Theophylline monohydrate

Since it was known that theophylline monohydrate can be thermally dehydrated to form either the stable Form I or the metastable Form I, the effect of different drying methods on the phase composition was studied [89], Using either a multichamber microscale fluid bed dryer or the hot stage of a variable-temperature XRPD diffractometer, Form I was produced when the drying was conducted at 40-50°C. Drying at 60°C in the VT-XRPD unit yielded only Form I, while mixtures of products were produced in the microscale fluid bed dryer even at temperatures as high as 90 °C. 

X-ray powder diffractometry can be used to study solid state reactions, provided the powder pattern of the reactant is different from that of the reaction product. The anhydrous and hydrated states of many pharmaceutical compounds exhibit pronounced differences in their powder x-ray diffraction patterns. Such differences were demonstrated earlier in the case of fluprednisolone and carbamazepine. Based on such differences, the dehydration kinetics of theophylline monohydrate (CvHgN H20) and ampicillin trihydrate (Ci6H19N304S 3H2O) were studied [66]. On heating, theophylline monohydrate dehydrated to a crystalline anhydrous phase, while the ampicillin trihydrate formed an amorphous anhydrate. In case of theophylline, simultaneous quantification of both the monohydrate and the anhydrate was possible. It was concluded that the initial rate of this reaction was zero order. By carrying out the reaction at several... 

As discussed above, one obtains a large amount of structural information upon completion of the data analysis, which will be illustrated using the example of theophylline monohydrate [20]. Table 7.3 contains a summary of intramolecular distances involving the non-hydrogen atoms in the structure, while Table 7.4 shows the intramolecular... 

Crystallographic parameters defining the unit cells of theophylline anhydrate and theophylline monohydrate phase... 

Intramolecular distances in theophylline monohydrate involving nonhydrogen atoms [20]... 

Fig. 7.5. Composition of the unit cell of the theophylline monohydrate crystal phase [20].

By use of the proper experimental conditions and Ltting the four models described above, it may be possible to arrive at a reasonable mechanistic interpretation of the experimental data. As an example, the crystal growth kinetics of theophylline monohydrate was studied by Rodriguez-Hornedo and Wu (1991). Their conclusion was that the crystal growth of theophylline monohydrate is controlled by a surface reaction mechanism rather than by solute diffusion in the bulk. Further, they found that the data was described by the screw-dislocation model and by the parabolic law, and they concluded that a defect-mediated growth mechanism occurred rather than a surface nucleation mechanism. 

Herman J, Remon JP, Visavamngroj N, Schwartz JB, Klinger GH. 1988. Formation of theophylline monohydrate during the pelletization of microcrystalline cellulose-anhydrous theophylline blends. Int. J. Pharm. 42 15-18. 

FIGURE 19 (a) 3D data plot with fitted plane twisted at t = tmax and (b) 3D parameter plot of ( ) DCPD dicalcium phosphate dihydrate, (O) spray-dried lactose, ( ) MCC. microcrystalline cellulose, (0) theophylline monohydrate, and ( ) HPMC hydroxypropyl methylcel-lulose for data gained with an eccentric table ting machine [47]. 

Hauschild, K., and Picker-Freyer, K. M. (2006), Evaluation of tableting and tablet properties of Kollidon SR The influence of moisture and mixtures with theophylline monohydrate, Pharm. Technol. Dev., 11(1), 125-140. 

Theophylline, 1011 in sport, 98 (metabolite), 421 quantification in plasma, 26 therapeutic drug monitoring, 110 Theophylline, anhydrous, 1011 Theophylline cholinate, 1011 Theophylline ethylenediamine compound, 1011 Theophylline hydrate, 1011 Theophylline monoethanolamine, 1011 Theophylline monohydrate, 1011 Theophylline olamine, 1011 Theophylline sodium aminoacetate, 1011 Theophylline sodium glycinate, 1011 Theophylline-7-acetic acid, 310 Theophylline-aminoisobutanol, 408 Theospan, 1011 Theovent, 1011 Thephorin, 880 Theralax, 397 Theralene, 1046 Therapav, 848... 

Interactions between water vapor and amorphous pharmaceutical solids were evaluated using isothermal microcalorimetry. " The desorption of water from theophylline monohydrate has been investigated using microcalorimetric approaches.The properties of surfactants and surface-active drugs in solution were studied by Attwood et al. " using calorimetry, while titration microcalorimetry has been utilized to elucidate the nature of specific interactions in several pharmaceutical polymer-surfactants systems. " Drug decomposition was evaluated as a function of different... 

Duddu, S.P. Das, N.G. Kelly, T.P. Sokoloski, T.D. Micro-calorimetric investigation of phase transitions 1. Is water desorption from theophylline monohydrate a single-step process Int. J. Pharm. 1995,114, 247-256. 

When theophylline monohydrate was dehydrated, it formed a metastable anhydrous phase, which then transformed to the stable anhydrate. The XRD patterns of the two anhydrate phases and the monohydrate were sufficiently different so that all three of them could be simultaneously identified in a sample (Fig. 7A). Anhydrous theophylline was granulated with an aqueous solution of PVP. During the wet-massing stage, the anhydrate transformed to the monohydrate. When the granules were dried, there was dehydration resulting in the formation of the metastable anhydrate, which then transformed to the stable... 

Fig. 7 (A) XRD patterns of theophylline phases. M, A, and A refer to theophylline monohydrate, stable anhydrous theophylline, and metastable anhydrous theophylline respectively. (B) Phase transitions during the drying of theophylline granules. PVP was the granulating agent. The integrated intensities of the 8.9, 9.4, and 7.0° 20 peaks unique to M, A, and A respectively were simultaneously monitored as a function of the drying time. (From Ref. . )...

The phase transitions of theophylline monohydrate were discussed earlier in the section dealing with Phase Transitions Induced During Processing (Fig. 7). High temperature XRD was used to investigate the dehydration of theophylline monohydrate (Fig. 11). This technique revealed that dehydration resulted in a metastable anhydrous phase, which then transformed to the stable anhydrate. Theophylline has been in widespread use for many years and its solid-state properties have been the subject of numerous investigations. Without high temperature XRD, it is unlikely that this metastable phase would have been identified. 

Fig. 11 High temperature XRD of theophylline monohydrate. XRD patterns were obtained at the temperatures indicated in the figure. The and o marks indicate peaks unique to metastable anhydrous theophylline (referred to as A in Fig. 7),...

Agbada Co O, York P. Dehydration of theophylline monohydrate powder-effects of particle size and sample weight. Int J Pharma 1994 106 33-40. 

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