Influence of processing-induced phase transformations on the dissolution of theophylline tablets

Abstract

INTRODUCTIONThe object of this investigation was to evaluate the influence of (1) processing-induced decrease in drug crystallinity and (2) phase transformations during dissolution, on the performance of theophylline tablet formulations. Anhydrous theophylline underwent multiple transformations (anhydrate → hydrate → anhydrate) during processing. Although the crystallinity of the anhydrate obtained finally was lower than that of the unprocessed drug, it dissolved at a slower rate. This decrease in dissolution rate was attributed to the accelerated anhydrate to hydrate transformation during the dissolution run. Water vapor sorption studies proved to be a good predictor of powder dissolution behavior. While a decrease in crystallinity was brought about either by milling or by granulation, the effect on tablet dissolution was pronounced only in the latter. Tablet formulations prepared from the granules exhibited higher hardness, longer disintegration time, and slower dissolution than those containing the milled drug. The granules underwent plastic deformation during compression resulting in harder tablets, with delayed disintegration. The high hardness coupled with rapid anhydrate → hydrate transformation during dissolution resulted in the formation of a hydrate layer on the tablet surface, which further delayed tablet disintegration and, consequently, dissolution. Phase transformations during processing and, more importantly, during dissolution influenced the observed dissolution rates. Product performance was a complex function of the physical state of the active and the processing conditions.The physicochemical properties of pharmaceuticals, including solubility and dissolution rate, can be influenced by the degree of crystallinity, solvation state, and crystal form. At room temperature, the anhydrate forms of ampicillin, theophylline, and glutethimide have a higher dissolution rate than their corresponding hydrates. 1 This difference in dissolution rate can be attributed to the difference in the free energy of hydration.1 Similarly, metastable forms, because of their higher free energy, are expected to dissolve more rapidly than their corresponding stable forms. This effect was observed with the metastable polymorphs of acetazolamide, carbamazepine, and indomethacin.2 However, this free energy difference between the stable and metastable forms can also provide the driving force for metastable → stable transformation in the dissolution medium. As a result, the observed difference in dissolution rate can be much lower than the predicted values. 3Although the physical form of a drug substance is carefully selected for dosage form manufacture, the processing conditions will determine the solid state of the drug in the final product. During tablet manufacture, processing steps may include milling, granulation, drying, and compression. Particle size as well as degree of crystallinity can be profoundly affected by milling as has been observed in case of griseofulvin. 4 The use of a binder solution for wet gra...

Investigation of Solid Phase Composition on Tablet Surfaces by Grazing Incidence X-ray Diffraction

“…MH. This phenomenon of transformation of the TP-MH to TP-AH is interesting and also of significance to the dissolution of the tablets (41). The dehydration of TP-MH due to the compaction has been reported earlier by two research groups (27,28).…”

Influence of the Solid Form of Siramesine Hydrochloride on its Behavior in Aqueous Environments

“…This is referred to as a processing induced transformation (6) and has been observed during wet granulation of for instance theophylline and carbamazepine (7)(8)(9). Furthermore, hydrate formation during in vitro dissolution, resulting in slower release, has been reported for theophylline, carbamazepine, and nitrofurantoin (10)(11)(12). Thus, if a compound is capable of hydrate formation, care must be taken to ensure that the most suitable form of the drug is chosen for development, and that phase transformations do not occur (or occur in a controlled manner) during processing and release (2,13).…”

Roller compaction of different pseudopolymorphic forms of Theophylline: Effect on compressibility and tablet properties

“…Polymorphic transitions may occur as a result of applied pressure during roller compaction or due to double compaction after tabletting. Even if the physical form of the material is carefully selected for the manufacture of a certain dosage form, the processing conditions may change the final solid state of the drug (Debnath and Suryanarayanan, 2004). Herting and Kleinebudde (2007) investigated the influence of changing the particle size in the binary starting mixture of microcrystalline cellulose (MCC) and Theophylline anhydrate on the flowability of granules.…”