Studies on the Vitrified and Cryomilled Bosentan.

In this paper, several experimental techniques [X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry, Fourier transform infrared spectroscopy, and broad-band dielectric spectroscopy] have been applied to characterize the structural and thermal properties, H-bonding pattern, and molecular dynamics of amorphous bosentan (BOS) obtained by vitrification and cryomilling of the monohydrate crystalline form of this drug. Samples prepared by these two methods were found to be similar with regard to their internal structure, H-bonding scheme, and structural (α) dynamics in the supercooled liquid state. However, based on the analysis of α-relaxation times (dielectric measurements) predicted for temperatures below the glass-transition temperature (Tg), as well as DSC thermograms, it was concluded that the cryoground sample is more aged (and probably more physically stable) compared to the vitrified one. Interestingly, such differences in physical properties turned out to be reflected in the lower intrinsic dissolution rate of BOS obtained by cryomilling (in the first 15 min of dissolution test) in comparison to the vitrified drug. Furthermore, we showed that cryogrinding of the crystalline BOS monohydrate leads to the formation of a nearly anhydrous amorphous sample. This finding, different from that reported by Megarry et al. [ Carbohydr. Res. 2011, 346, 1061-1064] for trehalose (TRE), was revealed on the basis of infrared and thermal measurements. Finally, two various hypotheses explaining water removal upon cryomilling have been discussed in the manuscript.

Application of Dominance-Based Rough Set Approach for Optimization of Pellets Tableting Process.

Multiple-unit pellet systems (MUPS) offer many advantages over conventional solid dosage forms both for the manufacturers and patients. Coated pellets can be efficiently compressed into MUPS in classic tableting process and enable controlled release of active pharmaceutical ingredient (APIs). For patients MUPS are divisible without affecting drug release and convenient to swallow. However, maintaining API release profile during the compression process can be a challenge. The aim of this work was to explore and discover relationships between data describing: composition, properties, process parameters (condition attributes) and quality (decision attribute, expressed as similarity factor f2) of MUPS containing pellets with verapamil hydrochloride as API, by applying a dominance-based rough ret approach (DRSA) mathematical data mining technique. DRSA generated decision rules representing cause-effect relationships between condition attributes and decision attribute. Similar API release profiles from pellets before and after tableting can be ensured by proper polymer coating (Eudragit® NE, absence of ethyl cellulose), compression force higher than 6 kN, microcrystalline cellulose (Avicel® 102) as excipient and tablet hardness ≥42.4 N. DRSA can be useful for analysis of complex technological data. Decision rules with high values of confirmation measures can help technologist in optimal formulation development.

Compressibility of gastroretentive pellets coated with Eudragit NE using a single-stroke and a rotary tablet press.

In this study, 15 kinds of powders with different compression mechanisms were used in the process of filling-binding substances in tablets with pellets. Applied substances possessed dominant brittle time-independent mechanism or time-dependent viscoplastic, viscoelastic mechanism of compression. Using 6 kN compression force in a single-stroke tablet press during 150 ms of compression, damage to the polymer film and pellet core was found in all formulations. As a result, the authors observed an increase of releasing rate of verapamil hydrochloride (VH). A larger contact area between powders and pellets and connected with this better protective properties were ensured by powders with time-independent compression mechanism (eg, D-sorbitol or D-mannitol). Unsymmetrically applied compression force was a reason for inconsistent densification and insufficient protection of the pellets. Taking into consideration the low rotation speed of the turret (10 rpm) in the rotary tablet press, the total compaction time was much longer than in the single-stroke tablet press. The compression time in the case of the rotary tablet press should be considered as the sum of the precompression (about 130 ms) and main compression (about 280 ms) phase times. Compression force applied by upper and lower punch in the precompression and main compression phase was affected uniformly on the pellets' surface, and when protected against fragmentation, allowed only some slight deformation. The powders in tablet formulation were fragmentized and rearranged independent of their compression mechanisms. It was found that the releasing rate of VH from pellets compressed by rotary tablet press with 6, 12, and 18 kN of compression force was similar to the releasing rate from uncompressed pellets.

