Use of conventional surfactant media as surrogates for FaSSIF in simulating in vivo dissolution of BCS class II drugs.

The usefulness of selected conventional surfactant media to enhance dissolution of BCS class II drugs similarly to fasted state simulated intestinal fluid (FaSSIF) and to predict the absorption of drugs in vivo was evaluated. Dissolution behavior of danazol (Danol), spironolactone (Spiridon) and N74 (phase I compound) was compared between FaSSIF, containing physiological levels of sodium taurocholate (STC) and lecithin, and dissolution media containing various concentrations of anionic surfactant, sodium lauryl sulfate (SLS) or non-ionic surfactant, polysorbate (Tween) 80. Although these media differed largely in their solubilization ability, micelle size, diffusivity and surface tension, similar dissolution enhancing levels were achieved between FaSSIF and drug-specific concentrations of conventional surfactants. The dissolution enhancement was shown, however, to be important only for danazol and N74, molecules that are characterized by high hydrophobicity. An in vivo pharmacokinetic dog study was carried out with N74. Comparison of observed plasma profiles with simulated profiles obtained using compartmental absorption and transit model (CAT) indicated that 0.1% SLS medium was the best to predict in vivo plasma profiles and pharmacokinetic parameters (C(max) and AUC). This study demonstrates the potential of substituting FaSSIF with more simple and cost-effective conventional surfactant media. Use of in vivo prognostic amounts of synthetic surfactants in dissolution testing could largely assist in industrial drug development as well as in quality control purposes.

Solvent-mediated solid phase transformations of carbamazepine: Effects of simulated intestinal fluid and fasted state simulated intestinal fluid.

Solvent-mediated transformations of carbamazepine (CBZ) anhydrate form III were investigated in Simulated Intestinal Fluid, a simple USP buffer medium, and in FaSSIF, which contains sodium taurocholate (STC) and lecithin, important surfactants that solubilize lipophilic drugs and lipids in the gastrointestinal tract. Raman spectroscopy (in situ) was utilized to reveal the connection between the changes in solid phase composition and dissolution rate while simultaneously detecting the solid state and the dissolved amount of CBZ. Initial dissolution rate was clearly higher in FaSSIF, while the solid phase data revealed that the crystallization of CBZ dihydrate was inhibited in both the dissolution media, albeit by different mechanisms. In SIF this inhibition was related to extensive needle growth, which impeded medium contact with the solid surface by forming a sterical barrier leading to retarded crystallization rates. Morphological changes from the needle-like dihydrate crystals to plate-like counterparts in FaSSIF, combined with the information that the transformation process was leveled off, evidenced strong hydrogen bonding behavior between the CBZ and STC molecules. These results underline the importance of biologically representative dissolution media in linking the in vitro dissolution results of solids that are capable of hydrate formation to their in vivo dissolution behavior.

Simultaneous measurement of liquid-phase and solid-phase transformation kinetics in rotating disc and channel flow cell dissolution devices.

Solvent-mediated solid-phase transformations may occur during dissolution tests which complicates the evaluation of dissolution rates in cases of metastable drugs. The purpose of this study was to determine the effects of solvent-mediated transformations of theophylline anhydrate (TP (A)) on the intrinsic dissolution rate in simulated gastric fluid at pH 1.2. A combined method set-up for simultaneous measurement of the dissolved quantity of drug and the solid form composition was constructed from in situ Raman spectroscopy and UV-vis-spectrophotometry. Transformation kinetics in the traditional USP rotating disc (RD) dissolution apparatus was compared with the recently introduced channel flow cell (CFC). Solid-phase data, supported by scanning electron micrographs taken off-line, explained the changes in the intrinsic dissolution rates due to hydrate formation. Kinetic modelling showed that first order kinetics fitted the data in CFC, but the conversion in RD was strongly S-shaped. These differences were related to dissimilar hydrodynamic conditions and diffusion characteristics in the two dissolution testing devices. In situ solid-phase measurement during dissolution testing can largely improve the understanding of the dissolution results of metastable drugs. This information is valuable in drug candidate selection as well as in explaining and controlling the behaviour of drug substances in the final drug products.

Does the preferred orientation of crystallites in tablets affect the intrinsic dissolution?

