covery is mostly driven by “activity screens” with little emphasis on “property
`screens.” This is exemplified by the fact that 40% of attrition in drug discovery and
`development is attributed to poor biopharmaceutics and pharmacokinetic proper-
`ties [l], which in turn are related to poor physicochemical properties. As a result,
`pharmaceutical companies have started to redesign their strategies by including
`property screens quite early in the discovery stage
`Preformulation is the study
`of fundamental properties and derived properties of drug substances. In other
`words, preformulation is the first opportunity to learn about the drug’s physico-
`chemical properties from the perspective of transforming a biologically active mol-
`ecule to a “druggable” molecule. The type and extent of preformulation activities
`vary in a discovery and generic setting.
`The main goal of a drug discovery program is to develop an orally deliverable
`molecule for obvious reasons of ease of manufacture and convenience of drug
`administration. More than 75% of the drug products in the market are oral formula-
`tions, of which more than half are solid dosage forms
`The “rule of five” devel-
`oped by Christopher Lipinski [4] is one of the “physicochemical screens” to weed
`out molecules with poor physicochemical properties very early in the drug discovery
`process. According to Lipinski’s rule, a drug will show poor oral absorption if it does
`not conform to any of the two physicochemical requirements listed in Table 1. The
`rule of five is applicable only to small molecules and it relates the chemical proper-
`ties of the drug to its solubility and permeability characteristics. During the initial
`stages of drug discovery, the preformulation activities are mainly focused on devel-
`oping a water—soluble compound for early activity studies and preclinical testing in
`animals. At this stage, the preformulation scientist is faced with the challenge of
`working with a limited quantity of compound (few milligrams) for testing a long list
`of physicochemical parameters. On the other hand, developing preclinical formula-
`tions can be quite a daunting task given the fact that toxicological studies require
`a high dose of drug (l0—l00 times above the effective dose) to be delivered in a
`small volume of the formulation. Preformulation activities increase as the molecule
`
`proceeds through the development phase. The “discovery and development phar-
`
`TABLE 1 Lipinski Rule of Five for Orally Active Compounds
`
`Physicochemical Parameter
`
`Lipinski rule
`
`Molecular weight
`log P
`Hydrogen bond donors
`
`Not more than 500Da
`Not more than 5
`
`Not more than 5 hydrogen bond donors expressed as the
`sum of OH’s and NH’s
`
`Hydrogen bond acceptors
`
`Not more than 10 expressed as the sum of OH’s and NH’s
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`PHYSICAL/BULK CHARACTERISTICS
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`935
`
`maceutics” documentation forms a significant portion of the investigational new
`drug application (IND) application and new drug application (NDA) filed to the
`U.S. Food and Drug Administration (FDA). In a generic setting, preformulation
`studies are mainly focused on developing a formulation that is bioequivalent to the
`innovator’s product with the main objective of filing an abbreviated new drug appli-
`cation (ANDA). A strong preformulation team can generate intellectual property
`in the form of new salts, solid—state forms, or new stabilized formulations of the drug
`for an innovator and/or a generic manufacturer.
`In the present chapter, the discussion is mainly focused on preformulation testing
`for oral solid dosage forms in a drug discovery setting. The chapter address the fol-
`lowing goals of preformulation:
`to gain knowledge about the physicochemical
`characteristics of the drug, (ii) to define the physical characteristics of the drug, (iii)
`to understand the stability characteristics of the drug, and (iv) to determine the
`compatibility of eXcipients with the drug. In this chapter, we have grouped all
`the parameters under three sections and discussed in a logical sequence for the
`convenience of the reader.
`
`6.2.2 PHYSICAL/BULK CHARACTERISTICS
`
`The bulk or physical characteristics of a drug substance are mainly dictated by its
`solid—state properties. Purity of the drug substance is a fundamental property that
`is characterized at the beginning of preformulation studies. In the initial stages of
`drug development, the drug is usually not very pure. Nevertheless, it is essential to
`know the purity of the material at hand using simple measurements such as melting
`point. This would serve to set drug specifications during later stages of drug develop-
`ment. Differential scanning calorimetry (DSC) requires very little sample (1-5 mg)
`and is a useful tool to estimate the purity of the compound. The drug sample is
`heated in a crucible, where the difference in heat between the sample and a refer-
`ence crucible is seen as an endotherm or eXotherm in the thermogram depending
`on whether heat is taken up or given up, respectively, by the sample. The integrated
`area under the endotherm or eXotherm gives a measure of the heat or enthalpy
`involved in this process. Melting is seen as an endothermic event and the purity of
`the sample will govern the peak position, shape, sharpness, and heat of fusion (AHf).
