Pharmaceutical Product Development: In Vitro-In Vivo Correlation, edited by Dakshina Murthy Chilukuri, Gangadhar Sunkara, and David Young. Oral Lipid-Based Formulations: Improving the Bioavailability of Poorly Water-Soluble Drugs, edited by David J. Aqueous Polymer Coatings for Pharmaceutical Dosage Forms, Third Edition, edited by James McGinity and Linda A.
It is now only about 10 years since the publication of the first edition of Polymorphism in Pharmaceutical Solids, which certainly received a positive response from drug development workers. In the first edition, the phase interconversion of polymorphs and solvatomorphs was covered only from a processing point of view, but in the current edition this important topic is now covered in two chapters, "Solid-State Phase Transformations". As in the first edition, the final section contains chapters grouped together as special topics.
Even though the scope of the second edition of Polymorphism in Pharmaceutical Solids has been greatly expanded relative to that of the first edition, there is simply no way that all developments in the field could have been covered in depth in a single volume.
CHARACTERIZATION METHODS FOR POLYMORPHS AND SOLVATOMORPHS
INTERCONVERSION OF POLYMORPHS AND SOLVATOMORPHS 13. Solid-State Phase Transformations 481
SPECIAL TOPICS RELATED TO POLYMORPHISM AND SOLVATOMORPHISM
Contributors
Theory and Principles of Polymorphic Systems
The conditions of a system can be controlled by manipulating the system's environment. H = ∆E PV + ∆ (5) Comparison of equations (3) and (5) indicates that the increase ∆ H in the enthalpy of the system at constant pressure is equal to the heat absorbed under these conditions. The ratio between the fugacity of a substance and that of the substance in the standard state has been termed the activity (a.
The free energy relationships between the two monotropic polymorphs are shown in Figure 4, including the enthalpy and free energy curves of the liquid (molten) state. The melting point of the most stable polymorph is higher than the transition point temperature. Form-1 is the most soluble polymorph at all temperatures below the melting point.
Conversely, if one polymorph is the most soluble form at all temperatures below that of the melting point of either form, then the two polymorphs must be monotropic.
Application of the Phase Rule to the Characterization of Polymorphic and
In general practice, workers make use of the usual transition point (defined as the temperature of equal phase stability at atmospheric pressure), but this point in the phase diagram must be distinguished from the S 1 –S 2 –V triple point. The pressure dependence of the S 1 – S 2 (Form-1/Form-2) phase transformation is known (25), and the phase diagram resulting from adding this data to the sublimation curve is shown in Figure 5. The S 1 –S 2 –V triple point is one where the reversible transformation of the crystalline polymorphs can take place.
The S 2 –V curve crosses the stable L–V fusion curve at an achievable temperature, which is the melting point of the S 2 phase. This in turn has the effect of causing the S 1 – S 2 – V triple point to exceed the melting point of the stable S 1 phase. At that point the pressure would drop to the characteristic (and negligible) vapor pressure of the anhydrate phase.
At that point the pressure would drop to that characteristic pressure of the dihydrate phase.
Computational Methodologies: Toward Crystal Structure and Polymorph Prediction
RMSD n is the minimum root-mean-square difference in the non-hydrogen atom positions for the n superimposed molecules of the 15 (default value) coordination cluster of the two structures]. As would be expected, the simulated powder patterns of the two crystal structures are obviously different (Fig. 1C. The comparison of the energetic fingerprints (17) (the center of mass distance, symmetry ratio and the components of the interaction). energy between a central molecule and each of its coordinating molecules) of the crystal structures adds further clarity to the debate about whether these two structures should be considered polymorphs (18).
This calibration of the powder sample similarity index was established (20) using polymorphs and redeterminations from different samples in different laboratories at different temperatures (with an approximate correction for thermal expansion) in the Cambridge Structural Database (CSD) (21). . The traditional approach to modeling organic crystals sums the energy of interactions between all molecules in the crystal, evaluated from the model intermolecular potential. Temperature affects organic crystal structures in an anisotropic manner, reflecting the nature of intermolecular interactions in different directions.
The current state-of-the-art method for most organic crystal structures is intermediate. A comparison of total lattice energies, E latt, completely neglects the effects of temperature and pressure on the relative stability of crystal structures. Although the crystal energy landscape should use free energies as a function of temperature and pressure in the range of practical importance, the lattice energy landscape is generally a worthwhile first approximation.
