Published by the University of Cape Town (UCT) under a non-exclusive license granted to UCT by the author. Complementary studies of the compounds using X-ray powder diffraction (XRD) and DSC enabled the identification and assignment of the desolvation products, viz.
CHAPTER 13: STRUCTURE SOLUTIONS AND DESCRIPTIONS FOR ST SOLVATES
CHAPTER 14: CONCLUSION
INTRODUCTION
- A GENERAL OVERVIEW OF INCLUSION COMPOUNDS
- DEFINITIONS AND CLASSIFICATION
- INCLUSION COMPOUNDS OF DRUG SUBSTANCES
- PHYSICOCHEMICAL TECHNIQUES USED TO INVESTIGATE THE DESOLVATION PROCESSES
- SULFONAMIDE DRUGS
- RECENT STUDIES OF DRUG INCLUSION COMPOUNDS
- POLYMORPHISM AND PSEUDOPOLYMORPHISM OF DRUGS
- THERMAL DECOMPOSITION OF DRUG SOLVATES (TGA-DSC)
- ALLIED TECHNIQUES
- PRACTICAL SIGNIFICANCE OF POLYMORPHISM
- HISTORICAL BACKGROUND
- ANTIBACTERIAL ACTION OF SULFONAMIDES
- THE IMPORTANCE OF SULFONAMIDES
On the other hand, if the crystallization of the drug results in blocking of the solvent of crystallization, whether stoichiometric or not. Failure to successfully investigate the polymorphism early in the drug's life can result in a toxic drug.
MeOX) OMe
SULFONAMIDE INCLUSION CHEMISTRY
In an effort to gather more information about the named compound's crystallizing properties, the study addressed several unresolved issues. This study represents a typical study of the solid-state behavior of drug substances using X-ray analysis and thermoanalytical methods in line with the overall topic of this project.
SUCCINYLSULFATHIAZOLE AND SULFATHIAZOLE
While it was easier to characterize forms I and II using TGA-DSC and XRD techniques, it proved quite difficult to distinguish between forms III and IV using the same techniques. Kruk in "The Biochemistry and Pharmacology of Antibacterial Agents", Croom Helm, Biology in Medicine Series, London, p.
THE MAIN OBJECTIVES AND SCOPE OF THIS WORK
- RECRYSTALLIZATION FROM SUITABLE SOLVENTS
- DETERMINATION OF STOICHIOMETRIC COMPOSITIONS
- THE TOPOLOGY OF SOLVENT INCLUSION
- CONFORMATIONS OF HOST MOLECULES
- THE KINETICS OF DESOLVATION
- IDENTIFICATION OF POLYMORPHS
- SELECTIVITY EXPERIMENTS
- DESOLVATION REACTIONS INVESTIGATED
- SELECTIVITY
These crystallizations were performed with the aim of revealing the existence of trends in the incorporation behavior of the two drugs. Analysis of rotation angles and molecular planes enabled the identification of the preferred one. conformational states of drug molecules in the solid state.
EXPERIMENTAL PROCEDURES
- CHARACTERIZATION OF SSTHYD AND ST
- PREPARATION OF HOST COMPOUND - SSTANHYD
- PREPARATION OF SOLVATES
- Crystal Growth
- MICROANALYSES
- DENSITY MEASUREMENTS
- THERMOANALYTICAL CHARACTERIZATIONS
- Thermomicroscopy
- Stability Tests
- KINETICS OF DESORPTION BY DYNAMIC TGA
- X-RAY POWDER DIFFRACTION TECHNIQUES
- SINGLE CRYSTAL X-RAY DIFFRACTION
- COMPUTATIONS
- Computations for SST solvates
- SELECTIVITY EXPERIMENTS BY GLC
- THERMOMICROSCOPY AND CRYSTAL STABILITIES
- GENERAL COMMENT
- CRYSTAL STABILITIES
- HOTSTAGE THERMOMICROSCOPY
- CRYSTAL DENSITIES
- MICROANALYSES
- THERMOMICROSCOPY AND CRYSTAL STABILITIES .1 GENERAL COMMENT
- THERMOANALYTICAL METHODS (TGA-DSC) .1 GENERAL COMMENT
- THERMOGRAVIMETRIC ANALYSIS
- THE TGA EXPERIMENTS
- DIFFERENTIAL SCANNING CALORIMETRY
- THE DSC EXPERIMENTS
- TGA-DSC THERMOGRAMS OF THE COMPOUNDS STUDIED
- TABULATION OF THERMAL RESULTS
- TGA Table of Results
- DSC Table of Results
- INTERPRETATION OF TGA-DSC RESULTS
- DESOLVATION KINETICS BY DYNAMIC TGA
- GENERAL
- THE PHYSICAL CHEMISTRY OF THE TECHNIQUE
- THE MODES OF DESOLVATION
- THE TGA KINETIC EXPERIMENT
- THE TGA KINETIC RESULTS
- INTERPRETATION OF THE KINETIC RESULTS
- DESOLVATION KINETICS BY DYNAMIC TGA .1 GENERAL
Subtle changes in the appearance of the crystals were photographed using a built-in Nikon Microflex AFX-II photomicrographic attachment. After approx. At 2 hours, crystals of some of the solvates became opaque and showed clear signs of deterioration. All calculations were performed using an external VAX-VMS computer at the Computer Center at the University of Cape Town.
