Starch acetate as a tablet matrix for sustained drug release.

The aim of this study was to investigate the effect of a high degree on substitution (DS) on starch acetate (SA) and SA concentration on tablet properties. SAs with a DS of 2.6 and 3.0 were used as matrix formers with propranolol hydrochloride (PH) as a model drug. The SA-3.0 powder had better compactibility than the SA-2.6 powder. A decrease in SA concentration decreased compactibility of PH/SA blended powders when compared to neat SA powders. In general, drug release was considerably slower from SA-3.0 matrices than from SA-2.6 matrices. Also, a decrease in SA concentration increased the drug release rate. Water penetration into 80% (w/w) SA-3.0 matrices was incomplete during 24-h dissolution tests. Diffusion path length increased with time and PH was released by Fickian diffusion. However, all other PH/SA tablets were completely hydrated during dissolution tests. Macroscopic cracks were formed during dissolution, which increased area available for Fickian diffusion and resulted in slow attenuation of the drug release rate. Crack formation, not been reported earlier, must be taken into account in order to understand drug release from SA matrices.     

Ultrasound transmission measurements for tensile strength evaluation of tablets

Ultrasound transmission measurements were performed to evaluate the tensile strength of tablets. Tablets consisting of one ingredient were compressed from dibasic calcium phosphate dehydrate, two grades of microcrystalline cellulose and two grades of lactose monohydrate powders. From each powder, tablets with five different tensile strengths were directly compressed. Ultrasound transmission measurements were conducted on every tablet at frequencies of 2.25 MHz, 5 MHz and 10 MHz and the speed of sound was calculated from the acquired waveforms. The tensile strength of the tablets was determined using a diametrical mechanical testing machine and compared to the calculated speed of sound values. It was found that the speed of sound increased with the tensile strength for the tested excipients. There was a good correlation between the speed of sound and tensile strength. Moreover, based on the statistical tests, the groups with different tensile strengths can be differentiated from each other by measuring the speed of sound. Thus, the ultrasound transmission measurement technique is a potentially useful method for non-destructive and fast evaluation of the tensile strength of tablets.     

Modifying drug release and tablet properties of starch acetate tablets by dry powder agglomeration

In this study three model drugs (N-acetyl-D-glucosamine (NAG), anhydrous caffeine, and propranolol hydrochloride) were agglomerated with starch acetate (SA) by mixing the binary powders on a stainless steel (SS) plate. Agglomeration was induced by triboelectrification of the particles during mixing, and it was evaluated as a method to achieve controlled drug release rate. These agglomerates, mixed with different amounts of a disintegrant, were compressed into tablets whose dissolution characteristics were determined. Triboelectric measurements showed that when the drugs were in contact with SS, charges of the opposite polarity were generated to SA (+) and caffeine and NAG (-) promoting adhesion. Instead, propranolol HCl was charged with the same polarity as SA. SEM micrographs showed that smaller caffeine particles, in spite of their larger negative charge, agglomerated less efficiently with SA than larger NAG particles. This emphasizes the importance of particle size in the agglomeration process. Propranolol HCl did not form agglomerates with SA since their particle sizes and charges were identical. As a result, agglomeration of powders prior to tablet compression allows for modification and control of the release rate of the drugs from the SA matrix tablets as well as the tensile strength of the tablets.     

Drug release phenomena within a hydrophobic starch acetate matrix: FTIR mapping of tablets after in vitro dissolution testing

The aim of this study was to assess the utility of Fourier transform infrared mapping to study the drug release phenomena within a hydrophobic matrix tablet. Starch acetate with a degree of substitution (2.7) was used as a hydrophobic matrix former. Anhydrous caffeine and riboflavin sodium phosphate were used as water soluble model drugs. The USP (XXVIII) paddle-method was selected as an in vitro dissolution test. Mapping of the diluted tablets' cross-section was performed by attenuated total reflection mode. Fourier transform infrared mapping can distinguish drug particles from the bulk matrix and it can be considered as a valuable method for obtaining both quantitative and qualitative information on drug release processes. The physicochemical properties of the drug compound strongly contribute to its release behavior when the USP paddle in vitro dissolution test is used. Mapping of the riboflavin product revealed a more homogenous matrix distribution due to its smaller particle size. Consequently, its dissolution release profile was more uniform than caffeine which possessed a wider particle size distribution and lower solubility. Mapping showed that caffeine became localized in the lower part of the tablet unlike riboflavin. The hydrodynamic conditions during the in vitro release test might contribute to this differentiation.     

