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

A Systematic Approach to the Development of Cilostazol Nanosuspension by Liquid Antisolvent Precipitation (LASP) and Its Combination with Ultrasound

Nanosizing is an approach to improve the dissolution rate of poorly soluble drugs. The first aim of this work was to develop nanosuspension of cilostazol with liquid antisolvent precipitation (LASP) and its combination with ultrasound. Second, to systematically study the effect of bottom-up processing factors on precipitated particles’ size and identify the optimal settings for the best reduction. After solvent and stabilizer screening, in-depth process characterization and optimization was performed using Design of Experiments. The work discusses the influence of critical factors found with statistical analysis: feed concentration, stabilizer amount, stirring speed and ultrasound energy governed by time and amplitude. LASP alone only generated particle size of a few microns, but combination with ultrasound was successful in nanosizing (d10 = 0.06, d50 = 0.33, d90 = 1.45 µm). Micro- and nanosuspension’s stability, particle morphology and solid state were studied. Nanosuspension displayed higher apparent solubility than equilibrium and superior dissolution rate over coarse cilostazol and microsuspension. A bottom-up method of precipitation-sonication was demonstrated to be a successful approach to improve the dissolution characteristics of poorly soluble, BCS class II drug cilostazol by reducing its particle size below micron scale, while retaining nanosuspension stability and unchanged crystalline form

Implementation of quality by design approach in manufacturing process optimization of dry granulated, immediate release, coated tablets – a case study

<p>The aim of this study was to optimize the process of tablets compression and identification of film-coating critical process parameters (CPPs) affecting critical quality attributes (CQAs) using quality by design (QbD) approach. Design of experiment (DOE) and regression methods were employed to investigate hardness, disintegration time, and thickness of uncoated tablets depending on slugging and tableting compression force (CPPs). Plackett–Burman experimental design was applied to identify critical coating process parameters among selected ones that is: drying and preheating time, atomization air pressure, spray rate, air volume, inlet air temperature, and drum pressure that may influence the hardness and disintegration time of coated tablets. As a result of the research, design space was established to facilitate an in-depth understanding of existing relationship between CPPs and CQAs of intermediate product (uncoated tablets). Screening revealed that spray rate and inlet air temperature are two most important factors that affect the hardness of coated tablets. Simultaneously, none of the tested coating factors have influence on disintegration time. The observation was confirmed by conducting film coating of pilot size batches.</p

Development of Composite, Reinforced, Highly Drug-Loaded Pharmaceutical Printlets Manufactured by Selective Laser Sintering&mdash;In Search of Relevant Excipients for Pharmaceutical 3D Printing

3D printing by selective laser sintering (SLS) of high-dose drug delivery systems using pure brittle crystalline active pharmaceutical ingredients (API) is possible but impractical. Currently used pharmaceutical grade excipients, including polymers, are primarily designed for powder compression, ensuring good mechanical properties. Using these excipients for SLS usually leads to poor mechanical properties of printed tablets (printlets). Composite printlets consisting of sintered carbon-stained polyamide (PA12) and metronidazole (Met) were manufactured by SLS to overcome the issue. The printlets were characterized using DSC and IR spectroscopy together with an assessment of mechanical properties. Functional properties of the printlets, i.e., drug release in USP3 and USP4 apparatus together with flotation assessment, were evaluated. The printlets contained 80 to 90% of Met (therapeutic dose ca. 600 mg), had hardness above 40 N (comparable with compressed tablets) and were of good quality with internal porous structure, which assured flotation. The thermal stability of the composite material and the identity of its constituents were confirmed. Elastic PA12 mesh maintained the shape and structure of the printlets during drug dissolution and flotation. Laser speed and the addition of an osmotic agent in low content influenced drug release virtually not changing composition of the printlet; time to release 80% of Met varied from 0.5 to 5 h. Composite printlets consisting of elastic insoluble PA12 mesh filled with high content of crystalline Met were manufactured by 3D SLS printing. Dissolution modification by the addition of an osmotic agent was demonstrated. The study shows the need to define the requirements for excipients dedicated to 3D printing and to search for appropriate materials for this purpose

Physicochemical Characterization of a Co-Amorphous Atorvastatin-Irbesartan System with a Potential Application in Fixed-Dose Combination Therapy

The aim of this study was to characterize a 1:1 molar ratio of a pharmacologically relevant co-amorphous atorvastatin-irbesartan (ATR-IRB) system obtained by quench cooling of the crystalline ATR/IRB physical mixture for potential use in the fixed-dose combination therapy. The system was characterized by employing standard differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and intrinsic dissolution rate studies. Quantum mechanical calculations were performed to obtain information regarding intermolecular interactions in the studied co-amorphous ATR-IRB system. The co-amorphous formulation showed a significant improvement in the intrinsic dissolution rate (IDR) of IRB over pure crystalline as well as its amorphous counterpart. An unusual behavior was observed for ATR, as the IDR of ATR in the co-amorphous formulation was slightly lower than that of amorphous ATR alone. Short-term physical aging studies of up to 8 h proved that the ATR-IRB co-amorphous system remained in the amorphous form. Furthermore, no physical aging occurred in the co-amorphous system. FT-IR, density functional theory calculations, and analysis of Tg value of co-amorphous system using the Couchman–Karasz equation revealed the presence of molecular interactions between APIs, which may contribute to the increased physical stability