`DSC is sensitive in detecting impurities to the extent of 0.002 mol %
`The DSC
`findings should be substantiated by a stability—indicating high—performance liquid
`chromatography (HPLC) assay. On the other hand, thin—layer chromatography
`(TLC) may be used to qualitatively detect the number of impurities in the drug
`sample. Impurity profiling is an important aspect of the drug development process,
`particularly for optimizing the synthetic process. The impurities can originate from
`many sources, including starting materials, intermediates, synthetic processes, or
`degradation reactions
`The regulatory guidelines stipulate that any impurity
`>0.05% of total daily dose (for drugs with a dose <2 g/day) or >0.l5% of total daily
`dose (for drugs with a dose >2 g/day) should be evaluated for its safety
`Organo—
`leptic properties such as color, taste, and odor are assessed qualitatively to set bulk
`drug specifications. If the drug has an unacceptable taste or odor, the chemistry
`group is advised to make a suitable salt form of the drug.
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`ROLE OF PREFORMULATION IN DEVELOPMENT OF SOLID DOSAGE FORMS
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`6.2.2.1 Crystallinity and Polymorphism
`
`The majority of the drugs exist in crystalline form and are characterized by their
`crystal habit and crystal lattice. The crystal habit describes the external morphology
`of the crystal, including shape and size, while the crystal lattice describes the internal
`arrangement of molecules in the crystal (Figures 1a and b). Drug molecules arrange
`in more than one way in a crystal, and this difference in the internal arrangement
`of crystals is known as polymorphism. The polymorphs have the same elemental
`composition but differ in their physical, chemical, thermodynamic, stability, and
`spectroscopic properties. A crystal lattice represents the space in which molecules
`arrange in different ways. Organic molecules arrange in one or more of the seven
`possible crystal systems: triclinic, monoclinic, orthorhombic, tetragonal, rhombohe—
`dral, hexagonal, and cubic
`Each crystal system is characterized by its three-
`dimensional geometry and angles between the different crystal faces. The crystal
`lattice geometry is obtained using single—crystal X—ray diffractometry (XRD) and
`the details can be found elsewhere
`The difference in the crystal lattice of a drug
`arises as a result of the difference in packing of the molecules if the molecules are
`conformationally rigid (e.g., chlordiazepoxide) or due to the differences in confor-
`mation for flexible drug molecules (e.g., piroxicam). Although polymorphs differ in
`their internal crystal lattice, it may not be necessarily reflected in their external
`crystal habit (Figure 1b). In other words, a drug can exist in different crystal habits
`without any change in the internal crystal lattice (isomorphs).
`For example,
`Crystal habit is mainly dependent on crystal growth conditions
`Figure 1a shows two different crystal habits for a given crystal lattice. A prismatic
`crystal habit will result if the growth is equal in all directions, while plates are formed
`if the growth is slow in one direction. Alternatively, needle—shaped crystals (acicular)
`are formed when the growth is slow in two directions. Thus, the crystal habits can
`
`(6)
`
`(b)
`
`(0)
`
`FIGURE 1 Schematic of crystal habits, polymorphs and amorphous drug forms. (a) Two
`crystal habits are shown. The internal crystal lattice is the same while the external morphol-
`ogy is different. (b) In a crystal the molecules are arranged in a regular fashion. However,
`the arrangement may vary depending on how the molecules orient themselves in the internal
`crystal lattice. The internal crystal lattice is different in all the three polymorphic forms. The
`polymorphs may or may not differ in their external morphology. (c) Random arrangement
`of molecules in amorphous form.