Most older methods for generating pilot crystal structures for lattice energy minimization use crystallography. The two alternative stacks of the same sheet (Fig. 2) were predicted to be so close in energy (42) to the global minimum of the lattice energy landscape that it allowed the later discovery of form II (15) and the observation of the intergrowth of polymorphic domains within the same single crystal (18). Computational prediction and X-ray determination of the crystal structures of 3-oxauracil and 5-hydroxyuracil – an informal blind test.
A study of the known and hypothetical crystal structures of pyridine: why are there four molecules in the asymmetric unit cell. Kinetic insights into the role of the solvent in the polymorphism of 5-fluorouracil from molecular dynamics simulations.
Classical Methods of Preparation
The second component of the route map for a cooling crystallization is the metastable zone width (MZW), illustrated in Figure 8. Increasing the cooling rate will "stretch" the metastable zone to encompass a larger area of the concentration–temperature continuum. The solvent can also determine polymorph selectivity via chemical interference with the formation of the crystalline solid at the nucleation point.
The supersaturation in this case could be controlled by varying the concentration of the starting solution and the addition of the antisolvent. There was also metastable to stable interconversion in the product slurry, on a time scale significantly slower than the observed crystallization. However, measurements of the growth rates of both forms show that in the intermediate range of supersaturation ratios.
Milling with and without solvent was used to prepare a dimorphic 1:1 cocrystal of caffeine and glutaric acid (91). A detailed study of cryogenic milling of indomethacin (93) produced amorphous material starting from all nonsolvated polymorphs, namely γ (stable), α, and δ (alternatively designated forms I, II, and IV, respectively). . The temperature dependence of the obtained solid forms was observed in thermally induced crystallization of anhydrous indomethacin (105).
Dehydration at higher temperatures (above 70°C) gave a sharp endothermic peak corresponding to the melting of the γ-form, whereas dehydration at a lower temperature (50°C) gave a peak corresponding to the melting of the α-form. The solvent-free form II of iopanic acid was prepared via desolvation of the benzene solvate (75). Relatively few solvates with other solvents are acceptable due to solvent toxicity.
Details of these methods and results are discussed in the previous four sections. Antisolvent crystallization of L-histidine polymorphs as a function of supersaturation ratio and solvent composition. The effect of the phase behavior of solvent-antisolvent systems on the gas-antisolvent crystallization of paracetamol.
Tailored” and charge transfer aids for control of crystal polymorphism of glycine.
Approaches to High-Throughput Physical Form Screening and Discovery
For example, an automated parallel crystallization study of the thiazide diuretic hydrochlorothiazide identified two polymorphs and seven solvates (16). Thus, it is possible to monitor the operation of the hardware and easily check the actual conditions used against the original protocol. As described in the section “Extent of Diversity of Physical Forms”, there are various ways to induce supersaturation and crystallization that can be easily implemented in automated crystallization systems.
Multivariate analysis techniques can be used to assess the completeness of the experimental search and try to identify relationships between the tested conditions and the observed results. Optical microscopy has wide application in the study and characterization of the organic solid state, and its various applications have been described in detail (88). Many instruments can also record digital images of each sample at the start of XRPD data collection.
The identity of any sample can be confirmed by comparing the experimental XRPD pattern with. Where the calculated profile takes into account all the observed diffraction peaks and a good fit is achieved, it can be concluded that the single crystal structure is representative of the sample (Fig. 16. Careful inspection of the final fit to the data can also reveal the presence of contaminant polycrystalline phases revealed.
The tick marks along the bottom of the plot show the calculated reflection positions. Controlling and predicting the structure and properties of pharmaceutical solids remains a significant challenge for those involved in the commercial development and manufacture of pharmaceuticals. Elucidation of crystal shape diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization.
Crystal engineering of the composition of pharmaceutical phases: multicomponent crystalline solids incorporating carbamazepine. Selective crystallization of the metastable form IV polymorph of tolbutamide in the presence of 2,6-di-O-methyl-beta-cyclodextrin in aqueous solution. Ab initio structure determination of the hygroscopic anhydrous form of a-lactose by X-ray powder diffraction.
Hydrogen bonding studies of cyclo[(2-methylamino-4,7-dimethoxyindan-2-carboxylic acid) (2-amino-4,7-dimethoxyindan-2-carboxylic acid)].
Structural Aspects of Polymorphism
Bravais Lattices
