S.L. Morissette et al. / Advanced Drug Delivery Reviews 56 (2004) 275-300
`
`295
`
`
`
`Fig. 8. Trimer unit of the itraconazole succinic acid co-crystal from single crystal X-ray structure (from [44], with permission).
`
`Co—crystals represent a class of pharmaceutical
`materials of interest, both in terms of projected diver-
`sity and applicability. The study of co-crystals, along
`with polymorphs, solvates, salts and hydrates,
`is
`perfectly suited to HT crystallization experimentation
`and should be considered part of the form selection
`processes.
`
`4. Post-screening analyses and form selection
`
`Several functional characteristics must be consid-
`
`ered in the selection of a suitable crystal form for a
`pharmaceutical dosage form. HT crystallization has
`the potential to create a larger pool of crystal forms for
`which functional parameters, such as dissolution rate,
`chemical stability, flow and compressibility, must be
`determined and compared. Strategies to accomplish
`ranking of the numerous forms must be devised. An
`example is the adaptation of HT for solubility mea-
`surement. The plot in Fig- 9 illustrates results of a
`plate-based kinetic dissolution assay in which various
`forms of a compound were placed in simulated gastric
`fluid and monitored for dissolution as a function of
`
`time. The schematic in Fig. 10 shows how such an
`analysis can be accomplished in a 96-well filter plate.
`The concentration at a given time point is determined
`after filtration of the suspension by quantification
`using either UV or HFLC with {TV detection.
`While the entire plate is filtered at one time,
`different time points can be achieved by timing the
`addition of dissolution medium such that the aliquot
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`
`aqueous medium was studied to assess their potential
`impact on bioavailability of the drug from a solid
`dosage form. Fig. 9 compares the dissolution profiles
`of the co-crystals into 0.1 N HCl to those of crystal-
`line itraconazole-free base (95 % of all crystalline
`particles < 10 um) and commercial Sporanox® beads
`(amorphous itraconazole). The malic acid co-crystal
`rivals the dissolution of the commercial product. In
`general,
`the co-crystals behave more similarly to
`Sporanox® than the crystalline-free base. The co-
`crystal forms achieve and sustain 4- to 20-fold higher
`concentrations than that achieved from the crystalline-
`free base. The practical
`implication is significant,
`since the ability to form a supersaturated solution,
`even transiently, can have dramatic impact on absorp-
`tion and bioavailability.
`
`E'
`
`5'
`T:N:6
`CO0
`E
`
`
`
`0
`
`100
`
`200
`
`300
`
`400
`
`Time (min)
`
`Fig. 9. Dissolution profiles into 0.1 N HCl at 25 °C plotted as
`itraconazole concentration ([itraconazole]) as a function of time for
`Sporanox® beads (i), crystalline itraconazole—free base (#) and co-
`crystals of itraconazole with L-malic acid (V), L-tartaric acid (0) and
`succinic acid (i) (from [44]], with permission).
`
`

`
`296
`
`SL. Morissette et al. / Advanced Drug Delivery Reviews 56 (2004) 2 75~300
`
`hmepomls—
`
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`media
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`Fig. 10. Schematic of a 96-well dissolution filter plate.
`
`for the longest time point desired is dispensed first and
`the shortest one comes last. Instead of varying the
`form along one axis of the plate, one can choose to
`study the dissolution of a single form into several
`different media (see Fig. 10). Equilibrium solubility
`can be determined in a variety of solvents and at
`different temperatures using a similar principle to the
`dissolution plate. A demonstration has been provided
`using automated React-IR analysis [109]. Other func-
`tional parameters, such as solid-state stability and
`thermal properties, can be adapted to HT. Such
`systems for ranking the stability of forms generated
`from HT crystallization await publication and review
`at a future date.
`
`5. Summary and outlook
`
`HT crystallization methodologies are capable of
`screening hundreds or thousands of crystallization
`conditions in parallel using small amounts of com-
`pound for the identification and characterization of
`diverse forms of active pharmaceutical ingredients. As
`demonstrated by numerous case studies from several
`stages of pharmaceutical development, such technol-
`ogies have begun to show promise in enabling more
`comprehensive exploration of solid form diversity.