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`PHYSICAL/BULK CHARACTERISTICS
`
`937
`
`be altered without any change in the internal crystal lattice by varying the crystalli-
`zation conditions. The polarity of the crystallizing solvent mainly influences the
`crystal habit by preferentially adsorbing to one surface of the crystal face. Similarly,
`surfactants or additives are added to the crystallization medium to prevent or
`promote the growth of a specific crystal habit
`Crystal habits mainly differ in
`physicomechanical properties such as packing, flow property, compressibility, and
`tablettability. Acetaminophen crystallizes as polyhedral crystals when crystallized
`from water and as plates when crystallized from ethanol—water (Figure 2a). Both
`these crystal habits are isomorphic [9], that is, have the same internal crystal arrange-
`ment, since their melting points and heats of fusion were similar (melting point
`178 “C and Mt‘
`l77kcal/mol). The polyhedral crystals have better flow and
`
`In[1/(1—D)]
`
`Thin platelike erystals
`
`— Polyhedral crystals
`
`O 10 20 3040 50 60 70 80
`
`Compression pressure (MPa)
`(b)
`
`FIGURE 2 Difference in crystal habit of acetaminophen and resultant difference in com-
`pressibility (a) Acetaminophen crystallizes as either platy crystals or polyhedral crystals
`depending on the solvent of crystallization. Both crystal habits have the same internal crystal
`lattice since they showed the same melting point. (b) Difference in compression behavior of
`two crystal habits. The x axis represents the compression pressure while the y axis represents
`the densification of the drug sample on compression. This plot is known as Heckel plot. The
`polyhedral crystal habit shows a higher densification implying better compressibility than
`plate like crystals. [From Garekani, H. A., Ford, J. L., Rubinstein, M. H., and Raj abi—Sahboomi,
`A. R., International Journal of Pharmaceutics, 187, 77-89, 1999. Reproduced with permission
`from Elsevier.)
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`938
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`ROLE OF PREFORMULATION IN DEVELOPMENT OF SOLID DOSAGE FORMS
`
`compression properties than platy crystals, which were brittle and fragmented
`during tableting (Figure 2b). Crystal habits are characterized using optical and
`electron microscopy, but their internal crystal lattice should be confirmed using
`DSC, XRD, and spectroscopic techniques.
`Polymorphs are generated by crystallizing the drug from various solvents. The
`solvents are usually those that are used in the synthesis and purification of the bulk
`drug but may also include solvents used in drug formulations [10]. By convention,
`polymorphs are named based on their order of discovery, such as forms I, II or A,
`B or 0L, B. In general form I is considered the most stable and least soluble form,
`while form II is considered the more soluble and least stable form. The least stable
`
`and more soluble polymorphic form is usually called the metastable form. They are
`not “unstable” but “metastable,” because the least stable form can remain stable
`
`provided the conditions are controlled to prevent its conversion to the more stable
`polymorphic form. Polymorphs are characterized by their solubility and stability
`differences with respect to temperature (Figure 3). Thermodynamically, polymorphs
`are classified as enantiotropic or monotropic depending on their thermal revers-
`ibility from one form to another [11]. Enantiotropic polymorphs are reversible
`polymorphs, where one form (form I) is more stable at higher temperature, while
`the other form (form II) is stable at lower temperature. They are characterized by
`a transition point (TS) below the melting points of both forms (Figure 3a). The
`transition point represents the temperature at which one form converts to another.
`In the temperature—solubility curve, this is represented by the intersection of the
`solubility curves of both forms; that is, at the transition temperature, both poly-
`morphs have the same solubility. As shown in Figure 3a, form II can convert to form
`I at a temperature above TS, while form I can convert to form II at a temperature
`below TS. On the other hand, monotropic polymorphs are not reversible but can
`only convert from the metastable form to the stable form. Here, TS is higher than
`the melting point of both forms (Figure 3c). Both forms are stable in the entire
`temperature range below T5.
`The different polymorphs are generated based on their solubility differences in
`a given solvent. According to Ostwald’s rule [12], the least stable or highly energetic
`form (form II, or metastable) will precipitate out first from a supersaturated solu-
`tion followed by the stable or less energetic form (form I). Supersaturation is
`achieved by antisolvent addition or by altering the temperature. So, if the initial
`precipitate is separated rapidly, it would have predominantly the metastable form.