Agreement between the observed (F0 ) and calculated (Fe) structure factors is expressed in terms of the residual factor, R, which is defined as:-. The IBM PC version of the program PLUT0116 was used to produce the crystal and molecular packing diagrams. In the case of the raw materials, SSTHYD, SSTANHYD and ST, wide melting temperature ranges were confirmed as per the literature reports 6,9s,120.
In the case of solvates, strong bubbling was noted as a confirmatory sign of the gas release process. Depending on the heating rate, the geometry of the system and gases flowing through it, there is usually a. As indicated in Fig. 5.1.3 b), a multistep thermal degradation profile of CuS04.5H20 yields the stoichiometry of the reaction.
A further anomaly observed in all thermograms is the apparent out-of-step appearance of the TGA peaks with them.
B (°Cmin-·)
INTERPRETATION OF KINETIC RESULTS
- INTRODUCTION
The tables are presented according to the order in which the structures were presented, i.e. intensity data collection and structure improvements. In addition to allowing easy cross-referencing, the contents of these tables are constantly referenced throughout this text. Due to the presence of S atoms in the SST host compound, all three compounds, namely SSTDI, SSTBU, and SSTPE, were suitable for solution by the heavy atom method.
In all three crystal structures that were solved, the arbitrary numbering scheme as indicated above (see Figure 7.1.3 (a)) was adopted. In this form, N(23) carries the hydrogen atom instead of N(l8), thus making the latter atom available for participation in the hydrogen bonding scheme shown in Figure 7.1.4 (b). c) Torsion angle SSTBU SSTPE SSTDI. A close inspection of other typical dihedral angles in the table above shows the same trend.
A similar example of dimerization was encountered when working with coordinate clathrates of the drug, 5-.
STRUCTURES OF SOLVATES
After structure solution, the two dioxane molecules were found to occupy independent crystallographic sites of symmetry I within the host–guest aggregate (see Figure 7.2.1 (b)). Hydrogen atoms were placed on ~P maps and added to idealized positions at 1.00A from their parent atoms. All non-hydrogen atoms were treated. anisotropically in the final refinement. 100) Projection of the structure of SSTDI showing two.
The dioxane molecule refined with normal U1= values (located at O,O,O) is held tightly by hydrogen bonding while the. Confirmatory characterization of SSTBU was performed with the aim of assessing the validity of the 1 : 0.89 H:G composition reported earlier6. The stereodiagram in 7.2.2 (b) illustrates the mode of association between the host and the guest whereby the guest molecules are trapped in cavities created by the host lattice (see Figure 7.2.2. c)) and engage in hydrogen bonding with the host.
The structures of SSTBU and SSTPE are isomorphic with respect to the host molecules and have solvent molecules occupying crystallographically equivalent sites in each case. In general, the structures resolved well except for the solvent molecules, which were characterized by high
X-RAY POWDER DIFFRACTION
- GENERAL
- THE SOLVATES AND THEIR DESOLVATION PRODUCTS
- DISCUSSION
X-RAY POWDER DIFFRACTION 1 GENERAL
It was commented earlier on the fact that the result of XRD experiments can be seriously affected by factors such as the preferred crystal orientation of the micro. In the case of SST solvates some serious difficulties were experienced in obtaining reproducible dust patterns. Given the large surface area exposed during the milling step, potential evaporation was blamed for the discrepancy.
Based on all spectra obtained, the near isomorphism of SSTBU and SSTPE was again evident in the remarkably similar XRD. In addition, the desolvation of SSTBU resulted in the solid whose powder pattern corresponds to that of MOD IV published by Burger et al.6. On the other hand, the desolvation of SSTPE yielded a powder pattern that matched none of the published patterns.
However, many of the observed peaks had counterparts in the patterns for MODS II-IV, thus indicating that the desolvation of SSTPE likely yields a mixture of these polymorphs. It was not possible to obtain powder patterns for the desolvation product of SSTDI as the final desolvation step in this species occurs almost simultaneously with the host melting (see Figure 5.3{e)).