The aim of this study was to examine the effect of preferred orientation of crystallites, i.e. texture, on the intrinsic dissolution rate of some active pharmaceutical ingredients. Although it has often been speculated that the intrinsic dissolution of pharmaceutical tablets is affected by texture, no experimental evidence of this effect has been reported. The texture of acetylsalicylic acid, tolbutamide, carbamazepine and entacapone tablets was measured using three different methods both before and after the dissolution measurements. To clarify the effect of texture, texturizing and less-texturizing batches of each material were used. The texturizing batches had big needle or plate-like particles and the less-texturizing batches were prepared by grinding the texturizing powders. The USP rotation disc method was used to measure the intrinsic dissolution rate of the samples. The results indicated that the acetylsalicylic acid, tolbutamide and entacapone tablets texturized strongly in compression and the grinding of the texturizing powders decreased the degree of texture. Also the carbamazepine tablets were slightly texturized. All of the texture measurement methods used were found to give acceptable and consistent results and therefore a special texture goniometer is not required to perform these measurements. The intrinsic dissolution rate of all the tablets compacted from the ground powder was slightly higher than the intrinsic dissolution rate of the more texturized samples. However, these differences were not significant on a large scale. After the dissolution tests the degree of texture of the samples was decreased. The intrinsic dissolution rates of the samples were presumably affected by several different parameters such as texture, solubility, pH, surface energetics and crystal strains. Although only small differences were found between the intrinsic dissolution rates of texturized and less texturized samples the effect of texture on the dissolution behavior of the pharmaceuticals should be considered when performing accurate intrinsic dissolution studies.

In situ measurement of solvent-mediated phase transformations during dissolution testing.

In this study, solvent-mediated phase transformations of theophylline (TP) and nitrofurantoin (NF) were measured in a channel flow intrinsic dissolution test system. The test set-up comprised simultaneous measurement of drug concentration in the dissolution medium (with UV-Vis spectrophotometry) and measurement of the solid-state form of the dissolving solid (in situ with Raman spectroscopy). The solid phase transformations were also investigated off-line with scanning electron microscopy. TP anhydrate underwent a transformation to TP monohydrate, and NF anhydrate (form beta) to NF monohydrate (form II). Transformation of TP anhydrate to TP monohydrate resulted in a clear decrease in the dissolution rate, while the transformation of NF anhydrate (form beta) to NF monohydrate (form II) could not be linked as clearly to changes in the dissolution rate. The transformation of TP was an order of magnitude faster than that of NF. The presence of a water absorbing excipient, microcrystalline cellulose, was found to delay the onset of the transformation of TP anhydrate. Combining the measurement of drug concentration in the dissolution medium with the solid phase measurement offers a deeper understanding of the solvent-mediated phase transformation phenomena during dissolution.

Depth profiling of compression-induced disorders and polymorphic transition on tablet surfaces with grazing incidence X-ray diffraction.

PURPOSE: The importance of induced crystal disorders like crystallite size, crystal defects, and amorphicity with respect to the dissolution rate of the drug has been discussed in many cases. Thus, the characterization of these properties is of great importance in the pharmaceutical formulation development, although the exact correlation between disorders and dissolution rate is still unclear. The aim of this study was to analyze pharmaceutical tablets with grazing incidence X-ray diffraction, which enables the depth profiling of the crystallographic properties of the tablets. To study and clarify the potential of grazing incidence diffraction in the analysis of pharmaceutical materials, the effect of the compaction process on the surface of tablets was examined. METHODS: Carbamazepine, tolbutamide, and chlorpropamide tablets, compacted using different compression pressures, were studied using grazing incidence angle X-ray diffraction. The effects of compression on the crystallographic properties were investigated as a function of the distance from the tablet surface. RESULTS: The surfaces of the tolbutamide and chlorpropamide tablets were disordered due to the compression. The manifestation of the disorder was deduced to be due to amorphicity, small crystallite size, and amount of crystal defects. The changes were mainly on the surface and diminished strongly as a function of the distance from the surface of the tablet. Moreover, the changes were dependent on the compression pressure used. The changes on the surface of the carbamazepine tablets were also due to the compression but these changes were not clearly dependent on the depth nor the compression pressure. The partial phase transition took place in the chlorpropamide tablets due to the compression. The magnitude of the transition was not highest on the surface because amorphization and texturization also took place on the tablet surface during the compression. CONCLUSIONS: The present study proved that grazing incidence X-ray diffraction is a potential novel research tool to reveal crystallographic transformations taking place on the surfaces of the tablets induced, for example, by compression pressure.