`Alternatively, the stable form can be melted and rapidly cooled to crystallize the
`metastable form. A stable or metastable polymorphic form is also used as a “seed”
`to preferentially grow and isolate the desired form during drug crystallization [13].
`Several rules have been proposed to differentiate enantiotropic and monotropic
`polymorphs [11, 13]. A simple way to differentiate enantiotropic and monotropic
`polymorphs is the use of the heat—cool cycle in DSC [11]. As shown in Figure 3b,
`the enantiotropic polymorph is characterized by the appearance of solid—solid
`endothermic transition of form II to I followed by melting of form I. On cooling
`the melt of form I followed by reheating, the same thermogram is regenerated,
`proving the reversibility of the polymorphs. In monotropic polymorphs (Figure 3d),
`the thermogram is characterized by melting of metastable (form II) and recrystal-
`lization to form I followed by melting of form I. On cooling and reheating the
`sample, the transition and recrystallization peaks are not seen, indicating the irre-
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`PHYSICAL/BULK CHARACTERISTICS
`
`939
`
`Temperature (°C)
`(C)
`
`I Endotherm
`
`—> Second heat
`cycle
`
`4: Cool Cycle
`
`Tcrys
`
`Tm,||
`
`:> First heat c cle
`Tm,|
`y
`
`
`Temperature (°C)
`(d)
`
`E
`In ‘
`2
`O
`<1)
`
`
`
`5
`=
`‘g
`I
`
`Temperature (°C)
`(a)
`
`—>Second heat
`Cycle
`
`4: Cool cycle
`
`:> First heat c cle
`Tm,|
`y
`
`
`l Endotherm
`
`
`
`Ts
`
`Temperature (°C)
`(b)
`
`E
`In
`2
`O
`<1)
`
`2
`2
`E
`E
`
`FIGURE 3 Difference between enantiotropic and monotropic polymorphs. (a) Solubility
`of enantiotropic polymorphs as function of temperature. The dotted line indicates the melting
`curve. Form 1 is less soluble below the transition temperature (Ts), while form 11 is more
`soluble above Ts. Form 1 has a higher melting point (Tm,I) than form 11 (Tm,II). Below Ts,
`form I is converted to form 11 and above Ts form 11 coverts to form I. (b) Thermogram gen-
`erated from heat—cool—heat cycle in DSC. In the first heating cycle two endotherms are seen
`corresponding to conversion of form 11 to form I and melting of form 1, respectively. On
`cooling both events show up as exotherms and on second heating cycle both endotherms
`reappear, indicating thermal reversibility of enantiotropic polymorphic pairs.
`Solubility
`of monotropic pairs as a function of temperature. The Ts is above melting point of both forms.
`Forms 1 and II are stable in entire temperature range and their corresponding melting points
`are shown. (d) On heating in DSC, form 11 melts (Tm,II) followed by recrystallization (Tcrys)
`and subsequent melting of form I (Tm,I). In cooling cycle only melting of form I is seen as
`an exotherm and on reheating only one endotherm corresponding to form I is seen. This is
`typical of monotropic polymorphs which converts from form 11 to stable form I and not vice
`versa.
`
`versible nature of these polymorphs. The heating rate in DSC is critical for char-
`acterizing the polymorphs, as a faster heating rate may not be able to identify the
`transition temperature, while a lower heating rate may lead to lower resolution of
`peaks. Therefore, it is a usual practice to generate DSC thermograms under differ-
`ent heating rates during polymorph characterization [11]. Also it is important to
`note that the sample preparation, particle size, and crucible type can affect the
`quality of the thermogram
`XRD is also another indispensable tool in identify-
`ing polymorphs. This is based on the differential scattering of X rays when passed
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`ROLE OF PREFORMULATION IN DEVELOPMENT OF SOLID DOSAGE FORMS
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`100
`
`Intensity
`
`01O
`
`100
`
`1 O
`
`20
`
`30
`
`30
`
`40
`
`50
`
`2 e
`
`(a)
`
`Intensity
`
`01O
`
`10
`
`20
`
`30
`
`30
`
`40
`
`50
`
`2 e
`
`(b)
`
`FIGURE 4 Schematic X—ray diffractograms of two polymorphic forms of a hypothetical
`drug. The x axis represents the detection angle and the y axis represents the intensity of the
`peak. As can be seen, there is a difference in the diffractograms due to the difference in the
`internal crystal lattice of polymorphs. The different internal arrangement in a crystal deflects
`the X ray at different angles.
