Theophylline hydrate

Dehydrations are chemical reactions that involve the loss of water. The acid-catalyzed dehydration of tetracycline yields the toxic epianhydrotetracycline [20]. The physical dehydration of theophylline hydrate and ampicillin trihydrate leads to a change of the crystalline structure of the drug [21]. 

Compound Nitrofurazone Sodium Ascorbate Ethyl Gallate Guaiphenesin Metharbitone Theophylline Hydrate Guanethidine Tacrine... 

Tubocurarine Chloride Tyramine Hydrochloride Theophylline Hydroflumethiazide Azacyclonol Hydrochloride Nitrofurantoin Theophylline Hydrate Ethisterone... 

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... 

Figure 6. Theophylline hydrate/anhydrate phase diagram from 4 to 40 °C. Reproduced from (Ticehurst et ah, 2002) with permission from Elsevier.

Shefter et al. used x-ray diffraction analysis to show that over-drying ampicillin trihydrate resulted in an unstable amorphous product, and that the drying of theophylline hydrate yielded a crystalline anhydrous form [26]. Kitamura et al. dehydrated (with vacuum) cefixime trihydrate to obtain a crystalline anhydrous form, which also proved to be unstable [27]. 

The same co-crystal hydrate is also obtained by the neat grinding of theophylline hydrate with anhydrous dtric add, the neat grinding of anhydrous theophylline with dtric acid monohydrate, as well as the neat grinding of theophylline monohydrate with dtric add monohydrate. Neat grinding of anhydrous theophylline and anhydrous dtric acid, by contrast, leads to the formation of an anhydrous co-crystal of 1 1 stoichiometry (Figure 8.18(c)). The similarity of the supramolecular motifs within the co-crystal hydrate to those observed in theophylline monohydrate and citric acid monohydrate crystals (Figure 8.19) suggests that, in the presence of water, the co-crystal hydrate could... 

Accelerated aging and crystal transformation rates have also been traced to high residual moisture content. Ando et al. studied the effect of moisture content on the crystallization of anhydrous theophylline in tablets [9]. Their results also indicate that anhydrous materials convert to hydrates at high levels of relative humidity. In addition, if hygroscopic materials (e.g., polyethylene glycol 6000) are also contained in the formulation, needle-like crystals form at the tablet surface and significantly reduce the release rate of the theophylline. 

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... 

Solids that form specific crystal hydrates sorb small amounts of water to their external surface below a characteristic relative humidity, when initially dried to an anhydrous state. Below this characteristic relative humidity, these materials behave similarly to nonhydrates. Once the characteristic relative humidity is attained, addition of more water to the system will not result in a further increase in relative humidity. Rather, this water will be sorbed so that the anhydrate crystal will be converted to the hydrate. The strength of the water-solid interaction depends on the level of hydrogen bonding possible within the lattice [21,38]. In some hydrates (e.g., caffeine and theophylline) where hydrogen bonding is relatively weak, water molecules can aid in hydrate stabilization primarily due to their space-filling role [21,38]. 

Case study theophylline anhydrate and monohydrate The type of structural information that can be obtained from the study of the x-ray diffraction of single crystals will be illustrated through an exposition of studies conducted on the anhydrate and hydrate phases of theophylline (3,7-dihydro-l,3-dimethyl-LH-purine-2,6-dione). The unit cell parameters defining the two phases are fisted in Table 7.2, while the structure of this compound and a suitable atomic numbering system is located in Fig. 7.3. 

A.M. Amado, M.M. Nolasco and P.J.A. Ribeiro-Claro, Probing pseudopolymorphic transitions in pharmaceutical solids using Raman spectroscopy Hydration and dehydration of theophylline, J. Pharm. Sci., 96, 1366-1379 (2007). 

Substances which have a long half-life when present in large amounts Theophylline, aspirin, alcohol, phenytoin, chloral hydrate, acetaminophen. 

In 0.1 M methanolic sodium hydroxide, the 6-chloropurine ketonu-cleoside 41b was cleaved after 30 min, whereas the theophylline derivative 41a was unaffected.26,27 The stability of the theophylline ketonu-cleoside 41a maybe explained by the establishment of a hydrogen bond between the 4 -gem-diol system (hydrate form of 41a) and the 2-keto group of theophylline. The assigned 4Ct (l) conformation would facilitate this bonding, whereas it could not occur with the 6-chloropurine derivative regardless of its conformation.27... 

The intrinsic dissolution rate method is most useful where the equilibrium method cannot be used. For example, when one wishes to examine the inLuence of crystal habit, solvates and hydrates, polymorphism, and crystal defects on apparent solubility, the intrinsic dissolution rate method will usually avoid the crystal transitions likely to occur in equilibrium methods. However, crystal transitions can still occur at the surface as in the case of anhydrous theophylline (De Smidt, 1986), where the anhydrous form converts to the hydrate and the intrinsic dissolution rate changes over time. In these cases, the application oflaer optical probe, which permits the detection of the drug concentration every few seconds, may prove to be very advantageous. 

Gould, P.L., Howard, J.R., and Oldershaw, G.A. The effect of hydrate formation on the solubility of theophylline in binary aqueous cosolvent systelimfej. Pharm., 51, 195-202, 1989. 

Rodriguez-Hornedo, N., Lechuga-Ballesteros, D., and Wu, H.-J. (1992). Phase transition and hetero-geneous/epitaxial nucleation of hydrated and anhydrous theophylline cryiibtUs J. Pharm., 85 149-162. 

Savolainen et al. investigated the role of Raman spectroscopy for monitoring amorphous content and compared the performance with that of NIR spectroscopy [41], Partial least squares (PLS) models in combination with several data pre-processing methods were employed. The prediction error for an independent test set was in the range of 2-3% for both NIR and Raman spectroscopy for amorphous and crystalline a-lactose monohydrate. The authors concluded that both techniques are useful for quantifying amorphous content however, the performance depends on process unit operation. Rantanen et al. performed a similar study of anhydrate/hydrate powder mixtures of nitrofurantoin, theophyllin, caffeine and carbamazepine [42], They found that both NIR and Raman performed well and that multivariate evaluation not always improves the evaluation in the case of Raman data. Santesson et al. demonstrated in situ Raman monitoring of crystallisation in acoustically levitated nanolitre drops [43]. Indomethazine and benzamide were used as model... 

There are many examples of second-order analyzers that are used in analytical chemistry including many hyphenated spectroscopic tools such as FTIR-TGA, IR-microscopy, as well as GC-MS, or even two-dimensional spectroscopic techniques. Another hyphenated technique that is being developed for the study of solid-state transitions in crystalline materials is dynamic vapor sorption coupled with NIR spectroscopy (DVS-NIR).26 DVS is a water sorption balance by which the weight of a sample is carefully monitored during exposure to defined temperature and humidity. It can be used to study the stability of materials, and in this case has been used to induce solid-state transitions in anhydrous theophylline. By interfacing an NIR spectrometer with a fiber-optic probe to the DVS, the transitions of the theophylline can be monitored spectroscopically. The DVS-NIR has proven to be a useful tool in the study of the solid-state transitions of theophylline. It has been used to identify a transition that exists in the conversion of the anhydrous form to the hydrate during the course of water sorption. 

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