Identification of a Solid Form – Theophylline Sample Using Different Analytical Procedures
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Context:
Introduction………………………………………………………….page (3)
Background……………………………………………………………page (4)
Method………………………………………………………………..page (6)
Results and discussion………………………………………page (7)
Conclusion…………………………………………………………..page (13)
Reference……………………………………………………………..page(14)
Introduction:
Theophylline (Fig.1 C7H8N4O2: 1, 3-dimethyl-7H-purine-2, 6-dioneis) is bronchodilator, used to treat symptoms such wheezing, shortness of breath caused by asthma, bronchospasm, and COPD (Rabe el at.,1995 ).Theophylline like many other drugs tends to exhibit polymorphism. As a result, each polymorph of the substance will tend to have different physical properties such as melting point, solubility, and density (Barbas R el at., 2007).Therefore, such drugs will display different physicochemical properties which could lead to the difference in drug processing, formulation, and bioavailability (Seton el at., 2010). Theophylline forms 4 different polymorphs (I, II, III &IV) in addition to a monohydrate according to previous works of literature (Suzuki et al. Ebisuzaki et al., 1997, Matsuoka, 2007). Monohydrate, can also be expressed by M, is monocyclic hydrate. The structure was first introduced in 1958 (Sutor, D. J., 1958).The packing. Looking at the structure packing[Sun et al., 2002, (CSD: Allen,2002) refcode THEOPH01, Fig.2], the theophylline forms a hydrogen-bonded dimer pairs, further hydrogen bonding will be formed with the water molecule to form layers. The structure of Form (I) has not yet been identified, however, is tend to be stable at higher temperatures. Among the 3 anhydrous forms only form (II) structure was identified (Ebisuzaki et al., 1997, COD refcode 4505533). Form (II) can be made by dehydration of Form (M) in low humidity or a temperature greater than 353K, Refer to Fig. (Zhu et al., 1996). Looking at Fig. (3) orthorhombic structure (space group Pna21, Table (1)) of From (II) a bilayer is formed due to the hydrogen bonding formed between N-HN and another two with C-H…O. From (III) was first suggested in 1997(Matsuo & Matsuoka, 2007).It was found that the structure to be highly metastable and will rapidly convert to the other two anhydrous forms and so its structure is not easily identified. From (III) can be formed by the dehydration of Form (M) in low pressure or vacuum, Refer to Fig. (Phadnis & Suryanarayanan, 1997). The 4th polymorph of theophylline was recently identified (Seton et al.,2010).It was historically suggested that Form (II) was the most thermodynamically stable but Form (IV) is suggested to be the most thermodynamically stable anhydrous polymorph of theophylline as it can be formed by slow, solvent-mediated conversion from anhydrous Form (II) and (I).The structure of Form (IV) is monoclinic , its molecules join in asymmetric unit ,as shown in the Fig (4). However when Form (I) and (II) will immediately convert to monohydrate form when water is added, which suggests that the monohydrate is the most thermodynamically stable form of theophylline(Fig.5)(Suzuki et al., 1989).So in this report, the student was supplied with a sample of unidentified solid form theophylline. Accordingly, the student was to plan a sequence of analytical tests that would help him/her to classify the form or forms present in the sample. The tests involved a combination of techniques such as Microscopy which can help us in the characterization of different forms of theophylline and if the sample is in its crystalline or other forms. Thermal analysis such as DSC and TGA that display changes in MP and peaks for phase changes. X-ray diffraction pattern or PXRD and Raman spectra are used to differentiate between the solid forms.
Therefore the aim of this experiment is to be able to identify the different solid forms of theophylline sample by planning various analytical tests such as powder X-ray and DSC.
Background:
Monohydrate
Theophylline
Form(I)
Theophylline Form(II)
Theophylline
Form( IV)
Sample
Molecular formula
C7H8N4O2?(H2O)
C7H8N4O2
C7H8N4O2
C7H8N4O2
C7H8N4O2
Molecular weight
198.18
180.164
180.164
180.17
180.164
Cryst Syst
Monoclinic
Monoclinic
Orthorhombic
Monoclinic
Orthorhombic
Space group
P21/c
Pna21
P21=c
Pna21
7.8935
24.612
7.7055