`
`through a powder sample. Typically, on passing through a powder sample, X rays
`will tend to get diffracted at Various angles, and at some angle of detection, the X
`rays diffracted from the different planes of the crystal converge to form an ampli-
`fied signal, which is detected by a photomultiplier tube. The angles at which the
`XRD peaks are obtained are characteristic for a polymorph (Figures 4a & b). The
`sample should be uniformly spread to get a good X—ray diffractogram, as an
`improper sample preparation may lead to Variation in intensities due to the pre-
`ferred orientation of a crystal in the XRD sample holder [14]. Other techniques,
`such as infrared (IR) spectroscopy and solid—state nuclear magnetic resonauce
`(NMR), are also used to characterize the polymorphs and are listed in Table 2.
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`941
`
`TABLE 2 Techniques to Characterize Different Crystalline Forms
`
`Technique
`
`Applications
`
`Thermal analysis
`Differential scanning Melting point, enthalpy of fusion, and crystallization; solid—state
`calorimetry
`transformations
`Thermogravimetric
`Stoichiometry of solvates and hydrates; identifying vaporization
`analysis
`and volatilization
`Visualization of solid—state transformations and desolvation
`Hot—stage microscopy
`events
`
`X—ray diffractometry
`
`Identifying polymorphs; quantification of degree of crystallinity;
`crystal lattice geometry and solid—state transformations
`
`Spectroscopy
`Infrared
`
`Near infrared
`
`Nuclear magnetic
`resonance
`
`Characterization of polymorphs based on functional groups;
`characterization of hydrates and solvates
`In situ analysis of solid—state conversions; identification and
`quantification of polymorphs in dosage forms
`Useful to understand difference in molecular arrangement of
`polymorphs, hydrates, and solvates
`
`TABLE 3 Difference in Solubilities of Polymorphs
`
`Drug
`
`Melting Point (°C)
`
`Solubility Ratio“
`
`Indomethacin
`Sulfathiazole
`Piroxicam
`
`157, 163
`177, 202
`136, 154
`
`1.1
`1.7
`1.3
`
`"Indicates ratio of solubility of low-melting polymorphic form to solu-
`bility of high-melting polymorphic form of drug.
`
`Polymorphism has significant implications in the solubility, bioavailability stabil-
`ity, processing, packaging, and storage of solid drug substances [15—17]. The met-
`stable polymorphic form may be used to improve the solubility of drug substances.
`Many drugs are known to exhibit polymorphism, particularly, steroids, barbiturates,
`anti—inflammatory drugs, and sulfonamides, which have a high probability of exhibit-
`ing polymorphism [15]. The existing knowledge on drug polymorphism is a good
`starting point for a preformulation scientist to anticipate polymorphs based on the
`drug chemistry. In some cases, polymorphism may provide an opportunity to improve
`the solubility of a drug. For example, form II of chloramphenicol palmitate has a
`higher dissolution rate resulting in significantly higher plasma concentration than
`form I when administered orally [15]. However, in many cases [16] the difference
`in solubility may not be significant enough to cause differences in oral bioavailability
`(Table 3). Although the polymorphs differ in their dissolution rates, it should be
`realized that once the drug goes into solution, they do not differ in their properties.
`If a drug’s absorption is limited by its poor membrane permeability, then the differ-
`ence in solubility of polymorphs may not impact its bioavailability. Similarly, if the
`drug dissolution is rapid in comparison to the gastrointestinal (GI) transit time, then
`the difference in polymorph solubility will not influence its bioavailability [16].