Influence of the type of cellulose on properties of multi-unit target releasing in stomach dosage form with verapamil hydrochloride.

Microcrystalline cellulose (MCC) and powdered cellulose (PC) are commonly used excipients for solid dosage forms e.g., pellets. The aim of this study was to compare the utility of the MCC and PC in the floating pellet cores comprising verapamil hydrochloride (VH) manufactured by extrusion and spheronization and influence on their physical properties like swelling, compressibility and VH release. It was found by scanning electron microscopy (SEM) investigation that porosity of surface of the pellets' cores increased with an increase of PC amount in composition. Differential scanning calorimetry (DSC) analysis indicated the lack of physicochemical interaction between PC and MCC either with VH or with any excipients in the pellet core. Formulation having the highest PC participation were characterized by the highest friability and compressibility and addition of MCC corresponded with a decrease of friability and compressibility. The results on pellets friability were not reflected by the results on the hardness test. It means that the PC contents growth contributes to the hardness growth. The swelling forces of physical mixture of powders containing PC and MCC was different and increased with increasing amount of PC in pellet's core. Pellets' cores were coated with Eudragit NE dispersion. It was found that VH release rate from coated pellets with higher amount of PC was considerably slower in comparison to the pellets containing highest MCC participation.

Influence of acrylic esters and methacyrlic esters on flotation of pellets and release rate of verapamil hydrochloride.

Eudragit RL (ERL) and Eudragit RS (ERS) are biocompatible cationic copolymers, pH-independent and insoluble in aqueous environment. In this study drug delivery system consisting of a capsule filled with floating pellets with verapamil hydrochloride (VH) is proposed. The release of VH in the stomach results in better solubility in an acid gastric environment in vivo and may result in greater amount of the VH absorbed and its higher concentration in plasma. The scope of this study was to investigate the influence of ERL and ERS ratio on VH release in 0,1 M HCl from floating coating pellets. The stability of this film was also investigated. The ERL film is much more permeable than ERS, and an increase of ERL film thickness did not retard the release rate. The combination of ERL and ERS are forms of the sustained release film. It was a necessary to add the uncoated pellets, which constituted the initial dose. The start of flotation depends on permeability of polymeric film, and decreases with addition of ERS. There is no change in the start flotation time after 12 months under room condition (25 degrees C/60% RH). The drug delivery from uncoated pellets and pellets coated with ERL/ERS is stable after 12 months under room condition (25 degrees C/60% RH).

Compressibility of floating pellets with verapamil hydrochloride coated with dispersion Kollicoat SR 30 D.

The purpose of this study was to work out a method of compression of floating pellets with verapamil hydrochloride (VH) in a dose of 40 mg. It was assumed that this form should reside in the stomach floating for several hours and gradually release the drug in a controlled way. Compression of pellets into tablets, being a modern technological process, is much more perfect than enclosing them in a hard gelatin capsule. Kollicoat SR 30 D was selected for coating. In experiments three plasticizers were examined-propylene glycol, triethyl citrate and dibuthyl sebecate (all at concentration of 10%). It was found that VH release from pellets coated by the films of the same thickness (70 microm), however, containing plasticizers is considerably different. Pellets were prepared by wet granulation of powder mixture, spheronization of the granulated mass and coating of the cores with a sustained release film. Two kinds of cellulose, microcrystalline and powdered, and sodium hydrocarbonate were the main components of pellet core. Proper pellet coating film thickness, ensuring obtaining desirable VH release profile and flotation effect, was defined. X compositions of tablets with pellets were examined in order to obtain formulation, from which VH release would mostly approximate pellets before compressing. The best formulation was evaluated taking into account the effect of compression force an tablet hardness and friability, and pellet agglomeration and flotation. Tablet cross-section photographs were taken confirming necessary coating film thickness preventing their deformation caused by compressing into tablets.