SELECTIVITY
- GENERAL
- THE GLC EXPERIMENT
- THE GLC RESULTS
- DISCUSSION
SELECTIVITY 1 GENERAL
It is clear from the calibration curve in Figure 9.3(b) that the detector used a flame ionization detector. The selectivity curve shows that SST does not distinguish between 1-butanol and 1-pentanol in mixtures with a low molecular weight fraction Xb(Xb~0.10). It appears that the extension of the chain structure with one methylene group is highly detectable due to the nature of the voids in the SST host structure.
THE OVERALL CONCLUSION ON SST SOLVATES
Of primary importance is the success with which SST polymorphism and pseudopolymorphism have been investigated. in particular, the interesting polymorphic interconversion scheme established for the desolvation of SSTBU can be considered as a key research in confirming the existence of six polymorphs of SST. The success of pharmaceutical maneuvering with solid-state SST lies in the confidence and reproducibility with which its polymorphs can be produced. An example of this fact can be taken from the polymorphs of the drug mebendazole cited earlier in CHAPTER 1, where the polymorphs must be properly characterized to enable the correct selection of the desired polymorph.
A potential industrial application of this study was exploited by means of the competition experiments which provoked further academic questions about the phenomenon of inclusion in general, i.e. determining the selective inclusion of specific types of gas molecules. Therefore, this study can be considered as a contribution to the solid-state chemistry of the drug, succinylsulfathiazole.
THERMAL ANALYSIS AND THE KINETICS OF DESOLVATION
- GENERAL BACKGROUND
- THE LAYOUT OF THIS CHAPTER
Severe crystal breakage problems were experienced during an attempt to collect intensity data for STPY26; Thus, only thermal and XRD data are presented for this compound. On the other hand, the 4-methylpyridine solvent gave thermal and XRD data of very poor quality and was subsequently abandoned. For compounds STPY2 and STPY26, only thermal data are presented and discussed since no kinetic data were obtained for them.
CHAPTER 1 2
- POWDER XRD CHARACTERIZATION OF ST COMPOUNDS
- NOTES ON THE DSC-XRD DUAL CHARACTERIZATION OF ST
- EXPERIMENTAL POWDER PATTERNS
- DISCUSSION
It was imperative to identify the starting material to assign the polymorphs resulting from desolvation and get an idea of the magnitude and proliferation of phase changes caused by inclusion. It was noted that neither the DSC nor the XRD technique alone was adequate in elucidating the complicated polymorphism of sulfathiazole, but that the two should complement each other to eliminate ambiguities. This identification was rather difficult because of the close similarity of the XRD patterns for Forms III and IV (see Figure 1.30) and the obscure melting points reported for these forms.36-155.
A look at the XRD patterns for the solvated species shows that they are all clearly different. This is consistent with X-ray analyzes of single crystals. discussed in CHAPTER 13), where crystal packing patterns were found to be different in the three solvates. Furthermore, the high-quality XRD patterns for the solvates and their reproducibility indicated the high degree of crystallinity and purity of these compounds.
However, the XRD patterns for the desolvated species are common to all compounds: Form I (see Figure 1.30) is obtained after the desolvation of all four compounds. From this study it was concluded that the predominance of Form I as the only identifiable desorption product is indicative of its stability compared to the other three polymorphic forms9.
CHAPTER 1 3
- THE HOST COMPOUND - SULFATHIAZOLE
- STRUCTURE SOLUTION AND REFINEMENT OF STPY
- DISCUSSION OF THE STPY STRUCTURE
- STRUCTURE SOLUTION AND REFINEMENT OF STPYl
- STRUCTURE SOLUTION AND REFINEMENT OF STPY2
- DISCUSSION OF THE STPY2 STRUCTURE
- DISCUSSION OF ST CRYSTAL STRUCTURES AND CONCLUSION
In Figure 13.1.4 (e), the shading represents the area occupied by the host ST molecules alone at successive parts of the unit cell parallel to the ab plane. The E map therefore yielded 76% of the total number of 46 non-hydrogen atoms. isotropic using the program SHELX 76. The question of the absolute structure of the crystal sample selected for analysis was considered.
A diagram of the cross-section of the unit cell along c, indicating the presence of continuous channels in this direction. After several cycles of anisotropic refinement, all hydrogen atoms were located in ~P syntheses. A diagram of the asymmetric unit of STPY2 with atomic nomenclature and. hydrogen bond indicated by a dashed line.
Common among them is the effect of the methyl substituent at various positions on the pyridine ring. In general, satisfactory characterization studies of ST solvates have been carried out, resulting in