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`More than the presence of metastable polymorph, it is the conversion of the
`metastable to the stable form during processing, storage, or use that is of great
`concern to the pharmaceutical scientist [17]. The unpredictability in “conditions”
`that result in the generation and conversion of one polymorphic form to another
`mainly aggravates such a situation [18]. This is exemplified by ritonavir, which is a
`classical case of appearance of a “new polymorphic form” after the drug was mar-
`keted [19]. Ritonavir, an anti—retroviral, drug was introduced in the market as a
`polymorphic form I in soft gelatin capsule in 1996. Two years later, a new polymor-
`phic form II appeared in the formulation due to some unknown reasons causing the
`drug to be less soluble. The drug manufacturer withdrew the product due to failure
`of the batches in dissolution tests. After eXtensive investigation and reformulation,
`the drug was reintroduced in the market in 1999.
`Nonetheless, in spite of their unpredictability, a good preformulation team will
`be able to anticipate the different polymorphs during drug development. It should
`not be an impossible task given the recent advancements in high—throughput genera-
`tion and characterization of polymorphs [20]. From an innovator’s perspective, the
`identification and thorough characterization of multiple polymorphs during drug
`discovery can eXtend the patent life and delay the market entry of generic manu-
`facturers. On the other hand, it is also an opportunity for the generic manufacturers
`to generate new polymorphs with better solubility and stability for gaining market
`entry. The patent dispute on ranitidine polymorphs is a good eXample in this regard
`[21]. Two polymorphic forms of ranitidine were patented by the innovator company
`and the generic manufacturers had to find an appropriate method to manufacture
`the desired polymorph without the accompanying impurity of the other polymorph.
`This provided an edge for the innovator to eXtend the drug’s market eXclusivity for
`a little longer than they would otherwise have had. If a pure polymorph cannot be
`generated, the eXtent of polymorphic impurity should be quantified and ensured
`from batch to batch. The preformulation scientist closely works with the synthetic
`chemist in setting specifications for polymorphs.
`
`6.2.2.2 Hydrates/Solvates
`
`In addition to drug molecules, solvent molecules also get incorporated in the crystal
`lattice, resulting in altered physicochemical properties. When the solvent is water,
`they are known as hydrates, while if it is any other solvent, they are known as
`solvates. They are also known as pseudopolymorphs or solvatomorphs. Hydrates
`are important in this regard as one—third of all marketed drugs are hydrates [13].
`Depending on how the water is arranged inside the crystals, they are classified as
`isolated hydrates, channel hydrates, and ion—associated hydrates [13]. In isolated
`hydrates, the water molecules are separated from each other by the intervening drug
`molecules in the crystal lattice (e.g., cephadrine dihydrate). Channel hydrates result
`when water molecules are linked to one another forming a channel (e.g., theophyl—
`line monohydrate). The water molecules may be present either stoichometrically or
`nonstoichometrically within the crystal lattice. Ion—associated hydrates are typically
`seen when the water is metal ion coordinated (e.g., nedocromil zinc). Nonstoicho—
`metric channel hydrates are problematic due to the presence of diffusible water,
`which can easily move in and out of the crystal lattices [13, 22].
`Hydrates or solvates are formed by crystallizing the drug in the presence of water
`or solvents. The hydrate formation is dictated by water activity in a given solvent
`
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`PHYSICAL/BULK CHARACTERISTICS
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`943
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`HeatflowPercentweightloss
`
`Temperature (°C)
`
`FIGURE 5 Characterization of hydrate. (a) TGA thermogram of monohydrate. The ther-
`mogram shows weight loss as a function of temperature. The step in the thermogram shows
`weight loss due to dehydration of a hydrate. (b) DSC thermogram showing endotherm at
`corresponding temperature (Tdehyd). The second endotherm indicates the melting point of
`the hydrate (Tm).
`
`[22]. Hydrates are characterized using gravimetric methods such as thermogravi—
`metric analysis (TGA) or by Karl Fischer titrometry [23]. In TGA, the loss of
`water/solvate on heating a sample is recorded as a thermogram (Figure 5). The mass
`change due to dehydration is seen as a step loss in the TGA thermogram. Based on
`the weight of the initial sample and its elemental composition, the number of water
`molecules can be calculated. The TGA curve in combination with a DSC thermo-
`
`gram helps to differentiate hydrates from other thermal transitions. In Figure 5,
`the endotherm in the DSC thermogram corresponds to water loss as indicated
`by the TGA curve. The TGA can be coupled to an IR or mass spectrometer
`to characterize solvates. Thermal microscopy is a useful qualitative tool
`to
`visualize the release of water from the drug crystals as a function of temperature
`[23].