`The technologies are likely to provide a landscape
`of potential operating conditions from which scientists
`and engineers can design robust and scalable process-
`es for transfer to manufacturing.
`The ability to conduct extensive crystallizations
`with small amounts of material using a variety of
`solvents, additives and conditions necessarily gener-
`ates large sets of data. However, the information by
`itself is of limited value, unless it can be properly
`analyzed. In order to extract maximum knowledge
`
`it is essential to have the ability to
`from the studies,
`design experiments, track samples in the process,
`collect the data in a relational database, and mine the
`information using statistical techniques and models in
`property space that assist the scientist to maximize the
`value of the data. Such models attempt to fit an output
`variable to physical properties or descriptors using
`techniques similar to those used in traditional quanti-
`tative structure activity relationships (QSAR). These
`models can be carefully extended to mixtures contain-
`ing compounds that were not included in the original
`experiments if validation suggests that the models are
`sufficiently stable. Significant models that are found in
`the analysis of the data can be stored in the database for
`later retrieval and use to direct iterative experiments.
`The power ofthis approach becomes increasingly more
`visible when several properties are being co-optimized,
`as can be very important in the pharmaceutical devel-
`opment process where such properties as oral bioavail-
`ability, stability and processability need to be
`reconciled. The availability of a map of conditions that
`lead to the formation of different forms (salts, hydrates,
`solvates, polymorphs, co-crystals) of the drug can be
`valuable to the process chemists or engineers as they
`develop scalable processes to produce materials suit-
`able for development and registration.
`For many years, the value of composition of matter
`(COM) patents on new chemical entities,
`including
`where appropriate, pharrnaceutically acceptable salts,
`has been well appreciated. However, it is only within
`the last decade or so that the application of COM
`patents has been significantly extended to cover all
`forms of the compound, including hydrates, solvates,
`co—crystals and polymorphs. Unlike salts, which for
`the most part can be prophetically claimed based on
`an understanding of the chemical structure of the
`compound and its ionization constants, the existence
`and identity of hydrates, solvates, co—crystals and
`polymorphs have defied prediction. Therefore,
`in
`order to obtain patent protection on these forms, some
`of which may have significantly different properties
`and relevance as development candidates, it is essen-
`tial to prepare them, identify conditions for making
`them and evaluate their properties as valuable new
`pharmaceutical materials.
`In general, discrete crystal forms are considered
`non-obvious and patentable. Given the diversity and
`greater complexity of chemical structures of today’s
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`S.L. Morissette et al. / Advanced Drug Delivery Reviews 56 (2004) 275-300
`
`297
`
`drug candidates [110], coupled with the advanced
`technology to identify novel forms, it is common to
`find multiple forms of drugs [61], some similar, some
`dramatically different in terms of their in vivo perfor-
`'mance. These forms are all candidates for separate
`intellectual property protection. Traerefore, it is incum-
`bent on the innovator of a new drug candidate to
`identify and patent these forms in order to optimally
`protect their investment in the compound. Recent case
`studies suggest that identifying and patenting all forms
`of new chemical entities should be a primary strategy
`of all innovators of novel drugs. In this regard, the use
`of HT crystallization technologies for rapid, compre-
`hensive discovery and characterization of solids form
`diversity offers significant advantages for the devel-
`opment of a strong intellectual property position.
`With the advent of HT crystallization methods,
`appreciation for the landscape of physical form for
`drug development has begun to change. Use of these
`systems has the potential to facilitate drug develop-
`ment by saving valuable time in selecting the optimal
`physical or chemical form of a given compound. HT
`systems that generate rich datasets offer the ability to
`develop a more fundamental understanding of the
`crystallization process, based on knowledge generated
`from large numbers of experiments on diverse com-
`pounds. Having such information at an early stage
`minimizes the risk of process modifications resulting
`in form changes and provides the opportunity to gain
`more comprehensive intellectual property coverage.
`In addition, comprehensive form data help address
`important regulatory questions related to the number
`.
`.
`.
`of solid forms of an API and the relationships between
`them-
`
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