Fast-dissolving sublingual solid dispersion and cyclodextrin complex increase the absorption of perphenazine in rabbits

Objectives The sublingual administration route as well as solid dispersion formation with macrogol 8000 and complexation with β‐cyclodextrin (β‐CyD) were investigated as ways for improving the absorption of perphenazine, a poorly water‐soluble drug subjected to substantial first‐pass metabolism. Methods The absorption of perphenazine was studied in rabbits after sublingual administration of perphenazine/macrogol solid dispersion, solid perphenazine/β‐CyD complex and plain micronized perphenazine, as well as after peroral administration of an aqueous perphenazine solution. Solid formulations were prepared by freeze‐drying (perphenazine/macrogol solid dispersion) or spray‐drying (perphenazine/β‐CyD complex). Key findings The value for area under the curve from 0 to 360 min (AUC_{0–360 min}) of perphenazine after peroral administration was only 8% of the AUC_{0–360 min} value obtained after intravenous administration, while the corresponding values for the sublingually administered formulations were 53% (perphenazine/macrogol solid dispersion), 41% (perphenazine/β‐CyD complex) and 64% (micronized perphenazine). There are three possible mechanisms to explain these results: avoidance of the first‐pass metabolism; good sublingual absorption of perphenazine; and rapid dissolution rate of perphenazine from the studied formulations. Conclusions With sublingual administration, the drug has to dissolve rapidly in a small volume of saliva. Based on the present absorption studies in rabbits, the solid dispersion preparation and cyclodextrin complexation were postulated to be useful ways to attain successful sublingual administration of perphenazine. Good sublingual absorption was also achieved by micronization of perphenazine. As far as we are aware, this paper is one of the first to evaluate the sublingual administration of a solid dispersion in vivo.     

Dynamic solid-state and tableting properties of four theophylline forms

Relationships between solid-state, densification and compact properties of theophylline monohydrate (TMO), a mixture of forms (TMIX), and anhydrous polymorphs I (TA-I) and II (TA-II) were evaluated. Solid-state identification of powders and compacts was accomplished by powder X-ray diffraction. A compaction simulator was used to assess deformation behaviour of the powders and to prepare compacts. Porosity and tensile strength of the compacts were determined after 1,24, and 168 h of storage at 22% relative humidity. TA-II was stable, whereas TA-I, TMIX and TMO partially transformed to the TA-II form during storage. All theophylline modifications primarily deformed by plastic flow. Increased water content decreased resistance towards densification and deformation of TMIX and TMO when compared to TA-II or TA-I, demonstrating viscoelasticity. Permanent densification behaviours of TMIX and TMO approached to that of TA-II during storage. Tensile strength of the different theophylline forms were practically equal after 1 h of storage. Tensile strength and porosity of TMIX and TMO compacts increased during the storage. Dynamic solid-state transformations from TMO, TMIX and TA-I to TA-II were associated with parallel changes in their densification and compact properties. The extent of these changes was also dependent on the materials' water content.     

Complexation with tolbutamide modifies the physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin

The physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and its tolbutamide (TBM) complex were studied. The kinetics of TBM/HP-beta-CD inclusion complex formation in solution were determined by the phase solubility method. Solid complexes were prepared by freeze-drying and spray-drying. Water sorption-desorption behaviour of the materials were studied and compacts were made using a compaction simulator. TBM and HP-beta-CD formed 1:1 inclusion complexes in aqueous solution with an apparent stability constant of 63 M(-1). HP-beta-CDs and TBM/HP-beta-CD complexes were amorphous whereas the freeze-dried and spray-dried TBMs were polymorphic forms II and I, respectively. Sorption-desorption studies showed that HP-beta-CDs were deliquescent at high relative humidities. TBM/HP-beta-CD complexes had slightly lower water contents at low relative humidities than the physical mixtures. However, at high humidities their water sorption and desorption behaviours were similar to those of corresponding physical mixtures, indicating a glass transition of the complexed materials. TBM/HP-beta-CD complexes demonstrated a worse compactability than similarly prepared HP-beta-CDs or physical mixtures. Also particle properties that resulted from these preparation methods affected the compactability of the materials. In conclusion, the physicochemical and tableting properties of HP-beta-CD were modified by complexation it with TBM.