`Hydrate formation and dehydration significantly influences the processing and
`storage of drug products [17]. Hydrates may take up further water or dehydrate to
`lose water. Dehydration of hydrates leads to several possibilities [24], as shown in
`Figure 6. Hydrates on dehydration can form isomorphic desolvates retaining the
`same crystal lattice as the hydrate but without the water. Alternatively, hydrates can
`lose water and become anhydrous crystals. They can also lose water, forming amor-
`phates with the loss of crystal lattice. Higher hydrates can lose water to form lower
`hydrates, for example, pentahydrate converting to di— or monohydrate. The hydrates
`also can exhibit polymorphism or on dehydration can convert to a different poly-
`morphic form [13, 17]. Such solid—state transformations are possible during process-
`ing, such as granulation, tableting, and storage [17]. In general, hydrates are less
`soluble than anhydrous forms while solvates are more soluble than ansolvates in
`water. Ampicillin trihydrate is a classical example which shows lower solubility and
`lower plasma concentration than anhydrous ampicillin [15]. Preformulation studies
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`ROLE OF PREFORMULATION IN DEVELOPMENT OF SOLID DOSAGE FORMS
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`Polymorphs
`
`Isomorphic
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`desolvate v\
`
`Anhydrous
`
`/'
`
`Hydrate
`
`/ \
`
`Lower hydrate
`
`Amorphous
`
`FIGURE 6 Various possibilities that arise from dehydration of hydrate. A hydrate can
`dehydrate reversibly into various solid—state forms. It can dehydrate to form an anhydrous
`form of the drug or to a lower hydrate. Hydrate can also dehydrate to form an isomorphic
`desolvate where the crystal lattice is retained except for the absence of water. The crystal
`structure may also collapse on dehydration to form an amorphous form. Hydrates on dehy-
`dration can also result in different polymorphs.
`
`provide valuable inputs to the formulator in selecting a suitable form of the drug.
`For example, ampicillin is hygroscopic and hence can be used in suspension dosage
`forms, while ampicillin trihydrate, which is non—hygroscopic, is used in solid dosage
`forms.
`
`6.2.2.3 Amorphate
`
`Unlike a crystalline drug, an amorphous form of the drug does not have a regular
`crystal lattice arrangement and the molecules are arranged in random order (Figure
`1c). Glass is a typical amorphous substance and so amorphous drugs are also known
`as glasses [25]. Amorphous form is prepared through milling, rapid cooling of a melt,
`rapid precipitation using an antisolvent, rapid dehydration of a hydrate, spray drying,
`or freeze drying [26]. Some of the above methods may also unintentionally produce
`an amorphous form during processing of the crystalline form of the drug [17]. For
`instance, milling during dosage form manufacture may produce an amorphous form
`unintentionally, as in the case of indomethacin. The amorphous form does not show
`a melting point but is characterized by a glass transition temperature (Tg). This
`temperature indicates the conversion of the amorphous form from a rigid glassy
`state to a more mobile rubbery state. Above Tg the amorphous form will tend to
`recrystallize and convert to the crystalline form, which then undergoes melting, as
`shown in Figure 7a. The Tg for an amorphous drug can vary depending on the
`storage conditions and thermal history of the sample and is sensitive to moisture,
`pressure, and temperature [26]. The Tg is seen only as a slight shift in the baseline
`due to a change in the specific heat capacity of the sample and is influenced by the
`heating rate in DSC [25]. In XRD, the amorphous form shows a shallow peak
`or halo, as opposed to sharp and intense peaks for a crystalline drug compound
`(Figure 7b).
`The main advantage of amorphous form of the drug substance state is its signifi-
`cantly higher solubility than the crystalline form of the drug, primarily due to the
`excess surface energy [16, 27]. Therefore,